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Synthesis of a New [3-(4-Chlorophenyl)-4-oxo-1,3-thiazolidin-5-ylidene]acetic Acid Derivative

Synthesis of a New [3-(4-Chlorophenyl)-4-oxo-1,3-thiazolidin-5-ylidene]acetic Acid Derivative molbank Communication Synthesis of a New [3-(4-Chlorophenyl)-4-oxo-1, 3-thiazolidin-5-ylidene]acetic Acid Derivative Jacek Szczepanski, ´ Helena Tuszewska and Nazar Trotsko * Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Lublin, 4A Chodzki, ´ 20-093 Lublin, Poland; jaacek.szczepanski.93@gmail.com (J.S.); tuszewska.helena93@gmail.com (H.T.) * Correspondence: nazar.trotsko@umlub.pl; Tel.: +48-81-448-72-44 Received: 3 July 2020; Accepted: 23 July 2020; Published: 28 July 2020 Abstract: The new methyl [3-(4-chlorophenyl)-2-{[(2,4-dichloro-1,3-thiazol-5-yl)methylidene] hydrazinylidene}-4-oxo-1,3-thiazolidin-5-ylidene]acetate was synthesized from 4-(4-chlorophenyl)- 1-(2,4-dichloro-1,3-thiazol-5-yl)methylidene-3-thiosemicarbazide using dimethyl acetylenedicarboxylate 1 13 as thia-Michael reaction acceptor. New compounds (3 and 4) were characterized by IR, H and C NMR spectroscopy methods. Keywords: thiazolidin-4-one; Michael addition; anti-T. gondii activity 1. Introduction Toxoplasmosis is a common parasitic infectious disease that occurs all over the world. Toxoplasmosis is caused by the protozoan Toxoplasma gondii, whose ultimate host is Felidae. Approximately 30% of people have positive antibodies indicating toxoplasmosis [1]. The basic danger of the disease is the possibility of congenital infections during pregnancy and the reactivation of the disease in immunocompromised persons. Over the last decade, the scientific value of thiazolidin-4-one derivatives has increased due to their wide spectrum of biological activities, including antidiabetic, anticancer, antibacterial, antifungal, anti-inflammatory, etc. The activity and mechanisms of action of thiazolidin-4-ones are described in numerous reviews [2–7]. It is also worth paying attention to the anti-T. gondii activity of thiazolidin-4-ones [8–12]. In addition, the currently used drugs are not 100% e ective for the treatment of toxoplasmosis, and this has prompted us to look for new synthetic compounds that could be used to combat this common parasite in the future. In our previous research [12], we identified (4-oxothiazolidin-5-yl/ylidene)acetic acid derivatives with antiparasitic activity against T. gondii (Figure 1). The highlighted fragments (green and orange color) in Figure 1 are favorable for anti-T. gondii activity. Based on previous studies, we designed a compound which contains both highlighted fragments. In this communication, we describe the synthesis of the previously unknown methyl [3-(4-chlorophenyl)-2-{[(2,4-dichloro-1,3-thiazol-5-yl)methylidene]hydrazinylidene}-4-oxo-1,3-thiaz olidin-5-ylidene]acetate, which has potential as an anti-T. gondii agent. Molbank 2020, 2020, M1150; doi:10.3390/M1150 www.mdpi.com/journal/molbank Molbank 2020, 2020, M1150 2 of 5 Molbank 2020, 2020, x FOR PEER REVIEW 2 of 5 previously identified Cl Cl compounds with anti-T. gondii activity Cl HO HO N IC =115.92 μM IC =129.42 μM 50 50 Br CH OH OH Cl Cl N new designed H C compound O S Cl O O S S H C H C O N O O O previously identified Cl Br compounds with IC =28.32 μM IC =27.74 μM 50 50 OH OH anti-T. gondii activity Figure 1. (4-Oxothiazolidin-5-yl/ylidene)acetic acid derivatives with anti-T. gondii activity and new Figure 1. (4-Oxothiazolidin-5-yl/ylidene)acetic acid derivatives with anti-T. gondii activity and new designed compound. designed compound. 2. Results and Discussion 2. Results and Discussion The targeted compound was synthesized by three-step synthesis starting from The targeted compound was synthesized by three-step synthesis starting from thiazolidine-2, thiazolidine-2,4-dione (TZD). TZD was converted into 2,4-dichloro-1,3-thiazol-5-carbaldehyde via a 4-dione (TZD). TZD was converted into 2,4-dichloro-1,3-thiazol-5-carbaldehyde via a Vilsmeier–Haack Vilsmeier–Haack reaction in accordance with the literature [13]. In the next step, reaction in accordance with the literature [13]. In the next step, 2,4-dichloro-1,3-thiazol-5-carbaldehyde 2,4-dichloro-1,3-thiazol-5-carbaldehyde (2) was condensed with (2) was condensed with 4-(4-chlorophenyl)-3-thiosemicarbazide to give the thiosemicarbazone (3). In the last step of synthesis, the targeted compound was obtained from 4-(4-chlorophenyl)- 1-(2,4-dichloro-1,3-thiazol-5-yl)methylidene-3-thiosemicarbazide (3) and dimethyl acetylenedicarboxylate Molbank 2020, 2020, x FOR PEER REVIEW 3 of 5 Molbank 2020, 2020, M1150 3 of 5 4-(4-chlorophenyl)-3-thiosemicarbazide to give the thiosemicarbazone (3). In the last step of synthesis, the targeted compound was obtained from 4-(4-chlorophenyl)-1-(2,4-dichloro-1,3-thiazol-5-yl)methylidene-3-thiosemicarbazide (3) and by thia-Michael addition of the sulfur atom to the triple bond and then cyclization to give the dimethyl acetylenedicarboxylate by thia-Michael addition of the sulfur atom to the triple bond and (4-oxothiazolidin-5-ylidene)acetic acid derivative 4 (Scheme 1), which illustrates that precursor 3 is then cyclization to give the (4-oxothiazolidin-5-ylidene)acetic acid derivative 4 (Scheme 1), which also useful for this type of reaction, if other compounds (maleic anhydride, maleimide derivatives etc.) illustrates that precursor 3 is also useful for this type of reaction, if other compounds (maleic are used as acceptors in the thia-Michael addition. anhydride, maleimide derivatives etc.) are used as acceptors in the thia-Michael addition. Cl Cl Cl Cl Cl NH iii N iii S Cl Cl 50% 62% 65% S N S O H C NH 3 S N Cl NH 1 2 4 Scheme 1. Synthetic route for compound 4. Reagents and conditions: (i) POCl3, DMF stirred for 1 h at rt, Scheme 1. Synthetic route for compound 4. Reagents and conditions: (i) POCl , DMF stirred for 1 heat for 1 h at 80–90 °C, brought to boil and heated for another 4 h; (ii) h at rt, heat for 1 h at 80–90 C, brought to boil and heated for another 4 h; (ii) 4-(4-chlorophenyl)- 4-(4-chlorophenyl)-3-thiosemicarbazide, EtOH, heated under reflux for 3 h; and (iii) dimethyl 3-thiosemicarbazide, EtOH, heated under reflux for 3 h; and (iii) dimethyl acetylenedicarboxylate, acetylenedicarboxylate, MeOH, heated under reflux for 30 min. MeOH, heated under reflux for 30 min. 1 13 The structures of compounds 3 and 4 were supported by IR, H, and C NMR spectroscopy 1 13 The structures of compounds 3 and 4 were supported by IR, H, and C NMR spectroscopy methods (see Supplementary Materials). The H NMR spectra exhibit the characteristic signals for methods (see Supplementary Materials). The H NMR spectra exhibit the characteristic signals for para-substituted phenyl ring as two doublets in the range 7.44 to 7.76 ppm with spin–spin coupling J para-substituted phenyl ring as two doublets in the range 7.44 to 7.76 ppm with spin–spin coupling = 8.7Hz. The signals derived from the proton of a CH=N group were observed at 8.29 ppm and 8.30 J = 8.7 Hz. The signals derived from the proton of a CH=N group were observed at 8.29 ppm and ppm for compounds 3 and 4, respectively. The characteristic proton signal of methylidene group 8.30 ppm (CH=) of for compound compounds 4 w 3aand s observed 4, respectively as singlet . The at 6.9characteristic 4 ppm. All rempr ain oton ing ssignal ignals ari of smethylidene ing from other group parts of the molecule were present. Similarly, C NMR confirmed present of all carbon atoms in (CH=) of compound 4 was observed as singlet at 6.94 ppm. All remaining signals arising from other molecule (details were presented in the experimental part). parts of the molecule were present. Similarly, C NMR confirmed present of all carbon atoms in molecule (details were presented in the experimental part). 3. Materials and Methods 3. Materials and Methods 3.1. General 3.1. General All commercial reagents and solvents were purchased from either Alfa Aesar (Lancaster, UK) or Sigma-Aldrich (St. Louis, MO, USA) and used without further purification. The melting points All commercial reagents and solvents were purchased from either Alfa Aesar (Lancaster, UK) were determined by using Gallenkamp MPD 350.BM 3.5 apparatus Sanyo (Moriguchi, Japan) and or Sigma-Aldrich (St. Louis, MO, USA) and used without further purification. The melting points are uncorrected. The purity of the compound was checked by TLC on plates with silica gel Si 60F254, were determined by using Gallenkamp MPD 350.BM 1 3.5 apparatus 13 Sanyo (Moriguchi, Japan) and produced by Merck Co. (Darmstadt, Germany). The H NMR and C NMR spectra were recorded are uncorrected. The purity of the compound was checked by TLC on plates with silica gel Si 60F , by a Bruker Avance 300 MHz instrument (Bruker Corporation, Billerica, MA, USA) using DMSO-d6 254 1 13 produced as solv by ent Mer and TMS ck Co. as (Darmstadt, an internal st Germany). andard. Chem The icalH shNMR ifts were and exprC essed NMR as spectra δ (ppm). wer IR spectrum e recorded by was recorded by Nicolet 6700 spectrometer (Thermo Scientific, Philadephia, PA, USA). Elemental a Bruker Avance 300 MHz instrument (Bruker Corporation, Billerica, MA, USA) using DMSO-d as analysis was performed by AMZ 851 CHX analyzer (PG, Gdańsk, Poland) and the results were solvent and TMS as an internal standard. Chemical shifts were expressed as  (ppm). IR spectrum was within ±0.4% of the theoretical value. recorded by Nicolet 6700 spectrometer (Thermo Scientific, Philadephia, PA, USA). Elemental analysis was performed by AMZ 851 CHX analyzer (PG, Gdansk, ´ Poland) and the results were within 0.4% of 3.2. 4-(4-Chlorophenyl)-1-(2,4-dichloro-1,3-thiazol-5-yl)methylidene-3-thiosemicarbazide (3) the theoretical value. To the 2,4-dichloro-1,3-thiazole-5-carbaldehyde (2) (1.27 g, 7 mmol) and 4-(4-chlorophenyl)-3-thiosemicarbazide (1.41 g, 7 mmol), anhydrous ethanol (20 mL) and glacial 3.2. 4-(4-Chlorophenyl)-1-(2,4-dichloro-1,3-thiazol-5-yl)methylidene-3-thiosemicarbazide (3) acetic acid (79 mg, 5 drops) were added. The reaction mixture was heated under reflux for 3 h. After To the 2,4-dichloro-1,3-thiazole-5-carbaldehyde (2) (1.27 g, 7 mmol) and 4-(4-chlorophenyl)- cooling, the precipitate was filtered off. After drying, precipitate was crystallized from acetic acid. 3-thiosemicarbazide (1.41 g, 7 mmol), anhydrous ethanol (20 mL) and −1 glacial acetic acid (79 mg, 5 drops) Yield 1.59 g (62%), orange powder, mp = 198–200 °C. IR ν (cm ): 3294 (NH), 3054 (CHar.), 1589, were1added. 549 (C=N). TheH NM reaction R (300 MHz, mixtureD was MSO heated -d6) δ: 7.44 (2H, under reflux d, J = for 8.7 Hz 3 h. , Ar H) After ; 7.56 cooling, (2H, d, the J = 8. precipitate 7 Hz, Ar was filterH) ed; 8.29 (1 o . After H, s, CH= drying,N pr ); 10 ecipitate .12 (1H, was s, NHCS crystallized NH); 12. from 16 (1H acetic , s, NHCS acid. NH). C NMR (75 MHz, DMSO-d6) δ: 128.1 (CHar.), 128.5 (CHar.), 130.1 (Car.), 130.5 (Car.), 133.3 (CH=N), 136.9 (N=CH-C), 138.3 Yield 1.59 g (62%), orange powder, mp = 198–200 C. IR  (cm ): 3294 (NH), 3054 (CH ), 1589, ar. 1549 (C=N). H NMR (300 MHz, DMSO-d ) : 7.44 (2H, d, J = 8.7 Hz, Ar H); 7.56 (2H, d, J = 8.7 Hz, Ar H); 8.29 (1H, s, CH=N); 10.12 (1H, s, NHCSNH); 12.16 (1H, s, NHCSNH). C NMR (75 MHz, DMSO-d ) : 128.1 (CH ), 128.5 (CH ), 130.1 (C ), 130.5 (C ), 133.3 (CH=N), 136.9 (N=CH-C), 6 ar. ar. ar. ar. 138.3 (=C(Cl)-N), 152.6 (S-C(Cl)=N), 176.6 (C=S). Anal. calc. for C H Cl N S (365.689) (%): C 36.13; 11 7 3 4 2 H 1.93; N 15.32. Found: C 36.07; H 1.89; N 15.27. Molbank 2020, 2020, M1150 4 of 5 3.3. Methyl [3-(4-chlorophenyl)-2-{[(2,4-dichloro-1,3-thiazol-5-yl)methylidene]hydrazinylidene}-4-oxo-1,3- thiazolidin-5-ylidene]acetate (4) To the thiosemicarbazone 3 (0.73 g, 2 mmol) dimethyl acetylenedicarboxylate (0.25 mL, 2 mmol) and methanol (15 mL) were added. The reaction mixture was heated under reflux for 30 min. After cooling, the precipitate was filtered o . After drying, precipitate was crystallized from a mixture of solvents DMF/acetic acid in volume ratio (1/1). Yield 0.62 g (65%), yellow powder, mp = 248–250 C. IR  (cm ): 3056 (CH ), 1730 (C=O ar. ester), 1690 (C=O thiazolidine), 1587, 1550 (C=N); H NMR (300 MHz, DMSO-d ) : 3.85 (3H, s, OCH ); 6.94 (1H, s, H COOC-CH=); 7.64 (2H, d, J = 8.7 Hz, Ar H); 7.76 (2H, d, J = 8.7 Hz, Ar H); 3 3 8.30 (1H, s, CH=N). C NMR (75 MHz, DMSO-d ) : 53.3 (OCH ); 117.1 (CH=C); 122.3 (CH=C); 6 3 130.3 (CH ); 131.1 (CH ); 133.7 (C ); 135.2 (N=CH-C); 140.8 (=C(Cl)-N); 141.3 (C ); 145.9 (CH=N); ar. ar. ar. ar. 158.5 (S-C(Cl)=N); 164.3 (C=N); 164.6 (C=O thiazolidine); 166.4 (C=O ester). Anal. calc. for C H Cl N O S (475.757) (%): C 40.39; H 1.91; N 11.78. Found: C 40.26; H 1.90; N 11.77. 16 9 3 4 3 2 4. Conclusions The result of our current research is the new (4-oxothiazolidin-5-ylidene)acetic acid derivative. It has been synthesized in good yield from 4-(4-chlorophenyl)-1-(2,4-dichloro-1,3-thiazol-5-yl) methylidene-3-thiosemicarbazide by thia-Michael reaction with next cyclization. This compound can be of interest to the medicinal science branch due to its potential as an anti-T. gondii agent. Supplementary Materials: The following are available online at http://www.mdpi.com/1422-8599/2020/3/M1150/s1, 1 13 Figures S1–S6: IR, H, and C NMR spectra for compounds 3 and 4. Author Contributions: Conceptualization, N.T.; methodology, N.T.; formal analysis, N.T.; investigation, J.S., H.T. and N.T.; writing—original draft preparation, N.T.; writing—review and editing, N.T.; visualization, J.S., H.T.; supervision, N.T. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Conflicts of Interest: The authors declare no conflict of interest. References 1. Tenter, A.M.; Heckeroth, A.R.; Weiss, L.M. Toxoplasma gondii: From animals to humans. Int. J. Parasitol. 2000, 30, 1217–1258. [CrossRef] 2. Kaminskyy, D.; Kryshchyshyn, A.; Lesyk, R. 5-Ene-4-thiazolidinones—An ecient tool in medicinal chemistry. Eur. J. Med. Chem. 2017, 140, 542–594. [CrossRef] [PubMed] 3. Havrylyuk, D.; Roman, O.; Lesyk, R. Synthetic approaches, structure activity relationship and biological applications for pharmacologically attractive pyrazole/pyrazoline–thiazolidine-based hybrids. Eur. J. Med. Chem. 2016, 113, 145–166. [CrossRef] [PubMed] 4. Chadna, N.; Bahia, M.S.; Kaur, M.; Silakari, O. Thiazolidine-2,4-dione derivatives: Programmed chemical weapons for key protein targets of various pathological conditions. Bioorg. Med. Chem. 2015, 23, 2953–2974. [CrossRef] [PubMed] 5. Tripathi, A.C.; Gupta, S.J.; Fatima, G.N.; Sonar, P.K.; Verma, A.; Saraf, S.K. 4-Thiazolidinones: The advances continue : : : . Eur. J. Med. Chem. 2014, 72, 52–77. [CrossRef] [PubMed] 6. Jain, V.S.; Vora, D.K.; Ramaa, C.S. Thiazolidine-2,4-diones: Progress towards multifarious applications. Bioorg. Med. Chem. 2013, 21, 1599–1620. [CrossRef] [PubMed] 7. Verma, A.; Saraf, S.K. 4-Thiazolidinone—A biologically active sca old. Eur. J. Med. Chem. 2008, 43, 897–905. [CrossRef] [PubMed] 8. Tenorio, R.P.; Carvalho, C.S.; Pessanha, C.S.; de Lima, J.G.; de Faria, A.R.; Alves, A.J.; de Melo, E.J.T.; Goes, A.J.S. Synthesis of thiosemicarbazone and 4-thiazolidinone derivatives and their in vitro anti-Toxoplasma gondii activity. Bioorg. Med. Chem. Lett. 2005, 15, 2575–2578. [CrossRef] [PubMed] Molbank 2020, 2020, M1150 5 of 5 9. De Aquino, T.M.; Liesen, A.P.; da Silva, R.E.A.; Lima, V.T.; Carvalho, C.S.; de Faria, A.R.; de Araujo, J.M.; de Lima, J.G.; Alves, A.J.; de Melo, E.J.T.; et al. Synthesis, anti-Toxoplasma gondii and antimicrobial activities of benzaldehyde 4-phenyl-3-thiosemicarbazones and 2-[(phenylmethylene)hydrazono]-4-oxo- 3-phenyl-5-thiazolidineacetic acids. Bioorg. Med. Chem. 2008, 16, 446–456. [CrossRef] [PubMed] 10. Liesen, A.P.; de Aquino, T.M.; Carvalho, C.S.; Lima, V.T.; de Araujo, J.M.; de Lima, J.G.; de Faria, A.R.; de Melo, E.J.T.; Alves, A.J.; Alves, E.W.; et al. Synthesis and evaluation of anti-Toxoplasma gondii and antimicrobial activities of thiosemicarbazides, 4-thiazolidinones and 1,3,4-thiadiazoles. Eur. J. Med. Chem. 2010, 45, 3685–3691. [CrossRef] [PubMed] 11. Carradori, S.; Secci, D.; Bizzarri, B.; Chimenti, P.; De Monte, C.; Guglielmi, P.; Campestre, C.; Rivanera, D.; Bordon, C.; Jones-Brando, L. Synthesis and biological evaluation of anti-Toxoplasma gondii activity of a novel sca old of thiazolidinone derivatives. J. Enzyme Inhib. Med. Chem. 2017, 32, 746–758. [CrossRef] [PubMed] 12. Trotsko, N.; Bekier, A.; Paneth, A.; Wujec, M.; Dzitko, K. Synthesis and in vitro anti-Toxoplasma gondii activity of novel thiazolidin-4-one derivatives. Molecules 2019, 24, 3029. [CrossRef] [PubMed] 13. Kotlyar, V.N.; Pushkarev, P.A.; Orlov, V.D.; Chernenko, V.N.; Desenko, S.M. Thiazole analogs of chalcones, capable of functionalization at the heterocyclic nucleus. Chem. Heterocycl. Compd. 2010, 46, 334–341. [CrossRef] © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Molbank Multidisciplinary Digital Publishing Institute

Synthesis of a New [3-(4-Chlorophenyl)-4-oxo-1,3-thiazolidin-5-ylidene]acetic Acid Derivative

Szczepański, Jacek; Tuszewska, Helena; Trotsko, Nazar
Molbank , Volume 2020 (3) – Jul 28, 2020
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Abstract

molbank Communication Synthesis of a New [3-(4-Chlorophenyl)-4-oxo-1, 3-thiazolidin-5-ylidene]acetic Acid Derivative Jacek Szczepanski, ´ Helena Tuszewska and Nazar Trotsko * Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Lublin, 4A Chodzki, ´ 20-093 Lublin, Poland; jaacek.szczepanski.93@gmail.com (J.S.); tuszewska.helena93@gmail.com (H.T.) * Correspondence: nazar.trotsko@umlub.pl; Tel.: +48-81-448-72-44 Received: 3 July 2020; Accepted: 23 July 2020; Published: 28 July 2020 Abstract: The new methyl [3-(4-chlorophenyl)-2-{[(2,4-dichloro-1,3-thiazol-5-yl)methylidene] hydrazinylidene}-4-oxo-1,3-thiazolidin-5-ylidene]acetate was synthesized from 4-(4-chlorophenyl)- 1-(2,4-dichloro-1,3-thiazol-5-yl)methylidene-3-thiosemicarbazide using dimethyl acetylenedicarboxylate 1 13 as thia-Michael reaction acceptor. New compounds (3 and 4) were characterized by IR, H and C NMR spectroscopy methods. Keywords: thiazolidin-4-one; Michael addition; anti-T. gondii activity 1. Introduction Toxoplasmosis is a common parasitic infectious disease that occurs all over the world. Toxoplasmosis is caused by the protozoan Toxoplasma gondii, whose ultimate host is Felidae. Approximately 30% of people have positive antibodies indicating toxoplasmosis [1]. The basic danger of the disease is the possibility of congenital infections during pregnancy and the reactivation of the disease in immunocompromised persons. Over the last decade, the scientific value of thiazolidin-4-one derivatives has increased due to their wide spectrum of biological activities, including antidiabetic, anticancer, antibacterial, antifungal, anti-inflammatory, etc. The activity and mechanisms of action of thiazolidin-4-ones are described in numerous reviews [2–7]. It is also worth paying attention to the anti-T. gondii activity of thiazolidin-4-ones [8–12]. In addition, the currently used drugs are not 100% e ective for the treatment of toxoplasmosis, and this has prompted us to look for new synthetic compounds that could be used to combat this common parasite in the future. In our previous research [12], we identified (4-oxothiazolidin-5-yl/ylidene)acetic acid derivatives with antiparasitic activity against T. gondii (Figure 1). The highlighted fragments (green and orange color) in Figure 1 are favorable for anti-T. gondii activity. Based on previous studies, we designed a compound which contains both highlighted fragments. In this communication, we describe the synthesis of the previously unknown methyl [3-(4-chlorophenyl)-2-{[(2,4-dichloro-1,3-thiazol-5-yl)methylidene]hydrazinylidene}-4-oxo-1,3-thiaz olidin-5-ylidene]acetate, which has potential as an anti-T. gondii agent. Molbank 2020, 2020, M1150; doi:10.3390/M1150 www.mdpi.com/journal/molbank Molbank 2020, 2020, M1150 2 of 5 Molbank 2020, 2020, x FOR PEER REVIEW 2 of 5 previously identified Cl Cl compounds with anti-T. gondii activity Cl HO HO N IC =115.92 μM IC =129.42 μM 50 50 Br CH OH OH Cl Cl N new designed H C compound O S Cl O O S S H C H C O N O O O previously identified Cl Br compounds with IC =28.32 μM IC =27.74 μM 50 50 OH OH anti-T. gondii activity Figure 1. (4-Oxothiazolidin-5-yl/ylidene)acetic acid derivatives with anti-T. gondii activity and new Figure 1. (4-Oxothiazolidin-5-yl/ylidene)acetic acid derivatives with anti-T. gondii activity and new designed compound. designed compound. 2. Results and Discussion 2. Results and Discussion The targeted compound was synthesized by three-step synthesis starting from The targeted compound was synthesized by three-step synthesis starting from thiazolidine-2, thiazolidine-2,4-dione (TZD). TZD was converted into 2,4-dichloro-1,3-thiazol-5-carbaldehyde via a 4-dione (TZD). TZD was converted into 2,4-dichloro-1,3-thiazol-5-carbaldehyde via a Vilsmeier–Haack Vilsmeier–Haack reaction in accordance with the literature [13]. In the next step, reaction in accordance with the literature [13]. In the next step, 2,4-dichloro-1,3-thiazol-5-carbaldehyde 2,4-dichloro-1,3-thiazol-5-carbaldehyde (2) was condensed with (2) was condensed with 4-(4-chlorophenyl)-3-thiosemicarbazide to give the thiosemicarbazone (3). In the last step of synthesis, the targeted compound was obtained from 4-(4-chlorophenyl)- 1-(2,4-dichloro-1,3-thiazol-5-yl)methylidene-3-thiosemicarbazide (3) and dimethyl acetylenedicarboxylate Molbank 2020, 2020, x FOR PEER REVIEW 3 of 5 Molbank 2020, 2020, M1150 3 of 5 4-(4-chlorophenyl)-3-thiosemicarbazide to give the thiosemicarbazone (3). In the last step of synthesis, the targeted compound was obtained from 4-(4-chlorophenyl)-1-(2,4-dichloro-1,3-thiazol-5-yl)methylidene-3-thiosemicarbazide (3) and by thia-Michael addition of the sulfur atom to the triple bond and then cyclization to give the dimethyl acetylenedicarboxylate by thia-Michael addition of the sulfur atom to the triple bond and (4-oxothiazolidin-5-ylidene)acetic acid derivative 4 (Scheme 1), which illustrates that precursor 3 is then cyclization to give the (4-oxothiazolidin-5-ylidene)acetic acid derivative 4 (Scheme 1), which also useful for this type of reaction, if other compounds (maleic anhydride, maleimide derivatives etc.) illustrates that precursor 3 is also useful for this type of reaction, if other compounds (maleic are used as acceptors in the thia-Michael addition. anhydride, maleimide derivatives etc.) are used as acceptors in the thia-Michael addition. Cl Cl Cl Cl Cl NH iii N iii S Cl Cl 50% 62% 65% S N S O H C NH 3 S N Cl NH 1 2 4 Scheme 1. Synthetic route for compound 4. Reagents and conditions: (i) POCl3, DMF stirred for 1 h at rt, Scheme 1. Synthetic route for compound 4. Reagents and conditions: (i) POCl , DMF stirred for 1 heat for 1 h at 80–90 °C, brought to boil and heated for another 4 h; (ii) h at rt, heat for 1 h at 80–90 C, brought to boil and heated for another 4 h; (ii) 4-(4-chlorophenyl)- 4-(4-chlorophenyl)-3-thiosemicarbazide, EtOH, heated under reflux for 3 h; and (iii) dimethyl 3-thiosemicarbazide, EtOH, heated under reflux for 3 h; and (iii) dimethyl acetylenedicarboxylate, acetylenedicarboxylate, MeOH, heated under reflux for 30 min. MeOH, heated under reflux for 30 min. 1 13 The structures of compounds 3 and 4 were supported by IR, H, and C NMR spectroscopy 1 13 The structures of compounds 3 and 4 were supported by IR, H, and C NMR spectroscopy methods (see Supplementary Materials). The H NMR spectra exhibit the characteristic signals for methods (see Supplementary Materials). The H NMR spectra exhibit the characteristic signals for para-substituted phenyl ring as two doublets in the range 7.44 to 7.76 ppm with spin–spin coupling J para-substituted phenyl ring as two doublets in the range 7.44 to 7.76 ppm with spin–spin coupling = 8.7Hz. The signals derived from the proton of a CH=N group were observed at 8.29 ppm and 8.30 J = 8.7 Hz. The signals derived from the proton of a CH=N group were observed at 8.29 ppm and ppm for compounds 3 and 4, respectively. The characteristic proton signal of methylidene group 8.30 ppm (CH=) of for compound compounds 4 w 3aand s observed 4, respectively as singlet . The at 6.9characteristic 4 ppm. All rempr ain oton ing ssignal ignals ari of smethylidene ing from other group parts of the molecule were present. Similarly, C NMR confirmed present of all carbon atoms in (CH=) of compound 4 was observed as singlet at 6.94 ppm. All remaining signals arising from other molecule (details were presented in the experimental part). parts of the molecule were present. Similarly, C NMR confirmed present of all carbon atoms in molecule (details were presented in the experimental part). 3. Materials and Methods 3. Materials and Methods 3.1. General 3.1. General All commercial reagents and solvents were purchased from either Alfa Aesar (Lancaster, UK) or Sigma-Aldrich (St. Louis, MO, USA) and used without further purification. The melting points All commercial reagents and solvents were purchased from either Alfa Aesar (Lancaster, UK) were determined by using Gallenkamp MPD 350.BM 3.5 apparatus Sanyo (Moriguchi, Japan) and or Sigma-Aldrich (St. Louis, MO, USA) and used without further purification. The melting points are uncorrected. The purity of the compound was checked by TLC on plates with silica gel Si 60F254, were determined by using Gallenkamp MPD 350.BM 1 3.5 apparatus 13 Sanyo (Moriguchi, Japan) and produced by Merck Co. (Darmstadt, Germany). The H NMR and C NMR spectra were recorded are uncorrected. The purity of the compound was checked by TLC on plates with silica gel Si 60F , by a Bruker Avance 300 MHz instrument (Bruker Corporation, Billerica, MA, USA) using DMSO-d6 254 1 13 produced as solv by ent Mer and TMS ck Co. as (Darmstadt, an internal st Germany). andard. Chem The icalH shNMR ifts were and exprC essed NMR as spectra δ (ppm). wer IR spectrum e recorded by was recorded by Nicolet 6700 spectrometer (Thermo Scientific, Philadephia, PA, USA). Elemental a Bruker Avance 300 MHz instrument (Bruker Corporation, Billerica, MA, USA) using DMSO-d as analysis was performed by AMZ 851 CHX analyzer (PG, Gdańsk, Poland) and the results were solvent and TMS as an internal standard. Chemical shifts were expressed as  (ppm). IR spectrum was within ±0.4% of the theoretical value. recorded by Nicolet 6700 spectrometer (Thermo Scientific, Philadephia, PA, USA). Elemental analysis was performed by AMZ 851 CHX analyzer (PG, Gdansk, ´ Poland) and the results were within 0.4% of 3.2. 4-(4-Chlorophenyl)-1-(2,4-dichloro-1,3-thiazol-5-yl)methylidene-3-thiosemicarbazide (3) the theoretical value. To the 2,4-dichloro-1,3-thiazole-5-carbaldehyde (2) (1.27 g, 7 mmol) and 4-(4-chlorophenyl)-3-thiosemicarbazide (1.41 g, 7 mmol), anhydrous ethanol (20 mL) and glacial 3.2. 4-(4-Chlorophenyl)-1-(2,4-dichloro-1,3-thiazol-5-yl)methylidene-3-thiosemicarbazide (3) acetic acid (79 mg, 5 drops) were added. The reaction mixture was heated under reflux for 3 h. After To the 2,4-dichloro-1,3-thiazole-5-carbaldehyde (2) (1.27 g, 7 mmol) and 4-(4-chlorophenyl)- cooling, the precipitate was filtered off. After drying, precipitate was crystallized from acetic acid. 3-thiosemicarbazide (1.41 g, 7 mmol), anhydrous ethanol (20 mL) and −1 glacial acetic acid (79 mg, 5 drops) Yield 1.59 g (62%), orange powder, mp = 198–200 °C. IR ν (cm ): 3294 (NH), 3054 (CHar.), 1589, were1added. 549 (C=N). TheH NM reaction R (300 MHz, mixtureD was MSO heated -d6) δ: 7.44 (2H, under reflux d, J = for 8.7 Hz 3 h. , Ar H) After ; 7.56 cooling, (2H, d, the J = 8. precipitate 7 Hz, Ar was filterH) ed; 8.29 (1 o . After H, s, CH= drying,N pr ); 10 ecipitate .12 (1H, was s, NHCS crystallized NH); 12. from 16 (1H acetic , s, NHCS acid. NH). C NMR (75 MHz, DMSO-d6) δ: 128.1 (CHar.), 128.5 (CHar.), 130.1 (Car.), 130.5 (Car.), 133.3 (CH=N), 136.9 (N=CH-C), 138.3 Yield 1.59 g (62%), orange powder, mp = 198–200 C. IR  (cm ): 3294 (NH), 3054 (CH ), 1589, ar. 1549 (C=N). H NMR (300 MHz, DMSO-d ) : 7.44 (2H, d, J = 8.7 Hz, Ar H); 7.56 (2H, d, J = 8.7 Hz, Ar H); 8.29 (1H, s, CH=N); 10.12 (1H, s, NHCSNH); 12.16 (1H, s, NHCSNH). C NMR (75 MHz, DMSO-d ) : 128.1 (CH ), 128.5 (CH ), 130.1 (C ), 130.5 (C ), 133.3 (CH=N), 136.9 (N=CH-C), 6 ar. ar. ar. ar. 138.3 (=C(Cl)-N), 152.6 (S-C(Cl)=N), 176.6 (C=S). Anal. calc. for C H Cl N S (365.689) (%): C 36.13; 11 7 3 4 2 H 1.93; N 15.32. Found: C 36.07; H 1.89; N 15.27. Molbank 2020, 2020, M1150 4 of 5 3.3. Methyl [3-(4-chlorophenyl)-2-{[(2,4-dichloro-1,3-thiazol-5-yl)methylidene]hydrazinylidene}-4-oxo-1,3- thiazolidin-5-ylidene]acetate (4) To the thiosemicarbazone 3 (0.73 g, 2 mmol) dimethyl acetylenedicarboxylate (0.25 mL, 2 mmol) and methanol (15 mL) were added. The reaction mixture was heated under reflux for 30 min. After cooling, the precipitate was filtered o . After drying, precipitate was crystallized from a mixture of solvents DMF/acetic acid in volume ratio (1/1). Yield 0.62 g (65%), yellow powder, mp = 248–250 C. IR  (cm ): 3056 (CH ), 1730 (C=O ar. ester), 1690 (C=O thiazolidine), 1587, 1550 (C=N); H NMR (300 MHz, DMSO-d ) : 3.85 (3H, s, OCH ); 6.94 (1H, s, H COOC-CH=); 7.64 (2H, d, J = 8.7 Hz, Ar H); 7.76 (2H, d, J = 8.7 Hz, Ar H); 3 3 8.30 (1H, s, CH=N). C NMR (75 MHz, DMSO-d ) : 53.3 (OCH ); 117.1 (CH=C); 122.3 (CH=C); 6 3 130.3 (CH ); 131.1 (CH ); 133.7 (C ); 135.2 (N=CH-C); 140.8 (=C(Cl)-N); 141.3 (C ); 145.9 (CH=N); ar. ar. ar. ar. 158.5 (S-C(Cl)=N); 164.3 (C=N); 164.6 (C=O thiazolidine); 166.4 (C=O ester). Anal. calc. for C H Cl N O S (475.757) (%): C 40.39; H 1.91; N 11.78. Found: C 40.26; H 1.90; N 11.77. 16 9 3 4 3 2 4. Conclusions The result of our current research is the new (4-oxothiazolidin-5-ylidene)acetic acid derivative. It has been synthesized in good yield from 4-(4-chlorophenyl)-1-(2,4-dichloro-1,3-thiazol-5-yl) methylidene-3-thiosemicarbazide by thia-Michael reaction with next cyclization. This compound can be of interest to the medicinal science branch due to its potential as an anti-T. gondii agent. Supplementary Materials: The following are available online at http://www.mdpi.com/1422-8599/2020/3/M1150/s1, 1 13 Figures S1–S6: IR, H, and C NMR spectra for compounds 3 and 4. Author Contributions: Conceptualization, N.T.; methodology, N.T.; formal analysis, N.T.; investigation, J.S., H.T. and N.T.; writing—original draft preparation, N.T.; writing—review and editing, N.T.; visualization, J.S., H.T.; supervision, N.T. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Conflicts of Interest: The authors declare no conflict of interest. References 1. Tenter, A.M.; Heckeroth, A.R.; Weiss, L.M. Toxoplasma gondii: From animals to humans. Int. J. Parasitol. 2000, 30, 1217–1258. [CrossRef] 2. Kaminskyy, D.; Kryshchyshyn, A.; Lesyk, R. 5-Ene-4-thiazolidinones—An ecient tool in medicinal chemistry. 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