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Synthesis, molecular docking, and cytotoxicity of quinazolinone and dihydroquinazolinone derivatives as cytotoxic agents

Synthesis, molecular docking, and cytotoxicity of quinazolinone and dihydroquinazolinone... Background: Cancer is the most cause of morbidity and mortality, and a major public health problem worldwide. In this context, two series of quinazolinone 5a–e and dihydroquinazolinone 10a–f compounds were designed, synthe- sized as cytotoxic agents. Methodology: All derivatives (5a–e and 10a–f ) were synthesized via straightforward pathways and elucidated by FTIR, H-NMR, CHNS elemental analysis, as well as the melting point. All the compounds were evaluated for their in vitro cytotoxicity effects using the MTT assay against two human cancer cell lines (MCF-7 and HCT-116) using doxorubicin as the standard drug. The test derivatives were additionally docked into the PARP10 active site using Gold software. Results and discussion: Most of the synthesized compounds, especially 5a and 10f were found to be highly potent against both cell lines. Synthesized compounds demonstrated IC in the range of 4.87–205.9 μM against HCT-116 cell line and 14.70–98.45 μM against MCF-7 cell line compared with doxorubicin with IC values of 1.20 and 1.08 μM after 72 h, respectively, indicated the plausible activities of the synthesized compounds. Conclusion: The compounds quinazolinone 5a–e and dihydroquinazolinone 10a–f showed potential activity against cancer cell lines which can lead to rational drug designing of the cytotoxic agents. Keywords: Quinazolinone, Dihydroquinazolinone Cytotoxicity, Docking, PARPs, Synthesis Introduction tumor formation [1–3]. The investigations reveal that Cancer is a complex disease resulting from perturbations cancer is the second major cause of mortality in 2015. in multiple intracellular regulatory systems and leading Moreover, there were 8.7 million deaths among 17.5 to a drastic increase in the number of the cells and thus million cases diagnosed with cancer globally [4]. Breast, lung, prostate, and colorectal cancers are recognized as widespread types of invasive cancer, which account for *Correspondence: n.adibpor@zums.ac.ir; momahdavi@tums.ac.ir about 4 in 10 of all diagnosed cases [5]. Depending on the Department of Medicinal Chemistry, School of Pharmacy, Zanjan University type and stage of cancer, the common cancer treatments of Medical Sciences, Zanjan, Iran Endocrinology and Metabolism Research Center, Endocrinology are radiotherapy, hormone therapy as well as surgery, and and Metabolism Clinical Sciences Institute, Tehran University of Medical chemotherapy. However, the central problem of the last Sciences, Tehran, Iran item is the failure in the distinction between healthy and Full list of author information is available at the end of the article © The Author(s) 2022. 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The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Taayoshi et al. BMC Chemistry (2022) 16:35 Page 2 of 12 cancerous cells, which results in inevitable adverse effects Quinazoline scaffold show diverse biologically and phar - on the healthy cells [6]. Along the same line, Multidrug macologically active anti-cancer [13], analgesic [14], anti- resistance (MDR) is another major source of conflict in tuberculosis [15], antihypertensive [16], anti-diabetes [17] the treatment of cancer due to the resistance of the can- anti-melanogenesis [18, 19], anti-urease [20], antifungal cerous cells against the traditional chemotherapeutic [21], and antibacterial [22, 23] agents. Quinazolinone is agents [7]. Therefore, the need for finding novel ways for a naturally occurring alkaloid that can be found in many cancer treatment is still needed. natural products with diverse biological activities [24– Quinazoline as nitrogen-containing heterocyclic com- 26]. There are several quinazolinone-based compounds pound is synthesized in the structure of many synthetic such as compounds A, B, and C (Fig.  1I) reported in the compounds using different synthetic methods includ - literature with high cytotoxicity against tested cell lines ing aza-diels–alder reaction, aza-wittig reaction, metal- [27–29]. The inhibition of poly (ADP-ribose) polymerase mediated reaction, and oxidative cyclization [8–12]. 10 (PARP10) enzyme is one of the ways through which Fig. 1 Identified representative lead candidates T aayoshi et al. BMC Chemistry (2022) 16:35 Page 3 of 12 Scheme 1 Methods for the synthesis of compounds 5a–e and 10a–f. Reagents and conditions: a H O, r.t., 2–5 h. b CuBr (1 mmol), Et N (1 mmol), 2 3 DMF (5 ml), 80°, 8–10 h. c K CO (1 mmol), EtOH (10 ml), reflux, 12–24 h. d CuI (7 mol%), H O/t-BuOH (1:1), Et N (1.3 mmol), r.t., 20–24 h 2 3 2 3 some quinazolinone analogs have demonstrated their novel quinazolinone and dihydroquinazolinone to obtain potent anticancer activity [30, 31]. The 3,4-dihydroquina - more effective cytotoxic agents. All synthesized deriva - zolinone moiety is another favored scaffold due to its tives were evaluated against MCF-7 and HCT-116 cancer considerable therapeutic potential in medicinal chem- cell lines (Fig. 1III). istry [32, 33], mainly because of its emerging role in the treatment of cancer [34, 35]. Compounds D and E are Results and discussion good examples of potent antitumor activities (Fig.  1II). Chemistry A bunch of methods has been proposed to synthesize Two straightforward synthetic pathways were adopted 3,4-dihydroquinazolinones with plausible yields. Take to synthesize the target compounds 5a–e and 10a–f as the examples of the multicomponent reaction (MCR) shown in Scheme 1. The sequence for the proposed reac - protocols investigated by Luke R. Odell et al. [36, 37], an tion initiated by treating commercially available isatoic organo-catalyzed enantioselective approach for the syn- anhydride (1) with aromatic and aliphatic amines (2) in thesis of chiral trifluoromethyl dihydroquinazolinones, H O at room temperature to obtain the corresponding as a biologically important scaffold, by Xie et al. [38], and 2-aminobenzamides (3) [42]. All compounds 3 were eas- the catalyst-free and hydrophobically-directed approach ily prepared and used without further purifications. Next, for the production of functionalized 3,4-dihydroquinazo- we employed the reaction of compound 3 and phenyl lin-2(1H)-one by Chandrasekharam et al. [39]. isothiocyanates (4) in the presence of CuBr and Et N in In 2016, we disclosed a novel multi-component strat- DMF to achieve the final product 5 (Scheme  1 Method egy to assemble 1,2,3-triazole derivatives of 2,3-dihyd- A). The second strategy is for the synthesis of compound roquinazolin-4(1H)-one via click reaction with in  situ 10a–f in which the intermediate 7 was produced through prepared organic azides [40]. Furthermore, we proposed the reaction between 2-aminobenzamides (3) and an innovative approach of Quinazolin-4(3H)-ones syn- 4-(prop-2-yn-1-yloxy)benzaldehyde (6) in the presence of thesis by employing CuBr and E t N in 2016 [41]. With K CO in ethanol at reflux. The presence of a triple bond 3 2 3 this information in hand, we focus on the synthesis of in dihydroquinazolinone (7) attracted us toward click Taayoshi et al. BMC Chemistry (2022) 16:35 Page 4 of 12 reaction to form 1,2,3-triazole ring. As a result, com- Table 2 Analysis of Variance for Transformed Response (λ = 0.273) pound 7 was reacted with the in situ prepared (azidome- thyl)benzene (9) under the Sharpless-type click reaction Source DF Adj SS Adj MS F-Value p-Value conditions [43]. It was found that performing the reac- Time 1 13.005 13.0049 308.96 0.000 tion in the presence of CuI (7  mol%) as the catalyst in Compound 23 106.448 4.6282 109.95 0.000 H O/t-BuOH (1:1) at room temperature within 24  h led Time*compound 23 5.271 0.2292 5.44 0.000 to the formation of the corresponding product 10a–f in Error 82 3.452 0.0421 plausible yields (Scheme 1 Method B) according to previ- Total 129 128.108 ously reported procedures [44, 45]. The structures of final products have been verified by FT-IR, H-NMR, as well as melting point, and CHNS elemental analysis. Biological activity Cytotoxic evaluation The selected compounds 5a–e and 10a–f were evaluated as possible cytotoxic agents against human colon cancer HCT-116 cell line and MCF-7 breast cancer cell line by MTT assay using doxorubicin as the standard drug. As shown in Table 1, the induced cellular toxicity in the cell lines was studied at 48 and 72 h. The IC value was cal- culated from the inhibition rates at the mentioned dura- tions. The analysis of variance for transformed response indicated that the cytotoxic effects of compounds depend on time, whether for the MCF-7 (Table  2) or HCT-116 Table 1 Cancer cell growth inhibitory effect of synthesized derivatives evaluated by MTT reduction assay 1 2 3 Compound R R R IC (µM) MCF-7 IC (µM) MCF-7 IC (µM) HCT- IC (µM) 50 50 50 50 48 h 72 h 116 HCT-116 48 h 72 h 5a Ph 2-Me-C H – 71.17 14.70 7.15 4.87 6 4 5b Chloromethyl Ph – 101.375 76.245 59.26 37.84 5c Cyclopropyl Ph – 74.92 50.40 59.24 29.15 5d 4-OMe-C H Ph – 28.84 24.99 39.22 17.76 6 4 5e Propyl Ph – 78.95 42.74 88.71 63.33 10a Benzyl – H 62.29 18.88 88.79 28.99 10b Benzyl – 4-F 139.4 98.45 183.9 63.99 10c Benzyl – 4-Cl 52.00 32.30 120.35 61.02 10d Benzyl – 4-Br 44.68 14.80 251.1 205.9 10e 4-F-benzyl – 2-Me 79.14 48.75 48.21 33.28 10f 4-F-benzyl – 4-F 41.47 16.30 40.35 10.08 DOX – – – 1.33 1.08 1.66 1.20 T aayoshi et al. BMC Chemistry (2022) 16:35 Page 5 of 12 Table 3 Analysis of Variance for Transformed Response Table 4 the toxicity assessments of 5a, 5d, and 10f gainst Hek- (λ = 0.333) 293 cell lines Source DF Adj SS Adj MS F-Value p-Value Compound IC (µM) Hek- 293 after 72 h Time 1 13.832 13.8318 302.12 0.000 5a 8.71 ± 1.23 compound 23 143.164 6.2245 135.96 0.000 5d 68.13 ± 12.28 Time*compound 23 5.216 0.2268 4.95 0.000 10f 56.11 ± 10.38 Error 83 3.800 0.0458 DOX 0.75 ± 0.09 Total 130 166.298 at R (5b, 5c, 5d, 5e) deteriorated the cytotoxicity poten- tial, significantly. From the screening data of 10a-d, it was revealed that electron-withdrawing substitutions at R 3 3 3 (10b, R = 4-F; 10c, R = 4-Cl and 10d, R = 4-Br) decrease the potency compared to 10a as unsubstituted deriva- 1 3 tive. By way of illustration 10b (R = benzyl; R = 4-F) recorded the least potency in this series with I C values of 183.9 and 63.99  μM. Interestingly, the replacement of benzyl in 10b with 4-F-benzyl moiety leads to a notice- able increase in the cytotoxicity in 10f with an IC value of 40.35 μM and 10.08 μM after 48 and 72 h. Overall, concerning the cytotoxic evaluations on 5a–e, it can be understood that 5d was the most active deriva- tive against MCF-7 while 5a containing Ph at R and 2-Me-C H at R was the most potent cytotoxic agent 6 4 (Table 3) cell lines. This is because the IC values in 72 h against HCT-116. Assessments of 10a–f revealed that with p-value < 0.0001 are less than those in 48 h. Moreo- 1 3 compound 10f bearing 4-F-benzyl at R and 4-F at R was ver, the results revealed that the IC values dramatically the most active cytotoxic agent against both tested cell decreased after 72 h in comparison with 48 h of the inter- lines. action of compounds with cells. Next, to determine the safety of 5a, 5d, and 10f as the The first structure–activity relationship (SAR) explo - most potent derivatives on normal cell line over cancer rations focused on MCF-7 cells. Assessments of 5a–e cell lines, these derivatives were examined on Hek293 as derivatives against MCF-7 demonstrated that 5d possess- normal cell lines by MTT reduction assay. Results were 1 2 ing R = 4-OMe-C H and R = Ph afforded good potency 6 4 presented in Table  4. As can be seen, derivative 5a dem- with an IC value of 28.84 μM and 24.99 μM after 48 and onstrated high toxicity against Hek-293 cell lines while 5d 1 2 72 h followed by 5a bearing R = Ph and R = 2-Me-C H . 6 4 and 10f demonstrated low toxicity in this cell line. It seems that increasing the bulkiness at R may improve the potency. Cytotoxic screening of 10a–f revealed that Molecular docking 10a as unsubstituted derivatives exhibited I C values of Poly (ADP-ribose) polymerases (PARPs) is a family of 62.29 μM and 18.88 μM after 48 and 72 h. The incorpo - proteins involved in diverse cellular functions, espe- ration of halogen groups at R position showed different cially DNA repair and maintenance of chromatin stabil- behavior so that 4-F (10b) reduced the activity compared ity via ADP ribosylation. PARP10 (ARTD10) is one of the to 10a while para-chlorine (10c) or para-bromine (10d) members of the PARP family that performs mono-ADP- improved the cytotoxic potency compared to 10a. Note- ribosylation onto the amino acids of protein substrates worthy, the substitution of 4-F-benzyl at R position of from donor nicotinamide adenine dinucleotide (NA D ) 10b produced the most potent derivative in this set with of target proteins [46]. Recent studies have linked the IC values of 41.47 μM and 16.30 μM after 48 and 72 h. activity of PARP10 to support cancer cell survival and With regards to the HCT-116 cancer cells, in testing DNA damage repairing [30]. The silencing of PARP10 the compounds 5a–e, it was shown that 5a was the most in MCF7 and CaCo2 cells decreased the proliferation promising cytotoxic agent with IC values of 7.15  μM rate that correlated with cancer [47]. Quinazolin-4-one and 4.87  μM after 48 and 72  h. Further investigations derivatives (Compound F, Fig. 2) were first discovered by illustrated that the replacement of Ph with other moieties Oregon Health and Science University as effective PARPs at R as well as the replacement of 2-Me-C H with Ph 6 4 Taayoshi et al. BMC Chemistry (2022) 16:35 Page 6 of 12 Fig. 2 The structure of the active compound against PARP10 Table 5 Docking scores and interactions of compounds against PARP10 (PDB ID: 5LX6) Compound ChemScore Interactions with key residue 5a 33.37 Ala911, Val913, Tyr914, Tyr919, Ala921, Leu926, Tyr932, Ile987 5d 28.34 His887, Ala911, Tyr919, Ala921 10f 36.96 His887, Ala911, Val913, Tyr914, Val918, Leu926, Tyr932, Ile987 Veliparib 37.89 Gly888, Tyr919, Ala921, Leu926, Ser927, Tyr932, Ile987 inhibitors involved in mono ADP-ribosylation [48, 49]. Further modification leads to the discovery of novel compounds (Compound G and H, Fig.  2) that inhibited PARP10 [50, 51]. According to the literature, the amino acids His887, Gly888, Asn910, Ala911, Tyr914, Tyr919, Ala921, Leu926, Ser927, and Tyr932 are the most impor- tant ones in the PARP10 active site [52, 53]. Regarding the similarity of reported PARP10 inhibitors with the designed structures, molecular docking evalua- tions were performed to study the binding mode of the most potent compounds 5a, 5d and 10f with PARP10 active site. Docking studies of the mentioned compounds were carried out using gold docking software. Validation of the molecular docking method was done by redocking Fig. 3. 3D interaction pattern of compound 5a within PARP10 active the crystallographic ligand of the target enzyme, against site PARP10 (PDB ID: 5LX6) which testified the validation of the docking calculations. The ChemScore fitness value of 5a, 5d, and 10f plus their interactions with residues in the of amino quinazolin-4(3H)-one. 2-methylphenyl moiety PARP10 active site were documented in Table 5. exhibited one pi-sigma interaction with Val913 and one Alignment of the best pose of veliparib in the active pi-alkyl interaction with Ala911 plus pi-alkyl interactions site of PARP10 and crystallographic ligand recorded and with Val913, Tyr917, Tyr919, Ile987. Also, pi-pi-T-shaped RMSD value of 0.63  Å. The docked structure veliparib and pi-alkyl interactions were recorded between phenyl exhibited the interaction of this compound with Tyr919, and Tyr919 and Ala911, respectively. Ala921, Leu926, Ser927, Tyr932, and Ile987 residues. According to the results of 5d docking studies (Fig.  4), Moreover, this compound showed three H-bond interac- the aromatic moiety of 4-methoxyphenyl presented a pi- tions with Gly888 and Ser927. sigma and a pi-pi-T shaped interaction with Ala911 and Figure 3 showed the docking interactions of compound Tyr919, respectively. Phenyl pendant demonstrated a pi- 5d within PARP10. Docking evaluation depicted four pi- pi-stacked interaction with His887 and a pi-alkyl inter- alkyl interactions between the amino quinazolin-4(3H)- action with Ala921. Amino-quinazolin-4(3H)-one also one ring and Ala921, Leu926, Tyr932, Ile987 as well as made a pi-alkyl interaction with Tyr919. one hydrogen bound interaction between Ala911 and NH T aayoshi et al. BMC Chemistry (2022) 16:35 Page 7 of 12 Experimental Materials and methods The measured data on melting points were evaluated on a Kofler hot stage apparatus and were uncorrected. The H- NMR and IR spectra were gained by employing Bruker 400-NMR and ALPHA FT-IR spectrometer on KBr disks, respectively. The chemical reagents were obtained from Aldrich and Merck as well. Moreover, the Spectroscopic data of final products, including H-NMR and are available in the supporting information and our previous studies [41, 42]. Syntheses of 3‑Substituted 2‑(Arylamino) quinazolin‑4(3H)‑ones 5 (Method A) Fig. 4. 3D interaction pattern of compound 5d within PARP10 active The corresponding 2-aminobenzamide derivatives (3) were site synthesized via the reaction of equivalent amounts of isa- toic anhydride (1) and an appropriate amine (2) in water at room temperature for 2–5 h [28]. After completion of the reaction, the precipitated products were precipitated and filtered off, dried at 60 °C, and used for the further reaction without any need for more purification. Then, A mixture of 2-aminobenzamide (3) (2  mmol), isothiocyanate deriv- ative (4) (2  mmol), CuBr (1  mmol),and E t N (1  mmol) in DMF (5 ml) was heated at 80° for 8–10 h. After the reaction completion (monitored by TLC), the mixture was filtered off through a bed of Celite and washed with AcOEt. Next, H O (20 ml) was added to the filtrate, it was extracted with ethyl acetate (3 × 15), and dried with N a SO . The solvent 2 4 was then removed under reduced pressure and the crude reaction mixture was purified by column chromatography on silica gel and petroleum ether (PE)/AcOEt (5:1) as elu- ent. All products were recrystallized from PE/AcOEt (1:1) Fig. 5. 3D interaction pattern of compound 10f within PARP10 active to give pure products 5 [44, 45]. site General procedure for the synthesis of 3‑substituted 2‑[4‑(prop‑2‑yn‑1‑yloxy) The 3D interaction pattern of compound 10f (Fig.  5) phenyl]‑2,3‑dihydroquinazolin‑4(1H)‑one derivatives 7 showed two pi-pi-T-shaped and one pi-alkyl interac- (Method B) tions with 4-fluorobenzyl moiety. The dihydroquinazo - A mixture of isatoic anhydride (1) (20  mmol) and various lin-4(1H)-one ring participated in pi-pi-T-shaped and amines (2) (20 mmol) in 50 ml water was stirred for 2–3 h pi-alkyl interactions with Tyr932 and Ala911. Also, the at room temperature. Monitored by TLC, having com- phenoxy linker was fixed through pi-pi-T-shaped interac - pleted the reactions, the resulting off-white precipitate (3) tion with His887 and Typ932. Triazole ring in the middle was filtered off, dried at 60 °C, and used for the next reac - of the molecules exhibited hydrogen bound with Typ932 tions without further purification [28]. Next, a mixture of plus two pi-sigma interactions with Leu926 and Ile987. 2-aminobenzamide (3) (1  mmol), 4-(prop-2-yn-1-yloxy) Terminal 2-fluorobenzyl triazole participated in van der benzaldehyde (4) (1  mmol), and potassium carbonate Waals, pi-sigma, and pi-alkyl interactions with Tyr932, (1 mmol) in 10 ml EtOH was refluxed for 12–24 h. Checked Val913, Ala91, respectively. by TLC, having completed the reactions, potassium car- Overall it was shown that the findings of the docking bonate was filtered off from the reaction medium and pure study of the most active derivatives were in line with the product 7 was obtained as yellow crystals after the solution results of cytotoxic effects. was cooled down to room temperature [44, 45]. Taayoshi et al. BMC Chemistry (2022) 16:35 Page 8 of 12 General procedure for the synthesis of 1,2,3‑triazole Yield: 76%. White crystal. M.p. 256–259 °C. IR (KBr) υ: −1 1 derivatives of 2,3‑dihydroquinazolin‑4(1H)‑one 10 (Method 3348, 1675, 1608  cm . H NMR (400  MHz, DMSO-d ) B) δ 8.06 (dd, J = 8.0, 1.6  Hz, 1H), 7.76 (d, J = 8.0  Hz, 2H), A solution of an arylmethyl chloride (8) (1.1 mmol), 0.06 7.63 (td, J = 7.7, 7.0, 1.6 Hz, 1H), 7.50–7.37 (m, 4H), 7.27 gr sodium azide (0.9 mmol), and 0.13 gr Et N (1.3 mmol) (t, J = 7.6 Hz, 1H), 7.18–7.12 (m, 3H), 7.94 (d, J = 7.8  Hz, in 4  ml water and 4  ml tert-butyl alcohol was stirred at 2H), 3.86 (s, 3H). C NMR (100 MHz, CDCl ) δ 168.86, room temperature for 30  min. Next, the prepared com- 159.6, 153.7, 145.13, 142.90, 140.11, 133.39, 130.65, pound 7 (0.5  mmol) and CuI (7  mol%) were added to 129.85, 125.10, 122.95, 121.92, 121.82, 119.86, 116.95, the reaction medium, and the mixture was stirred for 114.38, 56.35  ppm. MS: m/z (%) = 343 [M , 46%]. Anal. 20–24  h. Upon completion of the reaction, examined by Calcd for C H N O : C 73.45, H 4.99, N 12.24, Found: 21 17 3 2 TLC, the reaction mixture was diluted with 20  ml H O, C 73.32, H 5.16, N 12.39. poured in 20 gr ice and the final product 10 was filtered 3-isopropyl-2-(phenylamino)quinazolin-4(3H)-one of, washed with cold water, and purified by plate chroma - (5e): [41] tography using silica gel and PE/EtOAc (3:1) as eluent. Yield: 80%. White crystal. M.p. 143–146 °C. IR (KBr) υ: −1 1 3351, 1676, 1613  cm . H NMR (400 MHz, DMSO-d ) δ Analytical data 7.96 (d, J = 7.8 Hz, 1H), 7.47 (dd, J = 7.9, 1.6 Hz, 2H), 7.13 2-[(2-Methylphenyl)amino]-3-phenylquinazolin-4(3H)- (ddd, J = 8.4, 7.1, 1.6  Hz, 1H), 6.91 (t, J = 7.8, 1H), 6.68 one (5a) [41]: (dd, J = 8.2, 1.2 Hz, 1H), 6.54–6.47 (m, 2H), 6.37–6.33 (m, Yield: 77%. White crystal. M.p. 254–258  °C. IR (KBr) 2H), 4.46–3.73 (m, 1H), 1.15 (d, J = 6.6 Hz, 6H). MS: m/z −1 1 υ: 3336, 1681, 1610  cm . H NMR (400  MHz, DMSO- (%) = 279 [M , 47%]. Anal.Calcd for C H N O: C 73.10, 17 17 3 d ) δ 8.07 (dd, J = 8.0, 1.1 Hz, 1H), 7.72 (ddd, J = 8.2, 7.2, H 6.13, N 15.04, Found: C 73.39, H 5.95, N 15.24. 1.6  Hz, 1H), 7.66–7.58 (m, 6H), 7.50 (dd, J = 7.5, 1.2  Hz, 3-benzyl-2-(4-((1-benzyl-1H-1,2,3-triazol-4-yl)meth- 1H), 7.47–7.40 (m, 3H), 7.30–7.25 (m, 1H), 7.22–7.17 (m, oxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one (10a): [54] 1H), 2.34 (s, 3H). MS: m/z (%) = 327 [M , 48%]. Anal. Yield: 72%. White crystal. M.p. 65–68  °C. IR (KBr) υ: −1 1 Calcd for C H N O: C 77.04, H 5.23, N 12.84, Found: C 3390, 3058, 2929, 2840, 1655, 1610, 1230  cm . H NMR 21 17 3 77.16, H 5.05, N 13.01. (400  MHz, DMSO-d ) δ 8.29 (s, 1H), 7.71 (dd, J = 7.7, 3-(chloromethyl)-2-(phenylamino)quinazolin-4(3H)- 1.5 Hz, 1H), 7.41–7.22 (m, 14H), 7.01 (d, J = 8.6  Hz, 2H), one (5b): 6.77–6.54 (m, 2H), 5.70 (d, J = 2.4  Hz, 1H), 5.62 (s, 2H), Yield: 81%. White crystal. M.p. 194–197  °C. IR (KBr) 5.31 (d, J = 15.3 Hz, 1H), 5.11 (s, 2H), 3.80 (d, J = 15.3 Hz, −1 1 υ: 3353, 1689, 1616, 780  cm . H NMR (400  MHz, 1H). MS: m/z (%) = 501 [M , 21%]. Anal.Calcd for CDCl ) δ 8.25 (d, J = 7.9 Hz, 1H), 7.64 (t, J = 7.8  Hz, 1H), C H N O : C 74.23, H 5.43, N 13.96, Found: C 74.16, H 3 31 27 5 2 7.49–7.23 (m, 7H), 7.15–7.07 (m, 1H), 5.52 (s, 2H). C 5.25, N 13.81. NMR (100 MHz, CDCl ) δ 169.71, 153.4, 144.56, 141.96, 3-benzyl-2-(4-((1-(4-fluorobenzyl)-1H-1,2,3-triazol- 132.19, 129.86, 129.09, 122.13, 119.75, 119.26, 118.54, 4-yl)methoxy)phenyl)-2,3 dihydroquinazolin-4(1H)-one 2+ 115.38, 56.57 ppm. MS: m/z (%) = 287 [M + , 15%], 285 (10b): [54] [M , 45%]. Anal.Calcd for C H ClN O: C 63.20, H 4.23, Yield: 77%. White crystal. M.p. 83–86  °C. IR (KBr) 15 12 3 N 14.71, Found: C 63.16, H 3.96, N 14.92. υ: 3301, 3069, 2928, 2852, 1631, 1626, 1526, 1190, −1 1 3-cyclopropyl-2-(phenylamino)quinazolin-4(3H)-one 1002  cm . H NMR (400  MHz, C DCl ) δ 8.06 (d, (5c): J = 6.4  Hz, 1H), 7.56 (s, 1H), 7.45–7.13 (m, 14H), 6.93 Yield: 85%. White crystal. M.p. 141–144  °C. IR (KBr) (d, J = 8.7  Hz, 2H), 6.55 (d, J = 8.2  Hz, 1H), 5.61 (s, 1H), −1 1 υ: 3326, 1679, 1601  cm . H NMR (400  MHz, CDCl ) 5.57 (s, 2H), 5.28 (d, J = 15.3  Hz, 1H), 5.19 (s, 2H), 3.70 δ 8.16 (dd, J = 8.0, 1.6  Hz, 1H), 7.76 (d, J = 8.0  Hz, 2H), (d, J = 15.3 Hz, 1H). MS: m/z (%) = 519 [M , 19%]. Anal. 7.63 (td, J = 7.7, 7.0, 1.6 Hz, 1H), 7.50–7.37 (m, 4H), 7.24 Calcd for C H FN O : C 71.66, H 5.04, N 13.48, Found: 31 26 5 2 (t, J = 7.6 Hz, 1H), 7.18 (t, J = 7.4 Hz, 1H), 2.98–2.66 (m, C 71.77, H 5.21, N 13.31. 1H), 1.54–1.33 (m, 2H), 1.24–0.99 (m, 2H). C NMR 3-benzyl-2-(4-((1-(4-chlorobenzyl)-1H-1,2,3-triazol- (100 MHz, CDCl ) δ 168.81, 154.2, 144.31, 142.11, 4-yl)methoxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one 132.08, 129.85, 129.57, 121.99, 120.03, 119.51, 118.63, (10c): [54] 115.54, 26.30, 11.29  ppm. MS: m/z (%) = 277 [M , 44%]. Yield: 82%. White crystal. M.p. 84–87  °C. IR (KBr) υ: −1 1 C H N O: C 73.63, H 5.45, N 15.15, Found: C 73.56, H 3270, 3066, 2932, 2851, 1639, 1520, 1250, 777  cm . H 17 15 3 5.76, N 14.89. NMR (400 MHz, CDCl ) δ 8.06 (dd, J = 7.8, 1.5 Hz, 1H), 3-(4-methoxy phenyl)-2-(phenylamino)quinazolin- 7.56 (s, 1H), 7.50–7.36 (m, 2H), 7.37–7.25 (m, 10H), 4(3H)-one (5d): 7.26–7.17 (m, 3H), 6.93 (d, J = 8.7  Hz, 2H), 6.62–6.42 T aayoshi et al. BMC Chemistry (2022) 16:35 Page 9 of 12 MTT assay (m, 1H), 5.61 (d, J = 1.8  Hz, 1H), 5.57 (s, 2H), 5.28 (d, The cytotoxic activities of compounds 5a–e and 10a–f J = 15.3  Hz, 1H), 5.19 (s, 2H), 3.70 (d, J = 15.3  Hz, 1H). 2+ + were evaluated against cancerous cell lines. And the MS: m/z (%) = 537 [M + , 6%], 535 [M , 18%]. Anal. most potent cytotoxic agents (5a, 5d, and 10f ) against Calcd for C H ClN O : C 69.46, H 4.89, N 13.07, Found: 31 26 5 2 normal cell lines were examined by taking advantage of C 69.56, H 5.05, N 13.29. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetra- 3-benzyl-2-(4-((1-(4-bromobenzyl)-1H-1,2,3-triazol- zolium bromide) colorimetric assay as reported method 4-yl)methoxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one [32, 33]. The absorbance was read at 570  nm against a (10d): [54] test wavelength of 690 nm using Graphpad Prism 8.2.1 Yield: 83%. White crystal. M.p. 93–95  °C. IR (KBr) υ: −1 1 software. The inhibition percentage of compounds was 3319, 3061, 2939, 2844, 1636, 1531, 1210  cm . H NMR calculated as: OD –OD (400 MHz, CDCl ) δ 8.06 (dd, J = 7.8, 1.5  Hz, 1H), 7.56 wells treated with DMSO1% wells treated with /OD *100 (OD = absorb- (s, 1H), 7.46–7.16 (m, 15H), 6.93 (d, J = 8.7 Hz, 2H), 6.54 compounds wells treated with DMSO1% ance). Then, IC values were calculated by nonlinear (d, J = 8.0  Hz, 1H), 5.61 (d, J = 1.8  Hz, 1H), 5.57 (s, 2H), regression analysis. 5.28 (d, J = 15.3 Hz, 1H), 5.19 (s, 2H), 3.70 (d, J = 15.3 Hz, 2+ + 1H). MS: m/z (%) = 581 [M + , 15%], 579 [M , 15%]. Anal.Calcd for C H BrN O : C 64.14, H 4.51, N 12.06, 31 26 5 2 Molecular docking Found: C 64.16, H 4.45, N 11.81. Docking assessments of 5a, 5d, and 10f were performed 3-(4-f luorob enz yl)-2-(4-((1-(2-methylb enz yl)-1H- using the GOLD docking program according to previ- 1,2,3-triazol-4-yl)methoxy)phenyl)-2,3-dihydroquinazo- ously reported protocol [55, 56] The 3D-crystal struc - lin-4(1H)-one (10e): [54] ture of the PARP10 binding site (PDB ID: 5LX6) was Yield: 77%. White crystal. M.p. 63–65 °C. (KBr) υ: 3395, −1 1 retrieved from Protein Data Bank (http:// www. rcsb. 3061, 2929, 2836, 1661, 1616, 1596, 1246, 996  cm . H org). The protein structure was prepared using the Dis - NMR (400  MHz, DMSO-d ) δ 8.19 (s, 1H), 7.80–7.55 covery studio client so that waters and ligands were (m, 1H), 7.41–6.91 (m, 14H), 6.83–6.49 (m, 2H), 5.73 (d, removed from 5LX6 and all hydrogens were added. The J = 2.9 Hz, 1H), 5.63 (s, 2H), 5.21 (d, J = 15.4 Hz, 1H), 5.12 binding site of the enzyme was defined based on the (s, 2H), 3.87 (d, J = 15.3  Hz, 1H), 2.32 (s, 3H). MS: m/z native ligand Veliparib with a 8 Å radius. For validation (%) = 533 [M , 17%]. Anal.Calcd for C H FN O : C 32 28 5 2 of docking, the ChemScore function was chosen for 72.03, H 5.29, N 13.12, Found: C 72.19, H 5.11, N 13.01. docking of Veliparib inside the 5LX6. All other options 3-(4-fluorobenzyl)-2-(4-((1-(4-fluorobenzyl)-1H -1,2,3- were set as default. After validation, 5a, 5d and 10f triazol-4-yl)methoxy)phenyl)-2,3-dihydroquinazolin- compounds were sketched using Hyperchem software 4(1H)-one (10f ): [54] and energy minimized by the MM1 force field. The Yield: 71%. White crystal. M.p. 69–72  °C. IR (KBr) υ: −1 same docking procedure was applied for docking analy- 3280, 3045, 2920, 2836, 1648, 1601, 1203, 1010, 965  cm . ses of mentioned compounds with the GOLD docking H NMR (400  MHz, DMSO-d ) δ 8.29 (s, 1H), 7.71 program. The top-score binding poses were used for (dd, J = 7.8, 1.6  Hz, 1H), 7.50–7.07 (m, 12H), 7.00 (d, further analysis. Protein–ligand interactions were ana- J = 8.7  Hz, 2H), 6.83–6.58 (m, 2H), 5.73 (d, J = 2.4  Hz, lyzed with Discovery Studio Visualizer. 1H), 5.61 (s, 2H), 5.20 (d, J = 15.3  Hz, 1H), 5.11 (s, 2H), 3.86 (d, J = 15.3  Hz, 1H). MS: m/z (%) = 537 [M , 20%]. Anal.Calcd for C H F N O : C 69.26, H 4.69, N 13.03, 31 25 2 5 2 Conclusion Found: C 69.16, H 4.46, N 12.96. In the quest for effective anticancer agents, the series of quinazolinone 5a–e and dihydroquinazolinone 10a–f Cytotoxic evaluation were efficiently prepared and characterized. The syn - Cell lines and cell culture thetic compounds were evaluated for anticancer activ- The human cancer cells MCF-7and HCT-116 as well ity against two cell lines MCF-7 and HCT-116. Most of as Hek-293 as normal cells were purchased from Pas- the compounds, especially 5a, 5d, and 10f were found tor Institute of Iran. The cells were maintained in RPMI to have very good activity against tested cancerous cell 1640 medium supplemented with 10% heat-inactivated lines. Next safety and selectivity assessments of men- fetal bovine serum (Company: DNAbiotec, Cat number: tioned derivatives against normal cell lines revealed DB9723), and streptomycin (100  mg/mL) and penicillin that 5d and 10f had low toxicity against Hek-293 cell (100 U/ml) at 37 °C in a humidified atmosphere with 5% lines. The molecular docking studies validated the CO in the air. 2 Taayoshi et al. BMC Chemistry (2022) 16:35 Page 10 of 12 Funding outcome results from the anticancer activity and signi- This work was supported by a grant from Zanjan University of Medical fied the potential of these derivatives as potent PARP10 Sciences. inhibitors. As a result, these compounds can be modi- Availability of data and materials fied further for the development of new anticancer The datasets generated and/or analysed during the current study are available therapeutics. in the Worldwide Protein Data Bank (wwPDB) repository. (http:// www. rcsb. org). Abbreviations Declarations MDR: Multidrug resistance; MCR: Multicomponent reaction; MTT: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; OD: Opti- Ethics approval and consent to participate cal Density; 2D: 2-Dimensional; 3D: 3-Dimensional; RPMI 1640: Roswell Park Not applicable. Memorial Institute1640; Et N: Triethylamine; DMF: Dimethylformamide; TLC: Thin-layer chromatography; IC : Half-maximal inhibitory concentration. Consent for publication. Not applicable. Supplementary Information Competing interests The online version contains supplementary material available at https:// doi. The authors declare that they have no competing interests. org/ 10. 1186/ s13065- 022- 00825-x. Author details Additional file 1: Figure S1. H-NMR of 2-[(2-Methylphenyl)amino]- Department of Medicinal Chemistry, School of Pharmacy, Zanjan University 3-phenylquinazolin-4(3H)-one (5a). Figure S2. Mass data of 2-[(2-Meth- of Medical Sciences, Zanjan, Iran. Stem Cells Technology Research Center, Shi- ylphenyl)amino]-3-phenylquinazolin-4(3H)-one (5a). Figure S3. H-NMR raz University of Medical Sciences, Shiraz, Iran. Central Research Laboratory, of 3-(chloromethyl)-2-(phenylamino)quinazolin-4(3H)-one (5b). Figure Shiraz University of Medical Sciences, Shiraz, Iran. Endocrinology and Metab- S4. Mass data of 3-(chloromethyl)-2-(phenylamino)quinazolin-4(3H)-one olism Research Center, Endocrinology and Metabolism Clinical Sciences (5b). Figure S5. H-NMR of 3-cyclopropyl-2-(phenylamino)quinazolin- Institute, Tehran University of Medical Sciences, Tehran, Iran. Depar tment 4(3H)-one (5c). Figure S6. Mass data of 3-cyclopropyl-2-(phenylamino) of Pharmaceutical Biotechnology, School of Pharmacy, Hamadan University quinazolin-4(3H)-one (5c). Figure S7. H-NMR of 3-(4-methoxyphenyl)- of Medical Science Hamadan, Hamedan, Iran. Department of Medicinal 2-(phenylamino)quinazolin-4(3H)-one (5d). Figure S8. Mass data of Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Research Center, 3-(4-methoxyphenyl)-2-(phenylamino)quinazolin-4(3H)-one (5d). Figure Tehran University of Medical Sciences, Tehran, Iran. S9. H-NMR of 3-isopropyl-2-(phenylamino)quinazolin-4(3H)-one (5e). Figure S10. Mass data of 3-isopropyl-2-(phenylamino)quinazolin-4(3H)- Received: 27 January 2022 Accepted: 5 May 2022 one (5e). Figure S11. H-NMR of 3-benzyl-2-(4-((1-benzyl-1H-1,2,3-triazol- 4-yl)methoxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one (10a). Figure S12. Mass data of 3-benzyl-2-(4-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy) phenyl)-2,3-dihydroquinazolin-4(1H)-one (10a). Figure S13. H-NMR of 3-benzyl-2-(4-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy) References phenyl)-2,3 dihydroquinazolin-4(1H)-one (10b). Figure S14. Mass data 1. Giri RS, Thaker HM, Giordano T, Chen B, Nuthalapaty S, Vasu KK, Sudar- of 3-benzyl-2-(4-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy) sanam V. Synthesis and evaluation of quinazolinone derivatives as phenyl)-2,3 dihydroquinazolin-4(1H)-one (10b). Figure S15. H-NMR inhibitors of NF-κB, AP-1 mediated transcription and eIF-4E mediated of 3-benzyl-2-(4-((1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy) translational activation: Inhibitors of multi-pathways involve in cancer. Eur phenyl)-2,3-dihydroquinazolin-4(1H)-one (10c). Figure S16. Mass data J Med Chem. 2010;45(9):3558–63. of 3-benzyl-2-(4-((1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy) 2. Zarenezhad E, Farjam M, Iraji A. Synthesis and biological activity of phenyl)-2,3-dihydroquinazolin-4(1H)-one (10c). Figure S17. H-NMR pyrimidines-containing hybrids: focusing on pharmacological applica- of 3-benzyl-2-(4-((1-(4-bromobenzyl)-1H-1,2,3-triazol-4-yl)methoxy) tion. J Mol Struct. 2021;1230: 129833. phenyl)-2,3-dihydroquinazolin-4(1H)-one (10d). Figure S18. Mass data 3. Mottaghipisheh J, Doustimotlagh AH, Irajie C, Tanideh N, Barzegar A, Iraji of 3-benzyl-2-(4-((1-(4-bromobenzyl)-1H-1,2,3-triazol-4-yl)methoxy) A. The promising therapeutic and preventive properties of anthocyani- phenyl)-2,3-dihydroquinazolin-4(1H)-one (10d). Figure S19. H-NMR of dins/anthocyanins on prostate cancer. Cells. 2022;11(7):1070. 3-(4-fluorobenzyl)-2-(4-((1-(2-methylbenzyl)-1H-1,2,3-triazol-4-yl)methoxy) 4. Pishgar F, Ebrahimi H, Saeedi Moghaddam S, Fitzmaurice C, Amini phenyl)-2,3-dihydroquinazolin-4(1H)-one (10e). Figure S20. Mass of E. Global, regional and national burden of prostate cancer, 1990 to 3-(4-fluorobenzyl)-2-(4-((1-(2-methylbenzyl)-1H-1,2,3-triazol-4-yl)methoxy) 2015: results from the global burden of disease study 2015. J Urol. phenyl)-2,3-dihydroquinazolin-4(1H)-one (10e). Figure S21. H-NMR of 2018;199(5):1224–32. 3-(4-fluorobenzyl)-2-(4-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy) 5. Bray F, Jemal A, Grey N, Ferlay J, Forman D. Global cancer transitions phenyl)-2,3-dihydroquinazolin-4(1H)-one (10f ). Figure S21. 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Synthesis, molecular docking, and cytotoxicity of quinazolinone and dihydroquinazolinone derivatives as cytotoxic agents

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Abstract

Background: Cancer is the most cause of morbidity and mortality, and a major public health problem worldwide. In this context, two series of quinazolinone 5a–e and dihydroquinazolinone 10a–f compounds were designed, synthe- sized as cytotoxic agents. Methodology: All derivatives (5a–e and 10a–f ) were synthesized via straightforward pathways and elucidated by FTIR, H-NMR, CHNS elemental analysis, as well as the melting point. All the compounds were evaluated for their in vitro cytotoxicity effects using the MTT assay against two human cancer cell lines (MCF-7 and HCT-116) using doxorubicin as the standard drug. The test derivatives were additionally docked into the PARP10 active site using Gold software. Results and discussion: Most of the synthesized compounds, especially 5a and 10f were found to be highly potent against both cell lines. Synthesized compounds demonstrated IC in the range of 4.87–205.9 μM against HCT-116 cell line and 14.70–98.45 μM against MCF-7 cell line compared with doxorubicin with IC values of 1.20 and 1.08 μM after 72 h, respectively, indicated the plausible activities of the synthesized compounds. Conclusion: The compounds quinazolinone 5a–e and dihydroquinazolinone 10a–f showed potential activity against cancer cell lines which can lead to rational drug designing of the cytotoxic agents. Keywords: Quinazolinone, Dihydroquinazolinone Cytotoxicity, Docking, PARPs, Synthesis Introduction tumor formation [1–3]. The investigations reveal that Cancer is a complex disease resulting from perturbations cancer is the second major cause of mortality in 2015. in multiple intracellular regulatory systems and leading Moreover, there were 8.7 million deaths among 17.5 to a drastic increase in the number of the cells and thus million cases diagnosed with cancer globally [4]. Breast, lung, prostate, and colorectal cancers are recognized as widespread types of invasive cancer, which account for *Correspondence: n.adibpor@zums.ac.ir; momahdavi@tums.ac.ir about 4 in 10 of all diagnosed cases [5]. Depending on the Department of Medicinal Chemistry, School of Pharmacy, Zanjan University type and stage of cancer, the common cancer treatments of Medical Sciences, Zanjan, Iran Endocrinology and Metabolism Research Center, Endocrinology are radiotherapy, hormone therapy as well as surgery, and and Metabolism Clinical Sciences Institute, Tehran University of Medical chemotherapy. However, the central problem of the last Sciences, Tehran, Iran item is the failure in the distinction between healthy and Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Taayoshi et al. BMC Chemistry (2022) 16:35 Page 2 of 12 cancerous cells, which results in inevitable adverse effects Quinazoline scaffold show diverse biologically and phar - on the healthy cells [6]. Along the same line, Multidrug macologically active anti-cancer [13], analgesic [14], anti- resistance (MDR) is another major source of conflict in tuberculosis [15], antihypertensive [16], anti-diabetes [17] the treatment of cancer due to the resistance of the can- anti-melanogenesis [18, 19], anti-urease [20], antifungal cerous cells against the traditional chemotherapeutic [21], and antibacterial [22, 23] agents. Quinazolinone is agents [7]. Therefore, the need for finding novel ways for a naturally occurring alkaloid that can be found in many cancer treatment is still needed. natural products with diverse biological activities [24– Quinazoline as nitrogen-containing heterocyclic com- 26]. There are several quinazolinone-based compounds pound is synthesized in the structure of many synthetic such as compounds A, B, and C (Fig.  1I) reported in the compounds using different synthetic methods includ - literature with high cytotoxicity against tested cell lines ing aza-diels–alder reaction, aza-wittig reaction, metal- [27–29]. The inhibition of poly (ADP-ribose) polymerase mediated reaction, and oxidative cyclization [8–12]. 10 (PARP10) enzyme is one of the ways through which Fig. 1 Identified representative lead candidates T aayoshi et al. BMC Chemistry (2022) 16:35 Page 3 of 12 Scheme 1 Methods for the synthesis of compounds 5a–e and 10a–f. Reagents and conditions: a H O, r.t., 2–5 h. b CuBr (1 mmol), Et N (1 mmol), 2 3 DMF (5 ml), 80°, 8–10 h. c K CO (1 mmol), EtOH (10 ml), reflux, 12–24 h. d CuI (7 mol%), H O/t-BuOH (1:1), Et N (1.3 mmol), r.t., 20–24 h 2 3 2 3 some quinazolinone analogs have demonstrated their novel quinazolinone and dihydroquinazolinone to obtain potent anticancer activity [30, 31]. The 3,4-dihydroquina - more effective cytotoxic agents. All synthesized deriva - zolinone moiety is another favored scaffold due to its tives were evaluated against MCF-7 and HCT-116 cancer considerable therapeutic potential in medicinal chem- cell lines (Fig. 1III). istry [32, 33], mainly because of its emerging role in the treatment of cancer [34, 35]. Compounds D and E are Results and discussion good examples of potent antitumor activities (Fig.  1II). Chemistry A bunch of methods has been proposed to synthesize Two straightforward synthetic pathways were adopted 3,4-dihydroquinazolinones with plausible yields. Take to synthesize the target compounds 5a–e and 10a–f as the examples of the multicomponent reaction (MCR) shown in Scheme 1. The sequence for the proposed reac - protocols investigated by Luke R. Odell et al. [36, 37], an tion initiated by treating commercially available isatoic organo-catalyzed enantioselective approach for the syn- anhydride (1) with aromatic and aliphatic amines (2) in thesis of chiral trifluoromethyl dihydroquinazolinones, H O at room temperature to obtain the corresponding as a biologically important scaffold, by Xie et al. [38], and 2-aminobenzamides (3) [42]. All compounds 3 were eas- the catalyst-free and hydrophobically-directed approach ily prepared and used without further purifications. Next, for the production of functionalized 3,4-dihydroquinazo- we employed the reaction of compound 3 and phenyl lin-2(1H)-one by Chandrasekharam et al. [39]. isothiocyanates (4) in the presence of CuBr and Et N in In 2016, we disclosed a novel multi-component strat- DMF to achieve the final product 5 (Scheme  1 Method egy to assemble 1,2,3-triazole derivatives of 2,3-dihyd- A). The second strategy is for the synthesis of compound roquinazolin-4(1H)-one via click reaction with in  situ 10a–f in which the intermediate 7 was produced through prepared organic azides [40]. Furthermore, we proposed the reaction between 2-aminobenzamides (3) and an innovative approach of Quinazolin-4(3H)-ones syn- 4-(prop-2-yn-1-yloxy)benzaldehyde (6) in the presence of thesis by employing CuBr and E t N in 2016 [41]. With K CO in ethanol at reflux. The presence of a triple bond 3 2 3 this information in hand, we focus on the synthesis of in dihydroquinazolinone (7) attracted us toward click Taayoshi et al. BMC Chemistry (2022) 16:35 Page 4 of 12 reaction to form 1,2,3-triazole ring. As a result, com- Table 2 Analysis of Variance for Transformed Response (λ = 0.273) pound 7 was reacted with the in situ prepared (azidome- thyl)benzene (9) under the Sharpless-type click reaction Source DF Adj SS Adj MS F-Value p-Value conditions [43]. It was found that performing the reac- Time 1 13.005 13.0049 308.96 0.000 tion in the presence of CuI (7  mol%) as the catalyst in Compound 23 106.448 4.6282 109.95 0.000 H O/t-BuOH (1:1) at room temperature within 24  h led Time*compound 23 5.271 0.2292 5.44 0.000 to the formation of the corresponding product 10a–f in Error 82 3.452 0.0421 plausible yields (Scheme 1 Method B) according to previ- Total 129 128.108 ously reported procedures [44, 45]. The structures of final products have been verified by FT-IR, H-NMR, as well as melting point, and CHNS elemental analysis. Biological activity Cytotoxic evaluation The selected compounds 5a–e and 10a–f were evaluated as possible cytotoxic agents against human colon cancer HCT-116 cell line and MCF-7 breast cancer cell line by MTT assay using doxorubicin as the standard drug. As shown in Table 1, the induced cellular toxicity in the cell lines was studied at 48 and 72 h. The IC value was cal- culated from the inhibition rates at the mentioned dura- tions. The analysis of variance for transformed response indicated that the cytotoxic effects of compounds depend on time, whether for the MCF-7 (Table  2) or HCT-116 Table 1 Cancer cell growth inhibitory effect of synthesized derivatives evaluated by MTT reduction assay 1 2 3 Compound R R R IC (µM) MCF-7 IC (µM) MCF-7 IC (µM) HCT- IC (µM) 50 50 50 50 48 h 72 h 116 HCT-116 48 h 72 h 5a Ph 2-Me-C H – 71.17 14.70 7.15 4.87 6 4 5b Chloromethyl Ph – 101.375 76.245 59.26 37.84 5c Cyclopropyl Ph – 74.92 50.40 59.24 29.15 5d 4-OMe-C H Ph – 28.84 24.99 39.22 17.76 6 4 5e Propyl Ph – 78.95 42.74 88.71 63.33 10a Benzyl – H 62.29 18.88 88.79 28.99 10b Benzyl – 4-F 139.4 98.45 183.9 63.99 10c Benzyl – 4-Cl 52.00 32.30 120.35 61.02 10d Benzyl – 4-Br 44.68 14.80 251.1 205.9 10e 4-F-benzyl – 2-Me 79.14 48.75 48.21 33.28 10f 4-F-benzyl – 4-F 41.47 16.30 40.35 10.08 DOX – – – 1.33 1.08 1.66 1.20 T aayoshi et al. BMC Chemistry (2022) 16:35 Page 5 of 12 Table 3 Analysis of Variance for Transformed Response Table 4 the toxicity assessments of 5a, 5d, and 10f gainst Hek- (λ = 0.333) 293 cell lines Source DF Adj SS Adj MS F-Value p-Value Compound IC (µM) Hek- 293 after 72 h Time 1 13.832 13.8318 302.12 0.000 5a 8.71 ± 1.23 compound 23 143.164 6.2245 135.96 0.000 5d 68.13 ± 12.28 Time*compound 23 5.216 0.2268 4.95 0.000 10f 56.11 ± 10.38 Error 83 3.800 0.0458 DOX 0.75 ± 0.09 Total 130 166.298 at R (5b, 5c, 5d, 5e) deteriorated the cytotoxicity poten- tial, significantly. From the screening data of 10a-d, it was revealed that electron-withdrawing substitutions at R 3 3 3 (10b, R = 4-F; 10c, R = 4-Cl and 10d, R = 4-Br) decrease the potency compared to 10a as unsubstituted deriva- 1 3 tive. By way of illustration 10b (R = benzyl; R = 4-F) recorded the least potency in this series with I C values of 183.9 and 63.99  μM. Interestingly, the replacement of benzyl in 10b with 4-F-benzyl moiety leads to a notice- able increase in the cytotoxicity in 10f with an IC value of 40.35 μM and 10.08 μM after 48 and 72 h. Overall, concerning the cytotoxic evaluations on 5a–e, it can be understood that 5d was the most active deriva- tive against MCF-7 while 5a containing Ph at R and 2-Me-C H at R was the most potent cytotoxic agent 6 4 (Table 3) cell lines. This is because the IC values in 72 h against HCT-116. Assessments of 10a–f revealed that with p-value < 0.0001 are less than those in 48 h. Moreo- 1 3 compound 10f bearing 4-F-benzyl at R and 4-F at R was ver, the results revealed that the IC values dramatically the most active cytotoxic agent against both tested cell decreased after 72 h in comparison with 48 h of the inter- lines. action of compounds with cells. Next, to determine the safety of 5a, 5d, and 10f as the The first structure–activity relationship (SAR) explo - most potent derivatives on normal cell line over cancer rations focused on MCF-7 cells. Assessments of 5a–e cell lines, these derivatives were examined on Hek293 as derivatives against MCF-7 demonstrated that 5d possess- normal cell lines by MTT reduction assay. Results were 1 2 ing R = 4-OMe-C H and R = Ph afforded good potency 6 4 presented in Table  4. As can be seen, derivative 5a dem- with an IC value of 28.84 μM and 24.99 μM after 48 and onstrated high toxicity against Hek-293 cell lines while 5d 1 2 72 h followed by 5a bearing R = Ph and R = 2-Me-C H . 6 4 and 10f demonstrated low toxicity in this cell line. It seems that increasing the bulkiness at R may improve the potency. Cytotoxic screening of 10a–f revealed that Molecular docking 10a as unsubstituted derivatives exhibited I C values of Poly (ADP-ribose) polymerases (PARPs) is a family of 62.29 μM and 18.88 μM after 48 and 72 h. The incorpo - proteins involved in diverse cellular functions, espe- ration of halogen groups at R position showed different cially DNA repair and maintenance of chromatin stabil- behavior so that 4-F (10b) reduced the activity compared ity via ADP ribosylation. PARP10 (ARTD10) is one of the to 10a while para-chlorine (10c) or para-bromine (10d) members of the PARP family that performs mono-ADP- improved the cytotoxic potency compared to 10a. Note- ribosylation onto the amino acids of protein substrates worthy, the substitution of 4-F-benzyl at R position of from donor nicotinamide adenine dinucleotide (NA D ) 10b produced the most potent derivative in this set with of target proteins [46]. Recent studies have linked the IC values of 41.47 μM and 16.30 μM after 48 and 72 h. activity of PARP10 to support cancer cell survival and With regards to the HCT-116 cancer cells, in testing DNA damage repairing [30]. The silencing of PARP10 the compounds 5a–e, it was shown that 5a was the most in MCF7 and CaCo2 cells decreased the proliferation promising cytotoxic agent with IC values of 7.15  μM rate that correlated with cancer [47]. Quinazolin-4-one and 4.87  μM after 48 and 72  h. Further investigations derivatives (Compound F, Fig. 2) were first discovered by illustrated that the replacement of Ph with other moieties Oregon Health and Science University as effective PARPs at R as well as the replacement of 2-Me-C H with Ph 6 4 Taayoshi et al. BMC Chemistry (2022) 16:35 Page 6 of 12 Fig. 2 The structure of the active compound against PARP10 Table 5 Docking scores and interactions of compounds against PARP10 (PDB ID: 5LX6) Compound ChemScore Interactions with key residue 5a 33.37 Ala911, Val913, Tyr914, Tyr919, Ala921, Leu926, Tyr932, Ile987 5d 28.34 His887, Ala911, Tyr919, Ala921 10f 36.96 His887, Ala911, Val913, Tyr914, Val918, Leu926, Tyr932, Ile987 Veliparib 37.89 Gly888, Tyr919, Ala921, Leu926, Ser927, Tyr932, Ile987 inhibitors involved in mono ADP-ribosylation [48, 49]. Further modification leads to the discovery of novel compounds (Compound G and H, Fig.  2) that inhibited PARP10 [50, 51]. According to the literature, the amino acids His887, Gly888, Asn910, Ala911, Tyr914, Tyr919, Ala921, Leu926, Ser927, and Tyr932 are the most impor- tant ones in the PARP10 active site [52, 53]. Regarding the similarity of reported PARP10 inhibitors with the designed structures, molecular docking evalua- tions were performed to study the binding mode of the most potent compounds 5a, 5d and 10f with PARP10 active site. Docking studies of the mentioned compounds were carried out using gold docking software. Validation of the molecular docking method was done by redocking Fig. 3. 3D interaction pattern of compound 5a within PARP10 active the crystallographic ligand of the target enzyme, against site PARP10 (PDB ID: 5LX6) which testified the validation of the docking calculations. The ChemScore fitness value of 5a, 5d, and 10f plus their interactions with residues in the of amino quinazolin-4(3H)-one. 2-methylphenyl moiety PARP10 active site were documented in Table 5. exhibited one pi-sigma interaction with Val913 and one Alignment of the best pose of veliparib in the active pi-alkyl interaction with Ala911 plus pi-alkyl interactions site of PARP10 and crystallographic ligand recorded and with Val913, Tyr917, Tyr919, Ile987. Also, pi-pi-T-shaped RMSD value of 0.63  Å. The docked structure veliparib and pi-alkyl interactions were recorded between phenyl exhibited the interaction of this compound with Tyr919, and Tyr919 and Ala911, respectively. Ala921, Leu926, Ser927, Tyr932, and Ile987 residues. According to the results of 5d docking studies (Fig.  4), Moreover, this compound showed three H-bond interac- the aromatic moiety of 4-methoxyphenyl presented a pi- tions with Gly888 and Ser927. sigma and a pi-pi-T shaped interaction with Ala911 and Figure 3 showed the docking interactions of compound Tyr919, respectively. Phenyl pendant demonstrated a pi- 5d within PARP10. Docking evaluation depicted four pi- pi-stacked interaction with His887 and a pi-alkyl inter- alkyl interactions between the amino quinazolin-4(3H)- action with Ala921. Amino-quinazolin-4(3H)-one also one ring and Ala921, Leu926, Tyr932, Ile987 as well as made a pi-alkyl interaction with Tyr919. one hydrogen bound interaction between Ala911 and NH T aayoshi et al. BMC Chemistry (2022) 16:35 Page 7 of 12 Experimental Materials and methods The measured data on melting points were evaluated on a Kofler hot stage apparatus and were uncorrected. The H- NMR and IR spectra were gained by employing Bruker 400-NMR and ALPHA FT-IR spectrometer on KBr disks, respectively. The chemical reagents were obtained from Aldrich and Merck as well. Moreover, the Spectroscopic data of final products, including H-NMR and are available in the supporting information and our previous studies [41, 42]. Syntheses of 3‑Substituted 2‑(Arylamino) quinazolin‑4(3H)‑ones 5 (Method A) Fig. 4. 3D interaction pattern of compound 5d within PARP10 active The corresponding 2-aminobenzamide derivatives (3) were site synthesized via the reaction of equivalent amounts of isa- toic anhydride (1) and an appropriate amine (2) in water at room temperature for 2–5 h [28]. After completion of the reaction, the precipitated products were precipitated and filtered off, dried at 60 °C, and used for the further reaction without any need for more purification. Then, A mixture of 2-aminobenzamide (3) (2  mmol), isothiocyanate deriv- ative (4) (2  mmol), CuBr (1  mmol),and E t N (1  mmol) in DMF (5 ml) was heated at 80° for 8–10 h. After the reaction completion (monitored by TLC), the mixture was filtered off through a bed of Celite and washed with AcOEt. Next, H O (20 ml) was added to the filtrate, it was extracted with ethyl acetate (3 × 15), and dried with N a SO . The solvent 2 4 was then removed under reduced pressure and the crude reaction mixture was purified by column chromatography on silica gel and petroleum ether (PE)/AcOEt (5:1) as elu- ent. All products were recrystallized from PE/AcOEt (1:1) Fig. 5. 3D interaction pattern of compound 10f within PARP10 active to give pure products 5 [44, 45]. site General procedure for the synthesis of 3‑substituted 2‑[4‑(prop‑2‑yn‑1‑yloxy) The 3D interaction pattern of compound 10f (Fig.  5) phenyl]‑2,3‑dihydroquinazolin‑4(1H)‑one derivatives 7 showed two pi-pi-T-shaped and one pi-alkyl interac- (Method B) tions with 4-fluorobenzyl moiety. The dihydroquinazo - A mixture of isatoic anhydride (1) (20  mmol) and various lin-4(1H)-one ring participated in pi-pi-T-shaped and amines (2) (20 mmol) in 50 ml water was stirred for 2–3 h pi-alkyl interactions with Tyr932 and Ala911. Also, the at room temperature. Monitored by TLC, having com- phenoxy linker was fixed through pi-pi-T-shaped interac - pleted the reactions, the resulting off-white precipitate (3) tion with His887 and Typ932. Triazole ring in the middle was filtered off, dried at 60 °C, and used for the next reac - of the molecules exhibited hydrogen bound with Typ932 tions without further purification [28]. Next, a mixture of plus two pi-sigma interactions with Leu926 and Ile987. 2-aminobenzamide (3) (1  mmol), 4-(prop-2-yn-1-yloxy) Terminal 2-fluorobenzyl triazole participated in van der benzaldehyde (4) (1  mmol), and potassium carbonate Waals, pi-sigma, and pi-alkyl interactions with Tyr932, (1 mmol) in 10 ml EtOH was refluxed for 12–24 h. Checked Val913, Ala91, respectively. by TLC, having completed the reactions, potassium car- Overall it was shown that the findings of the docking bonate was filtered off from the reaction medium and pure study of the most active derivatives were in line with the product 7 was obtained as yellow crystals after the solution results of cytotoxic effects. was cooled down to room temperature [44, 45]. Taayoshi et al. BMC Chemistry (2022) 16:35 Page 8 of 12 General procedure for the synthesis of 1,2,3‑triazole Yield: 76%. White crystal. M.p. 256–259 °C. IR (KBr) υ: −1 1 derivatives of 2,3‑dihydroquinazolin‑4(1H)‑one 10 (Method 3348, 1675, 1608  cm . H NMR (400  MHz, DMSO-d ) B) δ 8.06 (dd, J = 8.0, 1.6  Hz, 1H), 7.76 (d, J = 8.0  Hz, 2H), A solution of an arylmethyl chloride (8) (1.1 mmol), 0.06 7.63 (td, J = 7.7, 7.0, 1.6 Hz, 1H), 7.50–7.37 (m, 4H), 7.27 gr sodium azide (0.9 mmol), and 0.13 gr Et N (1.3 mmol) (t, J = 7.6 Hz, 1H), 7.18–7.12 (m, 3H), 7.94 (d, J = 7.8  Hz, in 4  ml water and 4  ml tert-butyl alcohol was stirred at 2H), 3.86 (s, 3H). C NMR (100 MHz, CDCl ) δ 168.86, room temperature for 30  min. Next, the prepared com- 159.6, 153.7, 145.13, 142.90, 140.11, 133.39, 130.65, pound 7 (0.5  mmol) and CuI (7  mol%) were added to 129.85, 125.10, 122.95, 121.92, 121.82, 119.86, 116.95, the reaction medium, and the mixture was stirred for 114.38, 56.35  ppm. MS: m/z (%) = 343 [M , 46%]. Anal. 20–24  h. Upon completion of the reaction, examined by Calcd for C H N O : C 73.45, H 4.99, N 12.24, Found: 21 17 3 2 TLC, the reaction mixture was diluted with 20  ml H O, C 73.32, H 5.16, N 12.39. poured in 20 gr ice and the final product 10 was filtered 3-isopropyl-2-(phenylamino)quinazolin-4(3H)-one of, washed with cold water, and purified by plate chroma - (5e): [41] tography using silica gel and PE/EtOAc (3:1) as eluent. Yield: 80%. White crystal. M.p. 143–146 °C. IR (KBr) υ: −1 1 3351, 1676, 1613  cm . H NMR (400 MHz, DMSO-d ) δ Analytical data 7.96 (d, J = 7.8 Hz, 1H), 7.47 (dd, J = 7.9, 1.6 Hz, 2H), 7.13 2-[(2-Methylphenyl)amino]-3-phenylquinazolin-4(3H)- (ddd, J = 8.4, 7.1, 1.6  Hz, 1H), 6.91 (t, J = 7.8, 1H), 6.68 one (5a) [41]: (dd, J = 8.2, 1.2 Hz, 1H), 6.54–6.47 (m, 2H), 6.37–6.33 (m, Yield: 77%. White crystal. M.p. 254–258  °C. IR (KBr) 2H), 4.46–3.73 (m, 1H), 1.15 (d, J = 6.6 Hz, 6H). MS: m/z −1 1 υ: 3336, 1681, 1610  cm . H NMR (400  MHz, DMSO- (%) = 279 [M , 47%]. Anal.Calcd for C H N O: C 73.10, 17 17 3 d ) δ 8.07 (dd, J = 8.0, 1.1 Hz, 1H), 7.72 (ddd, J = 8.2, 7.2, H 6.13, N 15.04, Found: C 73.39, H 5.95, N 15.24. 1.6  Hz, 1H), 7.66–7.58 (m, 6H), 7.50 (dd, J = 7.5, 1.2  Hz, 3-benzyl-2-(4-((1-benzyl-1H-1,2,3-triazol-4-yl)meth- 1H), 7.47–7.40 (m, 3H), 7.30–7.25 (m, 1H), 7.22–7.17 (m, oxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one (10a): [54] 1H), 2.34 (s, 3H). MS: m/z (%) = 327 [M , 48%]. Anal. Yield: 72%. White crystal. M.p. 65–68  °C. IR (KBr) υ: −1 1 Calcd for C H N O: C 77.04, H 5.23, N 12.84, Found: C 3390, 3058, 2929, 2840, 1655, 1610, 1230  cm . H NMR 21 17 3 77.16, H 5.05, N 13.01. (400  MHz, DMSO-d ) δ 8.29 (s, 1H), 7.71 (dd, J = 7.7, 3-(chloromethyl)-2-(phenylamino)quinazolin-4(3H)- 1.5 Hz, 1H), 7.41–7.22 (m, 14H), 7.01 (d, J = 8.6  Hz, 2H), one (5b): 6.77–6.54 (m, 2H), 5.70 (d, J = 2.4  Hz, 1H), 5.62 (s, 2H), Yield: 81%. White crystal. M.p. 194–197  °C. IR (KBr) 5.31 (d, J = 15.3 Hz, 1H), 5.11 (s, 2H), 3.80 (d, J = 15.3 Hz, −1 1 υ: 3353, 1689, 1616, 780  cm . H NMR (400  MHz, 1H). MS: m/z (%) = 501 [M , 21%]. Anal.Calcd for CDCl ) δ 8.25 (d, J = 7.9 Hz, 1H), 7.64 (t, J = 7.8  Hz, 1H), C H N O : C 74.23, H 5.43, N 13.96, Found: C 74.16, H 3 31 27 5 2 7.49–7.23 (m, 7H), 7.15–7.07 (m, 1H), 5.52 (s, 2H). C 5.25, N 13.81. NMR (100 MHz, CDCl ) δ 169.71, 153.4, 144.56, 141.96, 3-benzyl-2-(4-((1-(4-fluorobenzyl)-1H-1,2,3-triazol- 132.19, 129.86, 129.09, 122.13, 119.75, 119.26, 118.54, 4-yl)methoxy)phenyl)-2,3 dihydroquinazolin-4(1H)-one 2+ 115.38, 56.57 ppm. MS: m/z (%) = 287 [M + , 15%], 285 (10b): [54] [M , 45%]. Anal.Calcd for C H ClN O: C 63.20, H 4.23, Yield: 77%. White crystal. M.p. 83–86  °C. IR (KBr) 15 12 3 N 14.71, Found: C 63.16, H 3.96, N 14.92. υ: 3301, 3069, 2928, 2852, 1631, 1626, 1526, 1190, −1 1 3-cyclopropyl-2-(phenylamino)quinazolin-4(3H)-one 1002  cm . H NMR (400  MHz, C DCl ) δ 8.06 (d, (5c): J = 6.4  Hz, 1H), 7.56 (s, 1H), 7.45–7.13 (m, 14H), 6.93 Yield: 85%. White crystal. M.p. 141–144  °C. IR (KBr) (d, J = 8.7  Hz, 2H), 6.55 (d, J = 8.2  Hz, 1H), 5.61 (s, 1H), −1 1 υ: 3326, 1679, 1601  cm . H NMR (400  MHz, CDCl ) 5.57 (s, 2H), 5.28 (d, J = 15.3  Hz, 1H), 5.19 (s, 2H), 3.70 δ 8.16 (dd, J = 8.0, 1.6  Hz, 1H), 7.76 (d, J = 8.0  Hz, 2H), (d, J = 15.3 Hz, 1H). MS: m/z (%) = 519 [M , 19%]. Anal. 7.63 (td, J = 7.7, 7.0, 1.6 Hz, 1H), 7.50–7.37 (m, 4H), 7.24 Calcd for C H FN O : C 71.66, H 5.04, N 13.48, Found: 31 26 5 2 (t, J = 7.6 Hz, 1H), 7.18 (t, J = 7.4 Hz, 1H), 2.98–2.66 (m, C 71.77, H 5.21, N 13.31. 1H), 1.54–1.33 (m, 2H), 1.24–0.99 (m, 2H). C NMR 3-benzyl-2-(4-((1-(4-chlorobenzyl)-1H-1,2,3-triazol- (100 MHz, CDCl ) δ 168.81, 154.2, 144.31, 142.11, 4-yl)methoxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one 132.08, 129.85, 129.57, 121.99, 120.03, 119.51, 118.63, (10c): [54] 115.54, 26.30, 11.29  ppm. MS: m/z (%) = 277 [M , 44%]. Yield: 82%. White crystal. M.p. 84–87  °C. IR (KBr) υ: −1 1 C H N O: C 73.63, H 5.45, N 15.15, Found: C 73.56, H 3270, 3066, 2932, 2851, 1639, 1520, 1250, 777  cm . H 17 15 3 5.76, N 14.89. NMR (400 MHz, CDCl ) δ 8.06 (dd, J = 7.8, 1.5 Hz, 1H), 3-(4-methoxy phenyl)-2-(phenylamino)quinazolin- 7.56 (s, 1H), 7.50–7.36 (m, 2H), 7.37–7.25 (m, 10H), 4(3H)-one (5d): 7.26–7.17 (m, 3H), 6.93 (d, J = 8.7  Hz, 2H), 6.62–6.42 T aayoshi et al. BMC Chemistry (2022) 16:35 Page 9 of 12 MTT assay (m, 1H), 5.61 (d, J = 1.8  Hz, 1H), 5.57 (s, 2H), 5.28 (d, The cytotoxic activities of compounds 5a–e and 10a–f J = 15.3  Hz, 1H), 5.19 (s, 2H), 3.70 (d, J = 15.3  Hz, 1H). 2+ + were evaluated against cancerous cell lines. And the MS: m/z (%) = 537 [M + , 6%], 535 [M , 18%]. Anal. most potent cytotoxic agents (5a, 5d, and 10f ) against Calcd for C H ClN O : C 69.46, H 4.89, N 13.07, Found: 31 26 5 2 normal cell lines were examined by taking advantage of C 69.56, H 5.05, N 13.29. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetra- 3-benzyl-2-(4-((1-(4-bromobenzyl)-1H-1,2,3-triazol- zolium bromide) colorimetric assay as reported method 4-yl)methoxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one [32, 33]. The absorbance was read at 570  nm against a (10d): [54] test wavelength of 690 nm using Graphpad Prism 8.2.1 Yield: 83%. White crystal. M.p. 93–95  °C. IR (KBr) υ: −1 1 software. The inhibition percentage of compounds was 3319, 3061, 2939, 2844, 1636, 1531, 1210  cm . H NMR calculated as: OD –OD (400 MHz, CDCl ) δ 8.06 (dd, J = 7.8, 1.5  Hz, 1H), 7.56 wells treated with DMSO1% wells treated with /OD *100 (OD = absorb- (s, 1H), 7.46–7.16 (m, 15H), 6.93 (d, J = 8.7 Hz, 2H), 6.54 compounds wells treated with DMSO1% ance). Then, IC values were calculated by nonlinear (d, J = 8.0  Hz, 1H), 5.61 (d, J = 1.8  Hz, 1H), 5.57 (s, 2H), regression analysis. 5.28 (d, J = 15.3 Hz, 1H), 5.19 (s, 2H), 3.70 (d, J = 15.3 Hz, 2+ + 1H). MS: m/z (%) = 581 [M + , 15%], 579 [M , 15%]. Anal.Calcd for C H BrN O : C 64.14, H 4.51, N 12.06, 31 26 5 2 Molecular docking Found: C 64.16, H 4.45, N 11.81. Docking assessments of 5a, 5d, and 10f were performed 3-(4-f luorob enz yl)-2-(4-((1-(2-methylb enz yl)-1H- using the GOLD docking program according to previ- 1,2,3-triazol-4-yl)methoxy)phenyl)-2,3-dihydroquinazo- ously reported protocol [55, 56] The 3D-crystal struc - lin-4(1H)-one (10e): [54] ture of the PARP10 binding site (PDB ID: 5LX6) was Yield: 77%. White crystal. M.p. 63–65 °C. (KBr) υ: 3395, −1 1 retrieved from Protein Data Bank (http:// www. rcsb. 3061, 2929, 2836, 1661, 1616, 1596, 1246, 996  cm . H org). The protein structure was prepared using the Dis - NMR (400  MHz, DMSO-d ) δ 8.19 (s, 1H), 7.80–7.55 covery studio client so that waters and ligands were (m, 1H), 7.41–6.91 (m, 14H), 6.83–6.49 (m, 2H), 5.73 (d, removed from 5LX6 and all hydrogens were added. The J = 2.9 Hz, 1H), 5.63 (s, 2H), 5.21 (d, J = 15.4 Hz, 1H), 5.12 binding site of the enzyme was defined based on the (s, 2H), 3.87 (d, J = 15.3  Hz, 1H), 2.32 (s, 3H). MS: m/z native ligand Veliparib with a 8 Å radius. For validation (%) = 533 [M , 17%]. Anal.Calcd for C H FN O : C 32 28 5 2 of docking, the ChemScore function was chosen for 72.03, H 5.29, N 13.12, Found: C 72.19, H 5.11, N 13.01. docking of Veliparib inside the 5LX6. All other options 3-(4-fluorobenzyl)-2-(4-((1-(4-fluorobenzyl)-1H -1,2,3- were set as default. After validation, 5a, 5d and 10f triazol-4-yl)methoxy)phenyl)-2,3-dihydroquinazolin- compounds were sketched using Hyperchem software 4(1H)-one (10f ): [54] and energy minimized by the MM1 force field. The Yield: 71%. White crystal. M.p. 69–72  °C. IR (KBr) υ: −1 same docking procedure was applied for docking analy- 3280, 3045, 2920, 2836, 1648, 1601, 1203, 1010, 965  cm . ses of mentioned compounds with the GOLD docking H NMR (400  MHz, DMSO-d ) δ 8.29 (s, 1H), 7.71 program. The top-score binding poses were used for (dd, J = 7.8, 1.6  Hz, 1H), 7.50–7.07 (m, 12H), 7.00 (d, further analysis. Protein–ligand interactions were ana- J = 8.7  Hz, 2H), 6.83–6.58 (m, 2H), 5.73 (d, J = 2.4  Hz, lyzed with Discovery Studio Visualizer. 1H), 5.61 (s, 2H), 5.20 (d, J = 15.3  Hz, 1H), 5.11 (s, 2H), 3.86 (d, J = 15.3  Hz, 1H). MS: m/z (%) = 537 [M , 20%]. Anal.Calcd for C H F N O : C 69.26, H 4.69, N 13.03, 31 25 2 5 2 Conclusion Found: C 69.16, H 4.46, N 12.96. In the quest for effective anticancer agents, the series of quinazolinone 5a–e and dihydroquinazolinone 10a–f Cytotoxic evaluation were efficiently prepared and characterized. The syn - Cell lines and cell culture thetic compounds were evaluated for anticancer activ- The human cancer cells MCF-7and HCT-116 as well ity against two cell lines MCF-7 and HCT-116. Most of as Hek-293 as normal cells were purchased from Pas- the compounds, especially 5a, 5d, and 10f were found tor Institute of Iran. The cells were maintained in RPMI to have very good activity against tested cancerous cell 1640 medium supplemented with 10% heat-inactivated lines. Next safety and selectivity assessments of men- fetal bovine serum (Company: DNAbiotec, Cat number: tioned derivatives against normal cell lines revealed DB9723), and streptomycin (100  mg/mL) and penicillin that 5d and 10f had low toxicity against Hek-293 cell (100 U/ml) at 37 °C in a humidified atmosphere with 5% lines. The molecular docking studies validated the CO in the air. 2 Taayoshi et al. BMC Chemistry (2022) 16:35 Page 10 of 12 Funding outcome results from the anticancer activity and signi- This work was supported by a grant from Zanjan University of Medical fied the potential of these derivatives as potent PARP10 Sciences. inhibitors. As a result, these compounds can be modi- Availability of data and materials fied further for the development of new anticancer The datasets generated and/or analysed during the current study are available therapeutics. in the Worldwide Protein Data Bank (wwPDB) repository. (http:// www. rcsb. org). Abbreviations Declarations MDR: Multidrug resistance; MCR: Multicomponent reaction; MTT: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; OD: Opti- Ethics approval and consent to participate cal Density; 2D: 2-Dimensional; 3D: 3-Dimensional; RPMI 1640: Roswell Park Not applicable. Memorial Institute1640; Et N: Triethylamine; DMF: Dimethylformamide; TLC: Thin-layer chromatography; IC : Half-maximal inhibitory concentration. Consent for publication. Not applicable. Supplementary Information Competing interests The online version contains supplementary material available at https:// doi. The authors declare that they have no competing interests. org/ 10. 1186/ s13065- 022- 00825-x. Author details Additional file 1: Figure S1. H-NMR of 2-[(2-Methylphenyl)amino]- Department of Medicinal Chemistry, School of Pharmacy, Zanjan University 3-phenylquinazolin-4(3H)-one (5a). Figure S2. Mass data of 2-[(2-Meth- of Medical Sciences, Zanjan, Iran. Stem Cells Technology Research Center, Shi- ylphenyl)amino]-3-phenylquinazolin-4(3H)-one (5a). Figure S3. H-NMR raz University of Medical Sciences, Shiraz, Iran. Central Research Laboratory, of 3-(chloromethyl)-2-(phenylamino)quinazolin-4(3H)-one (5b). Figure Shiraz University of Medical Sciences, Shiraz, Iran. Endocrinology and Metab- S4. Mass data of 3-(chloromethyl)-2-(phenylamino)quinazolin-4(3H)-one olism Research Center, Endocrinology and Metabolism Clinical Sciences (5b). Figure S5. H-NMR of 3-cyclopropyl-2-(phenylamino)quinazolin- Institute, Tehran University of Medical Sciences, Tehran, Iran. Depar tment 4(3H)-one (5c). Figure S6. Mass data of 3-cyclopropyl-2-(phenylamino) of Pharmaceutical Biotechnology, School of Pharmacy, Hamadan University quinazolin-4(3H)-one (5c). Figure S7. H-NMR of 3-(4-methoxyphenyl)- of Medical Science Hamadan, Hamedan, Iran. Department of Medicinal 2-(phenylamino)quinazolin-4(3H)-one (5d). Figure S8. Mass data of Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Research Center, 3-(4-methoxyphenyl)-2-(phenylamino)quinazolin-4(3H)-one (5d). Figure Tehran University of Medical Sciences, Tehran, Iran. S9. H-NMR of 3-isopropyl-2-(phenylamino)quinazolin-4(3H)-one (5e). Figure S10. Mass data of 3-isopropyl-2-(phenylamino)quinazolin-4(3H)- Received: 27 January 2022 Accepted: 5 May 2022 one (5e). Figure S11. H-NMR of 3-benzyl-2-(4-((1-benzyl-1H-1,2,3-triazol- 4-yl)methoxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one (10a). Figure S12. Mass data of 3-benzyl-2-(4-((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy) phenyl)-2,3-dihydroquinazolin-4(1H)-one (10a). Figure S13. H-NMR of 3-benzyl-2-(4-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy) References phenyl)-2,3 dihydroquinazolin-4(1H)-one (10b). Figure S14. Mass data 1. Giri RS, Thaker HM, Giordano T, Chen B, Nuthalapaty S, Vasu KK, Sudar- of 3-benzyl-2-(4-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy) sanam V. Synthesis and evaluation of quinazolinone derivatives as phenyl)-2,3 dihydroquinazolin-4(1H)-one (10b). Figure S15. H-NMR inhibitors of NF-κB, AP-1 mediated transcription and eIF-4E mediated of 3-benzyl-2-(4-((1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy) translational activation: Inhibitors of multi-pathways involve in cancer. Eur phenyl)-2,3-dihydroquinazolin-4(1H)-one (10c). Figure S16. Mass data J Med Chem. 2010;45(9):3558–63. of 3-benzyl-2-(4-((1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy) 2. Zarenezhad E, Farjam M, Iraji A. Synthesis and biological activity of phenyl)-2,3-dihydroquinazolin-4(1H)-one (10c). Figure S17. H-NMR pyrimidines-containing hybrids: focusing on pharmacological applica- of 3-benzyl-2-(4-((1-(4-bromobenzyl)-1H-1,2,3-triazol-4-yl)methoxy) tion. J Mol Struct. 2021;1230: 129833. phenyl)-2,3-dihydroquinazolin-4(1H)-one (10d). Figure S18. Mass data 3. Mottaghipisheh J, Doustimotlagh AH, Irajie C, Tanideh N, Barzegar A, Iraji of 3-benzyl-2-(4-((1-(4-bromobenzyl)-1H-1,2,3-triazol-4-yl)methoxy) A. The promising therapeutic and preventive properties of anthocyani- phenyl)-2,3-dihydroquinazolin-4(1H)-one (10d). Figure S19. H-NMR of dins/anthocyanins on prostate cancer. Cells. 2022;11(7):1070. 3-(4-fluorobenzyl)-2-(4-((1-(2-methylbenzyl)-1H-1,2,3-triazol-4-yl)methoxy) 4. Pishgar F, Ebrahimi H, Saeedi Moghaddam S, Fitzmaurice C, Amini phenyl)-2,3-dihydroquinazolin-4(1H)-one (10e). Figure S20. Mass of E. Global, regional and national burden of prostate cancer, 1990 to 3-(4-fluorobenzyl)-2-(4-((1-(2-methylbenzyl)-1H-1,2,3-triazol-4-yl)methoxy) 2015: results from the global burden of disease study 2015. J Urol. phenyl)-2,3-dihydroquinazolin-4(1H)-one (10e). Figure S21. H-NMR of 2018;199(5):1224–32. 3-(4-fluorobenzyl)-2-(4-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy) 5. Bray F, Jemal A, Grey N, Ferlay J, Forman D. Global cancer transitions phenyl)-2,3-dihydroquinazolin-4(1H)-one (10f ). Figure S21. Mass of according to the Human Development Index (2008–2030): a population- 3-(4-fluorobenzyl)-2-(4-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy) based study. Lancet Oncol. 2012;13(8):790–801. phenyl)-2,3-dihydroquinazolin-4(1H)-one (10f ). 6. Banerjee A, Pathak S, Subramanium VD, Murugesan DGR, Verma RS. Strategies for targeted drug delivery in treatment of colon cancer: current trends and future perspectives. Drug Discov Today. 2017;22(8):1224–32. Acknowledgements 7. Awasthi R, Roseblade A, Hansbro PM, Rathbone MJ, Dua K, Bebawy M. Not applicable. Nanoparticles in cancer treatment: opportunities and obstacles. Curr Drug Targets. 2018;19(14):1696–709. Author contributions 8. Liu S, Yuan D, Li S, Xie R, Kong Y, Zhu X. Synthesis and evaluation of novel MM proposed the research work and designed the chemical experiments. 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Journal

BMC ChemistrySpringer Journals

Published: May 18, 2022

Keywords: Quinazolinone; Dihydroquinazolinone Cytotoxicity; Docking; PARPs; Synthesis

References