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(E)-3-(4-Chlorophenyl)-1-(2-fluoro-4-methoxyphenyl)-2-propen-1-one

(E)-3-(4-Chlorophenyl)-1-(2-fluoro-4-methoxyphenyl)-2-propen-1-one molbank Short Note Nicholas Bailey , Alaina Atanes and Bradley O. Ashburn * Ashburn Group, Mathematics, Natural, and Health Sciences Division, University of Hawai‘i West O‘ahu, 91-1001 Farrington Hwy, Kapolei, HI 96707, USA; nmbailey@hawaii.edu (N.B.); aatanes@hawaii.edu (A.A.) * Correspondence: bashburn@hawaii.edu Abstract: Natural products known as chalcones show promise as chemotherapeutic agents for the neglected tropical disease known as leishmaniasis. Our objective is to synthesize new targets of oppor- tunity that may lead to better treatments of this debilitating disease. Claisen-Schmidt condensation 0 0 of 4-chlorobenzaldehyde with 2 -fluoro-4 -methoxyacetophenone using aqueous sodium hydrox- ide in ethanol yielded the novel compound (E)-3-(4-chlorophenyl)-1-(2-fluoro-4-methoxyphenyl)- 2-propen-1-one. The product was obtained in good yield and purity after recrystallization from ethyl acetate/hexane. With the known antiparasitic properties of halogenated chalcones, this novel compound is suitable for antileishmanial activity study. Keywords: chalcone; synthesis; aldol; leishmaniasis; neglected tropical disease 1. Introduction Leishmaniasis is the second largest parasitic killer behind malaria. The disease is caused by the flesh-eating protozoan parasite of the genus Leishmania and is transmitted through the bites of phlebotomine sandflies. There are three main forms of leishmaniasis: cutaneous, mucocutaneous, and visceral (kala-azar). Symptoms such as severe skin disfig- Citation: Bailey, N.; Atanes, A.; Ashburn, B.O. (E)-3-(4-Chlorophenyl) urement, scarring of the mouth and nose, and organ failure afflict over 1 million people -1-(2-fluoro-4-methoxyphenyl)-2- annually [1–3]. propen-1-one. Molbank 2021, 2021, The World Health Organization classifies leishmaniasis as a neglected tropical disease M1184. https://doi.org/ (NTD), meaning it occurs in tropical or subtropical regions of the Earth. The disease is 10.3390/M1184 endemic in Northern Africa, the Middle East, the Mediterranean, parts of Asia, and Central America; impacting those who live in poverty the most. These people typically do not Academic Editor: Fawaz Aldabbagh have the access, finances, or ability to obtain treatments, which need intravenous delivery Received: 8 December 2020 over multiple sessions, thus creating an unfortunate health disparity. The skin lesions Accepted: 21 January 2021 and disfiguration caused by the cutaneous and mucosal forms may result in individuals Published: 25 January 2021 becoming outcasts from their communities and could cause a significant reduction in quality of life. Publisher’s Note: MDPI stays neutral The areas affected are growing due to vector habitat increase from the warming global with regard to jurisdictional claims in climate; with more than 1 billion people in approximately 90 countries at risk of infection published maps and institutional affil- due to living in areas where leishmaniasis is endemic. There are no vaccines [4] and current iations. drug treatments suffer from toxicity, high cost, and poor efficacy [5]. Even after treatment, the parasite is not eradicated, it remains dormant in the body to potentially strike again. The discovery of new effective and affordable medications is imperative to improve the lives of millions worldwide. Fortunately, a group of natural products known as chal- Copyright: © 2021 by the authors. cones possess a diverse set of biological activities. These activities include antifungal [6,7], Licensee MDPI, Basel, Switzerland. antioxidant [7], and anticancer [8] activity. Recent literature has illustrated the potential This article is an open access article for chalcones as a new antileishmanial agent for all three forms of leishmaniasis [9–11]. distributed under the terms and Numerous chalcones reported in literature have exhibited inhibitory activity on promastig- conditions of the Creative Commons otes and/or amastigotes of various Leishmania species [6,7,9,12]. In a study done by Ortalli Attribution (CC BY) license (https:// et al. 31 chalcones were synthesized. Sixteen of them were found to be active against creativecommons.org/licenses/by/ promastigotes of L. donovani. Out of the most promising compounds, one contained a 4.0/). Molbank 2021, 2021, M1184. https://doi.org/10.3390/M1184 https://www.mdpi.com/journal/molbank Molbank 2020, 2020, x FOR PEER REVIEW 2 of 4 Numerous chalcones reported in literature have exhibited inhibitory activity on pro- mastigotes and/or amastigotes of various Leishmania species [6,7,9,12]. In a study done by Ortalli et al. 31 chalcones were synthesized. Sixteen of them were found to be active against promastigotes of L. donovani. Out of the most promising compounds, one con- tained a fluorine as well as had low toxicity and high selectivity. Given the potential chal- cones have for effectively inhibiting the disease, our objective is to discover new chalcone- Molbank 2020, 2020, x FOR PEER REVIEW 2 of 4 based targets of opportunity that may lead to better treatments for leishmaniasis. Numerous chalcones reported in literature have exhibited inhibitory activity on pro- 2. Results mastigotes and/or amastigotes of various Leishmania species [6,7,9,12]. In a study done by Ortalli et al. 31 chalcones were synthesized. Sixteen of them were found to be active (E)-3-(4-Chlorophenyl)-1-(2-fluoro-4-methoxyphenyl)-2-propen-1-one 3 was synthe- Molbank 2021, 2021, M1184 against promastigotes of L. donovani. Out of the most promising compounds, 2one con of 4 - sized via a Claisen–Schmidt condensation (Scheme 1). The reaction was performed by tained a fluorine as well as had low toxicity and high selectivity. Given the potential chal- adding 4-chlorobenzadehyde 1, 2′-fluoro-4′-methoxyacetonphenone 2, and ethanol to a cones have for effectively inhibiting the disease, our objective is to discover new chalcone- round bottom flask at room temperature. Aqueous NaOH was added and allowed to stir based targets of opportunity that may lead to better treatments for leishmaniasis. fluorine as well as had low toxicity and high selectivity. Given the potential chalcones for 40 min. Optimization of purification methods resulted in the following yields: 78% have for effectively inhibiting the disease, our objective is to discover new chalcone-based 2. R tar esu gets ltsof opportunity that may lead to better treatments for leishmaniasis. with recrystallization using ethanol and 85% mixed solvent recrystallization EtOAc/hex- (E)-3-(4-Chlorophenyl)-1-(2-fluoro-4-methoxyphenyl)-2-propen-1-one 3 was synthe- anes. 2. Results sized via a Claisen–Schmidt condensation (Scheme 1). The reaction was performed by (E)-3-(4-Chlorophenyl)-1-(2-fluoro-4-methoxyphenyl)-2-propen-1-one 3 was synthe- adding 4-chlorobenzadehyde 1, 2′-fluoro-4′-methoxyacetonphenone 2, and ethanol to a sized via a Claisen–Schmidt condensation (Scheme 1). The reaction was performed by round bottom flask at room temperat 0 ure. Aq 0 ueous NaOH was added and allowed to stir adding 4-chlorobenzadehyde 1, 2 -fluoro-4 -methoxyacetonphenone 2, and ethanol to a for 40 min. Optimization of purification methods resulted in the following yields: 78% round bottom flask at room temperature. Aqueous NaOH was added and allowed to stir with recrystallization using ethanol and 85% mixed solvent recrystallization EtOAc/hex- for 40 min. Optimization of purification methods resulted in the following yields: 78% with recrystallization using ethanol and 85% mixed solvent recrystallization EtOAc/hexanes. anes. Scheme 1. Claisen–Schmidt condensation to form chalcone 3. 3. Discussion 1 13 The purified compound exhibited the expected spectroscopic signals ( H-NMR, C- Scheme 1. Claisen–Schmidt condensation to form chalcone 3. Scheme 1. Claisen–Schmidt condensation to form chalcone 3. NMR, IR, and ESI-MS) confirming the successful synthesis of chalcone 3. Using Figure 1 3. Discussion as reference, the H-NMR (CDCl3) spectrum shows confirmatory assignments such as the 3. Discussion 1 13 The purified compound exhibited the expected spectroscopic signals ( H-NMR, C- pair of doublets integrating as two hydrogens each for H1 and H2 (J = 8.4 Hz) and the H3 1 13 The purified compound exhibited the expected spectroscopic signals ( H-NMR, C- NMR, IR, and ESI-MS) confirming the successful synthesis of chalcone 3. Using Figure 1 and H4 J value of 15.6 Hz indicating a trans alkene geometry. In addition, both H3 and NMR, IR, and ESI-MS) confirming the successful synthesis of chalcone 3. Using Figure 1 as reference, the H-NMR (CDCl ) spectrum shows confirmatory assignments such as the 1 6 5 as re pair ferenc of doublets e, the H-NMR (CDCl integrating as two 3) spectr hydrogens um shows co each for H1 nfirm anda H2 tory as (J = 8.4 signments Hz) and the such as the H3 H4 have a small coupling to fluorine despite the coupling being a J and J, respectively. and H4 J value of 15.6 Hz indicating a trans alkene geometry. In addition, both H3 and H4 pair of doublets integrating as two hydrogens each for H1 and H2 (J = 8.4 Hz) and the H3 This long-range coupling is attributed to the conformation of chalcone 3. Specifically, the 6 5 have a small coupling to fluorine despite the coupling being a J and J, respectively. This and H4 J value of 15.6 Hz indicating a trans alkene geometry. In addition, both H3 and most stable conformation brings the fluorine in close spatial proximity to H3 and H4 re- long-range coupling is attributed to the conformation of chalcone 3. Specifically, the most 6 5 H4 have a small coupling to fluorine despite the coupling being a J and J, respectively. stable conformation brings the fluorine in close spatial proximity to H3 and H4 resulting in sulting in the long-range coupling. Positioning of H5, H6, and H7 were corroborated by This long-range coupling is attributed to the conformation of chalcone 3. Specifically, the the long-range coupling. Positioning of H5, H6, and H7 were corroborated by the J values 3 4 the J values of H5 and H6 to each other (8.7 Hz each) and the J of H6 and H7 (2.4 Hz most stable conformation brings the fluorine in close spatial proximity to H3 and H4 re- of H5 and H6 to each other (8.7 Hz each) and the J of H6 and H7 (2.4 Hz each). All spectra each). All spectra c sulting in t an be hfo e long-r und in ang the Supplementary Mater e coupling. Positioning of H5i, H6 als. , and H7 were corroborated by can be found in the Supplementary Materials. 3 4 the J values of H5 and H6 to each other (8.7 Hz each) and the J of H6 and H7 (2.4 Hz each). All spectra can be found in the Supplementary Materials. Figure 1. NMR assignment of chalcone 3. Figure 1. NMR assignment of chalcone 3. Figure 1. NMR assignment of chalcone 3. Notable confirmatory C-NMR signals include the , -unsaturated carbonyl peak (C7) at 186.9 ppm and the doublet of C9 with a coupling constant of 253 Hz indicative Notable confirmatory C-NMR signals include the α,β-unsaturated carbonyl peak Notable confirmatory C-NMR signals include the α,β-unsaturated carbonyl peak of an aryl fluoride. The vinylic carbons C5 and C6 were delineated by analyzing the (C7) at 186.9 ppm and the doublet of C9 with a coupling constant of 253 Hz indicative of (C7) at 186.9 ppm and the doublet of C9 with a coupling constant of 253 Hz indicative of shielding/deshielding effects of the various substituents. Such as the aryl chloride, which an aryl fluoride. The vinylic carbons C5 and C6 were delineated by analyzing the shield- an aryl fluoride. The vinylic carbons C5 and C6 were delineated by analyzing the shield- deshields C5 while also shielding C6. Furthermore, C2 and C3 were differentiated by ing/deshielding effects of the various substituents. Such as the aryl chloride, which evaluating the deshielding effects of carbonyl resonance. FT-IR exhibited the following sub- ing/deshielding effects of the various substituents. Such as the aryl chloride, which 1 1 deshields C5 while also shielding C6. Furthermore, C2 and C3 were differentiated by eval- stantiating signals: a sharp , unsaturated carbonyl stretch at 1658 cm and a 1587 cm deshields C5 while also shielding C6. Furthermore, C2 and C3 were differentiated by eval- + + alkene stretch. ESI-MS analysis shows an [M + Na] ion at 313 m/z, an [M + 1 + Na] at uating the deshielding effects of carbonyl resonance. FT-IR exhibited the following sub- uating the deshielding effects of carbon + yl resonance. FT-IR exhibite +d the following sub- −1 −1 314 m/z, an [M + 2 + Na] ion at 315 m/z, and an [M + 3 + Na] ion at 316 m/z. The stantiating signals: a sharp α,β unsaturated carbonyl stretch at 1658 cm and a 1587 cm + + −1 −1 ratio of [M + Na] to [M + 2 + Na] peaks are approximately 3:1, which further confirms stantiating signals: a sharp α,β unsaturated carbonyl stretch at 1658 cm and a 1587 cm alkene stretch. ESI-MS analysis shows an [M + Na]⁺ ion at 313 m/z, an [M + 1 + Na]⁺ at 314 the structure. alkene stretch. m E/S zI-M , an [ S M an + 2 + Na alysis] sh ⁺ ion ows an at 315 m [M /z, + Na and a]n⁺ i [M on + 3 + at 31 Na] 3 m⁺ i/ oz n a , an [M t 316 m + /z 1 + N . The rat a]i⁺o of [M at 314 + Na]⁺ to [M + 2 + Na]⁺ peaks are approximately 3:1, which further confirms the structure. m/z, an [M + 2 + Na]⁺ ion at 315 m/z, and an [M + 3 + Na]⁺ ion at 316 m/z. The ratio of [M + Na]⁺ to [M + 2 + Na]⁺ peaks are approximately 3:1, which further confirms the structure. Molbank 2021, 2021, M1184 3 of 4 4. Materials and Methods All chemicals, reagents, and solvents used were obtained from commercial sources (Sigma Aldrich, St. Louis, MO, USA and Fisher Scientific, Waltham, MA, USA) and used without further purification. Thin-layer chromatography (TLC) was used to monitor reactions and performed using aluminum sheets precoated with silica gel 60 (HF , Merck, Waltham, MA, USA), and visualized with UV radiation (Fisher Scientific, Waltham, MA, 1 13 USA). The product was characterized by H-NMR, C-NMR, IR, ESI-MS, and melting point analyses. IR spectra were recorded on a ThermoFisher iS5 FT-IR (Waltham, MA, USA). Melting point was determined in open capillaries using a Stuart SMP3 melting point apparatus 1 13 (Cole-Parmer, Vernon Hills, IL, USA). H and C-NMR spectra were collected using a 500 MHz Bruker AV-500 NMR spectrometer (NuMega Resonance Labs, San Diego, CA, USA). Spectra were referenced to residual CHCl . Chemical shifts were quoted in ppm and coupling constants (J) were recorded in hertz (Hz). Electrospray ionization (ESI) mass spectrum was acquired using a Perkin Elmer PE-SCIEX API-150 spectrometer (NuMega Resonance Labs, San Diego, CA, USA). A solution of aqueous NaOH (0.25 mL, 3.75 mmol, 15 M) was added to a round-bottom 0 0 flask containing 4-chlorobenzaldehyde 1 (0.351 g, 2.50 mmol), 2 -fluoro-4 -methoxyacetophenone 2 (0.420 g, 2.50 mmol), and ethanol (5 mL, anhydrous). The mixture was stirred at room temperature for 30 min (monitored by TLC in 10% EtOAc/hexanes and visualized with UV radiation) during which a yellow-white precipitate formed. The mixture was diluted with water (10 mL), neutralized with 1 M aq. HCl, then cooled to 0 C, and collected in vacuo, washing twice with ice-cold water (10 mL portions). The crude product was purified by recrystallization from hot ethyl acetate (5 mL) and hexane (10 mL) to yield pure chalcone 3 as light-yellow crystals (0.629 g, 2.13 mmol, 85%) and stored under inert atmosphere. (E)-3-(4-Chlorophenyl)-1-(2-fluoro-4-methoxyphenyl)-2-propen-1-one (3): mp 98–100 C; H-NMR (CDCl , 500 MHz): 7.89 ppm (1H, t, J = 8.7 Hz, H5), 7.72 ppm (1H, dd, 3 H-H J = 15.7 Hz, J = 2.0 Hz, H3), 7.55 ppm (2H, d, J = 8.4 Hz, H2), 7.43 ppm (1H, H-H H-F H-H dd, J = 15.6 Hz, J = 2.8 Hz, H4), 7.36 ppm (2H, d, J = 8.4 Hz, H1), 6.79 ppm H-H H-F H-H (1H, dd, J = 8.7 Hz, J = 2.4 Hz, H6), 6.65 ppm (1H, dd, J = 13 Hz, J = 2.4 Hz, H-H H-H H-F H-H H7), 3.87 ppm (3H, s, H8); C-NMR (CDCl , 125 MHz): 186.9 ppm (d, J = 3.7 Hz, C7), 164.8 ppm (d, J = 13 Hz, C11), 163.3 ppm (d, J = 253 Hz, C9) 142.5 ppm (C5), 136.5 ppm (C1), 133.7 ppm (C4), 132.9 ppm (d, J = 3.8 Hz, C13), 129.8 ppm (C3), 129.4 ppm (C2), 126.2 ppm (d, J = 8.8 Hz, C6), 119.6 ppm (d, J = 13 Hz, C8), 111.1 ppm (d, J = 1.25 Hz, C12), 1 1 102 ppm (d, J = 28 Hz, C10), 56.1 ppm (C14); FT-IR (KBr) 1658 cm (C=O), 1587 cm (C=C), 809 cm (Ar-Cl); MS (ESI) m/z calc for C H O FCl + Na 313; found 312.9, m/z 16 12 2 calc for C H O FCl+H 291; found 291.2. 16 12 2 1 13 Supplementary Materials: Copies of the H, C-NMR, IR, and MS spectra are available online. Author Contributions: Conceptualization, B.O.A.; methodology, B.O.A.; investigation, B.O.A., A.A. and N.B.; writing—original draft preparation, B.O.A., A.A. and N.B.; writing—review and editing, B.O.A., A.A. and N.B. All authors have read and agreed to the published version of the manuscript. Funding: This project was supported by grants from the National Institutes of Health (NIH), Na- tional Institute of General Medical Sciences (NIGMS), and IDeA Networks of Biomedical Research Excellence (INBRE), Award number: P20GM103466. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Data Availability Statement: The data presented in this study are available in the Supplementary Materials. Conflicts of Interest: The authors declare no conflict of interest. References 1. WHO. Leishmaniasis in high-burden countries: An epidemiological update based on data reported in 2014. Wkly. Epidemiol. Rec. 2016, 91, 287–296. 2. Savoia, D. Recent updates and perspectives on leishmaniasis. J. Infect. Dev. Ctries. 2015, 9, 588–596. [CrossRef] [PubMed] Molbank 2021, 2021, M1184 4 of 4 3. Pace, D. Leishmaniasis. J. Infect. 2014, 69 (Suppl. 1), S10–S18. [CrossRef] [PubMed] 4. Hotez, P.J.; Pecoul, B. “Manifesto” for advancing the control and elimination of neglected tropical diseases. PLoS Negl. Trop. Dis. 2010, 4, e718. [CrossRef] 5. Barbosa, J.F.; de Figueiredo, S.M.; Monteiro, F.M.; Rocha-Silva, F.; Gaciele-Melo, C.; Coelho, S.S.C.; Lyon, S.; Caligiorne, R.B. New approaches on leishmaniasis treatment and prevention: A review of recent patents. Recent Pat. Endocr. Metab. Immune Drug Discov. 2015, 9, 90–102. [CrossRef] [PubMed] 6. Hussain, T.; Zia-ur-Rehman, M.; Zaheer, M.; Ashraf, C.M.; Bolte, M. 1-[4-(1H-Imidazol-1-yl)phenyl]-3-phenylprop-2-en-1-ones—A potential pharmacophore bearing anti-leishmanial activity. J. Chem. Res. 2016, 40, 199–204. [CrossRef] 7. Hussain, T.; Siddiqui, H.L.; Zia-ur-Rehman, M.; Yasinzai, M.M.; Parvez, M. Anti-oxidant, anti-fungal and anti-leishmanial activities of novel 3-[4-(1H-imidazol-1-yl) phenyl]prop-2-en-1-ones. Eur. J. Med. Chem. 2009, 44, 4654–4660. [CrossRef] [PubMed] 8. Karthikeyan, C.; Moorthy, N.S.; Ramasamy, S.; Vanam, U.; Manivannan, E.; Karunagaran, D.; Trivedi, P. Advances in chalcones with anticancer activities. Recent Pat. Anti-Cancer Drug Discov. 2015, 10, 97–115. [CrossRef] [PubMed] 9. Ortalli, M.; Ilari, A.; Colotti, G.; Ionna, I.D.; Battista, T.; Bisi, A.; Gobbi, S.; Rampa, A.; Di Martino, R.M.C.; Gentilomi, G.A.; et al. Identification of chalcone-based antileishmanial agents targeting trypanothione reductase. Eur. J. Med. Chem. 2018, 152, 527–541. [CrossRef] [PubMed] 10. De Mello, M.V.P.; Abrahim-Vieira, B.A.; Domingos, T.F.S.; de Jesus, J.B.; de Souza, A.C.C.; Rodrigues, C.R.; de Souza, A.M.T. A comprehensive review of chalcone derivatives as antileishmanial agents. Eur. J. Med. Chem. 2018, 150, 920–929. [CrossRef] [PubMed] 11. Tajuddeen, N.; Isah, M.B.; Suleiman, M.A.; van Heerden, F.R.; Ibrahim, M.A. The chemotherapeutic potential of chalcones against leishmaniases: A review. Int. J. Antimicrob. Agents. 2018, 51, 311–318. [CrossRef] [PubMed] 12. Chen, M.; Christensen, S.B.; Blom, J.; Lemmich, E.; Nadelmann, L.; Fich, K.; Theander, T.G.; Kharazmi, A.; Licochalcone, A. A Novel Antiparasitic Agent with Potent Activity against Human Pathogenic Protozoan Species of Leishmania. Antimicrob. Agents Chemother. 1993, 37, 2550–2556. [CrossRef] [PubMed] http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Molbank Multidisciplinary Digital Publishing Institute

(E)-3-(4-Chlorophenyl)-1-(2-fluoro-4-methoxyphenyl)-2-propen-1-one

Bailey, Nicholas; Atanes, Alaina; Ashburn, Bradley O.
Molbank , Volume 2021 (1) – Jan 25, 2021
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molbank Short Note Nicholas Bailey , Alaina Atanes and Bradley O. Ashburn * Ashburn Group, Mathematics, Natural, and Health Sciences Division, University of Hawai‘i West O‘ahu, 91-1001 Farrington Hwy, Kapolei, HI 96707, USA; nmbailey@hawaii.edu (N.B.); aatanes@hawaii.edu (A.A.) * Correspondence: bashburn@hawaii.edu Abstract: Natural products known as chalcones show promise as chemotherapeutic agents for the neglected tropical disease known as leishmaniasis. Our objective is to synthesize new targets of oppor- tunity that may lead to better treatments of this debilitating disease. Claisen-Schmidt condensation 0 0 of 4-chlorobenzaldehyde with 2 -fluoro-4 -methoxyacetophenone using aqueous sodium hydrox- ide in ethanol yielded the novel compound (E)-3-(4-chlorophenyl)-1-(2-fluoro-4-methoxyphenyl)- 2-propen-1-one. The product was obtained in good yield and purity after recrystallization from ethyl acetate/hexane. With the known antiparasitic properties of halogenated chalcones, this novel compound is suitable for antileishmanial activity study. Keywords: chalcone; synthesis; aldol; leishmaniasis; neglected tropical disease 1. Introduction Leishmaniasis is the second largest parasitic killer behind malaria. The disease is caused by the flesh-eating protozoan parasite of the genus Leishmania and is transmitted through the bites of phlebotomine sandflies. There are three main forms of leishmaniasis: cutaneous, mucocutaneous, and visceral (kala-azar). Symptoms such as severe skin disfig- Citation: Bailey, N.; Atanes, A.; Ashburn, B.O. (E)-3-(4-Chlorophenyl) urement, scarring of the mouth and nose, and organ failure afflict over 1 million people -1-(2-fluoro-4-methoxyphenyl)-2- annually [1–3]. propen-1-one. Molbank 2021, 2021, The World Health Organization classifies leishmaniasis as a neglected tropical disease M1184. https://doi.org/ (NTD), meaning it occurs in tropical or subtropical regions of the Earth. The disease is 10.3390/M1184 endemic in Northern Africa, the Middle East, the Mediterranean, parts of Asia, and Central America; impacting those who live in poverty the most. These people typically do not Academic Editor: Fawaz Aldabbagh have the access, finances, or ability to obtain treatments, which need intravenous delivery Received: 8 December 2020 over multiple sessions, thus creating an unfortunate health disparity. The skin lesions Accepted: 21 January 2021 and disfiguration caused by the cutaneous and mucosal forms may result in individuals Published: 25 January 2021 becoming outcasts from their communities and could cause a significant reduction in quality of life. Publisher’s Note: MDPI stays neutral The areas affected are growing due to vector habitat increase from the warming global with regard to jurisdictional claims in climate; with more than 1 billion people in approximately 90 countries at risk of infection published maps and institutional affil- due to living in areas where leishmaniasis is endemic. There are no vaccines [4] and current iations. drug treatments suffer from toxicity, high cost, and poor efficacy [5]. Even after treatment, the parasite is not eradicated, it remains dormant in the body to potentially strike again. The discovery of new effective and affordable medications is imperative to improve the lives of millions worldwide. Fortunately, a group of natural products known as chal- Copyright: © 2021 by the authors. cones possess a diverse set of biological activities. These activities include antifungal [6,7], Licensee MDPI, Basel, Switzerland. antioxidant [7], and anticancer [8] activity. Recent literature has illustrated the potential This article is an open access article for chalcones as a new antileishmanial agent for all three forms of leishmaniasis [9–11]. distributed under the terms and Numerous chalcones reported in literature have exhibited inhibitory activity on promastig- conditions of the Creative Commons otes and/or amastigotes of various Leishmania species [6,7,9,12]. In a study done by Ortalli Attribution (CC BY) license (https:// et al. 31 chalcones were synthesized. Sixteen of them were found to be active against creativecommons.org/licenses/by/ promastigotes of L. donovani. Out of the most promising compounds, one contained a 4.0/). Molbank 2021, 2021, M1184. https://doi.org/10.3390/M1184 https://www.mdpi.com/journal/molbank Molbank 2020, 2020, x FOR PEER REVIEW 2 of 4 Numerous chalcones reported in literature have exhibited inhibitory activity on pro- mastigotes and/or amastigotes of various Leishmania species [6,7,9,12]. In a study done by Ortalli et al. 31 chalcones were synthesized. Sixteen of them were found to be active against promastigotes of L. donovani. Out of the most promising compounds, one con- tained a fluorine as well as had low toxicity and high selectivity. Given the potential chal- cones have for effectively inhibiting the disease, our objective is to discover new chalcone- Molbank 2020, 2020, x FOR PEER REVIEW 2 of 4 based targets of opportunity that may lead to better treatments for leishmaniasis. Numerous chalcones reported in literature have exhibited inhibitory activity on pro- 2. Results mastigotes and/or amastigotes of various Leishmania species [6,7,9,12]. In a study done by Ortalli et al. 31 chalcones were synthesized. Sixteen of them were found to be active (E)-3-(4-Chlorophenyl)-1-(2-fluoro-4-methoxyphenyl)-2-propen-1-one 3 was synthe- Molbank 2021, 2021, M1184 against promastigotes of L. donovani. Out of the most promising compounds, 2one con of 4 - sized via a Claisen–Schmidt condensation (Scheme 1). The reaction was performed by tained a fluorine as well as had low toxicity and high selectivity. Given the potential chal- adding 4-chlorobenzadehyde 1, 2′-fluoro-4′-methoxyacetonphenone 2, and ethanol to a cones have for effectively inhibiting the disease, our objective is to discover new chalcone- round bottom flask at room temperature. Aqueous NaOH was added and allowed to stir based targets of opportunity that may lead to better treatments for leishmaniasis. fluorine as well as had low toxicity and high selectivity. Given the potential chalcones for 40 min. Optimization of purification methods resulted in the following yields: 78% have for effectively inhibiting the disease, our objective is to discover new chalcone-based 2. R tar esu gets ltsof opportunity that may lead to better treatments for leishmaniasis. with recrystallization using ethanol and 85% mixed solvent recrystallization EtOAc/hex- (E)-3-(4-Chlorophenyl)-1-(2-fluoro-4-methoxyphenyl)-2-propen-1-one 3 was synthe- anes. 2. Results sized via a Claisen–Schmidt condensation (Scheme 1). The reaction was performed by (E)-3-(4-Chlorophenyl)-1-(2-fluoro-4-methoxyphenyl)-2-propen-1-one 3 was synthe- adding 4-chlorobenzadehyde 1, 2′-fluoro-4′-methoxyacetonphenone 2, and ethanol to a sized via a Claisen–Schmidt condensation (Scheme 1). The reaction was performed by round bottom flask at room temperat 0 ure. Aq 0 ueous NaOH was added and allowed to stir adding 4-chlorobenzadehyde 1, 2 -fluoro-4 -methoxyacetonphenone 2, and ethanol to a for 40 min. Optimization of purification methods resulted in the following yields: 78% round bottom flask at room temperature. Aqueous NaOH was added and allowed to stir with recrystallization using ethanol and 85% mixed solvent recrystallization EtOAc/hex- for 40 min. Optimization of purification methods resulted in the following yields: 78% with recrystallization using ethanol and 85% mixed solvent recrystallization EtOAc/hexanes. anes. Scheme 1. Claisen–Schmidt condensation to form chalcone 3. 3. Discussion 1 13 The purified compound exhibited the expected spectroscopic signals ( H-NMR, C- Scheme 1. Claisen–Schmidt condensation to form chalcone 3. Scheme 1. Claisen–Schmidt condensation to form chalcone 3. NMR, IR, and ESI-MS) confirming the successful synthesis of chalcone 3. Using Figure 1 3. Discussion as reference, the H-NMR (CDCl3) spectrum shows confirmatory assignments such as the 3. Discussion 1 13 The purified compound exhibited the expected spectroscopic signals ( H-NMR, C- pair of doublets integrating as two hydrogens each for H1 and H2 (J = 8.4 Hz) and the H3 1 13 The purified compound exhibited the expected spectroscopic signals ( H-NMR, C- NMR, IR, and ESI-MS) confirming the successful synthesis of chalcone 3. Using Figure 1 and H4 J value of 15.6 Hz indicating a trans alkene geometry. In addition, both H3 and NMR, IR, and ESI-MS) confirming the successful synthesis of chalcone 3. Using Figure 1 as reference, the H-NMR (CDCl ) spectrum shows confirmatory assignments such as the 1 6 5 as re pair ferenc of doublets e, the H-NMR (CDCl integrating as two 3) spectr hydrogens um shows co each for H1 nfirm anda H2 tory as (J = 8.4 signments Hz) and the such as the H3 H4 have a small coupling to fluorine despite the coupling being a J and J, respectively. and H4 J value of 15.6 Hz indicating a trans alkene geometry. In addition, both H3 and H4 pair of doublets integrating as two hydrogens each for H1 and H2 (J = 8.4 Hz) and the H3 This long-range coupling is attributed to the conformation of chalcone 3. Specifically, the 6 5 have a small coupling to fluorine despite the coupling being a J and J, respectively. This and H4 J value of 15.6 Hz indicating a trans alkene geometry. In addition, both H3 and most stable conformation brings the fluorine in close spatial proximity to H3 and H4 re- long-range coupling is attributed to the conformation of chalcone 3. Specifically, the most 6 5 H4 have a small coupling to fluorine despite the coupling being a J and J, respectively. stable conformation brings the fluorine in close spatial proximity to H3 and H4 resulting in sulting in the long-range coupling. Positioning of H5, H6, and H7 were corroborated by This long-range coupling is attributed to the conformation of chalcone 3. Specifically, the the long-range coupling. Positioning of H5, H6, and H7 were corroborated by the J values 3 4 the J values of H5 and H6 to each other (8.7 Hz each) and the J of H6 and H7 (2.4 Hz most stable conformation brings the fluorine in close spatial proximity to H3 and H4 re- of H5 and H6 to each other (8.7 Hz each) and the J of H6 and H7 (2.4 Hz each). All spectra each). All spectra c sulting in t an be hfo e long-r und in ang the Supplementary Mater e coupling. Positioning of H5i, H6 als. , and H7 were corroborated by can be found in the Supplementary Materials. 3 4 the J values of H5 and H6 to each other (8.7 Hz each) and the J of H6 and H7 (2.4 Hz each). All spectra can be found in the Supplementary Materials. Figure 1. NMR assignment of chalcone 3. Figure 1. NMR assignment of chalcone 3. Figure 1. NMR assignment of chalcone 3. Notable confirmatory C-NMR signals include the , -unsaturated carbonyl peak (C7) at 186.9 ppm and the doublet of C9 with a coupling constant of 253 Hz indicative Notable confirmatory C-NMR signals include the α,β-unsaturated carbonyl peak Notable confirmatory C-NMR signals include the α,β-unsaturated carbonyl peak of an aryl fluoride. The vinylic carbons C5 and C6 were delineated by analyzing the (C7) at 186.9 ppm and the doublet of C9 with a coupling constant of 253 Hz indicative of (C7) at 186.9 ppm and the doublet of C9 with a coupling constant of 253 Hz indicative of shielding/deshielding effects of the various substituents. Such as the aryl chloride, which an aryl fluoride. The vinylic carbons C5 and C6 were delineated by analyzing the shield- an aryl fluoride. The vinylic carbons C5 and C6 were delineated by analyzing the shield- deshields C5 while also shielding C6. Furthermore, C2 and C3 were differentiated by ing/deshielding effects of the various substituents. Such as the aryl chloride, which evaluating the deshielding effects of carbonyl resonance. FT-IR exhibited the following sub- ing/deshielding effects of the various substituents. Such as the aryl chloride, which 1 1 deshields C5 while also shielding C6. Furthermore, C2 and C3 were differentiated by eval- stantiating signals: a sharp , unsaturated carbonyl stretch at 1658 cm and a 1587 cm deshields C5 while also shielding C6. Furthermore, C2 and C3 were differentiated by eval- + + alkene stretch. ESI-MS analysis shows an [M + Na] ion at 313 m/z, an [M + 1 + Na] at uating the deshielding effects of carbonyl resonance. FT-IR exhibited the following sub- uating the deshielding effects of carbon + yl resonance. FT-IR exhibite +d the following sub- −1 −1 314 m/z, an [M + 2 + Na] ion at 315 m/z, and an [M + 3 + Na] ion at 316 m/z. The stantiating signals: a sharp α,β unsaturated carbonyl stretch at 1658 cm and a 1587 cm + + −1 −1 ratio of [M + Na] to [M + 2 + Na] peaks are approximately 3:1, which further confirms stantiating signals: a sharp α,β unsaturated carbonyl stretch at 1658 cm and a 1587 cm alkene stretch. ESI-MS analysis shows an [M + Na]⁺ ion at 313 m/z, an [M + 1 + Na]⁺ at 314 the structure. alkene stretch. m E/S zI-M , an [ S M an + 2 + Na alysis] sh ⁺ ion ows an at 315 m [M /z, + Na and a]n⁺ i [M on + 3 + at 31 Na] 3 m⁺ i/ oz n a , an [M t 316 m + /z 1 + N . The rat a]i⁺o of [M at 314 + Na]⁺ to [M + 2 + Na]⁺ peaks are approximately 3:1, which further confirms the structure. m/z, an [M + 2 + Na]⁺ ion at 315 m/z, and an [M + 3 + Na]⁺ ion at 316 m/z. The ratio of [M + Na]⁺ to [M + 2 + Na]⁺ peaks are approximately 3:1, which further confirms the structure. Molbank 2021, 2021, M1184 3 of 4 4. Materials and Methods All chemicals, reagents, and solvents used were obtained from commercial sources (Sigma Aldrich, St. Louis, MO, USA and Fisher Scientific, Waltham, MA, USA) and used without further purification. Thin-layer chromatography (TLC) was used to monitor reactions and performed using aluminum sheets precoated with silica gel 60 (HF , Merck, Waltham, MA, USA), and visualized with UV radiation (Fisher Scientific, Waltham, MA, 1 13 USA). The product was characterized by H-NMR, C-NMR, IR, ESI-MS, and melting point analyses. IR spectra were recorded on a ThermoFisher iS5 FT-IR (Waltham, MA, USA). Melting point was determined in open capillaries using a Stuart SMP3 melting point apparatus 1 13 (Cole-Parmer, Vernon Hills, IL, USA). H and C-NMR spectra were collected using a 500 MHz Bruker AV-500 NMR spectrometer (NuMega Resonance Labs, San Diego, CA, USA). Spectra were referenced to residual CHCl . Chemical shifts were quoted in ppm and coupling constants (J) were recorded in hertz (Hz). Electrospray ionization (ESI) mass spectrum was acquired using a Perkin Elmer PE-SCIEX API-150 spectrometer (NuMega Resonance Labs, San Diego, CA, USA). A solution of aqueous NaOH (0.25 mL, 3.75 mmol, 15 M) was added to a round-bottom 0 0 flask containing 4-chlorobenzaldehyde 1 (0.351 g, 2.50 mmol), 2 -fluoro-4 -methoxyacetophenone 2 (0.420 g, 2.50 mmol), and ethanol (5 mL, anhydrous). The mixture was stirred at room temperature for 30 min (monitored by TLC in 10% EtOAc/hexanes and visualized with UV radiation) during which a yellow-white precipitate formed. The mixture was diluted with water (10 mL), neutralized with 1 M aq. HCl, then cooled to 0 C, and collected in vacuo, washing twice with ice-cold water (10 mL portions). The crude product was purified by recrystallization from hot ethyl acetate (5 mL) and hexane (10 mL) to yield pure chalcone 3 as light-yellow crystals (0.629 g, 2.13 mmol, 85%) and stored under inert atmosphere. (E)-3-(4-Chlorophenyl)-1-(2-fluoro-4-methoxyphenyl)-2-propen-1-one (3): mp 98–100 C; H-NMR (CDCl , 500 MHz): 7.89 ppm (1H, t, J = 8.7 Hz, H5), 7.72 ppm (1H, dd, 3 H-H J = 15.7 Hz, J = 2.0 Hz, H3), 7.55 ppm (2H, d, J = 8.4 Hz, H2), 7.43 ppm (1H, H-H H-F H-H dd, J = 15.6 Hz, J = 2.8 Hz, H4), 7.36 ppm (2H, d, J = 8.4 Hz, H1), 6.79 ppm H-H H-F H-H (1H, dd, J = 8.7 Hz, J = 2.4 Hz, H6), 6.65 ppm (1H, dd, J = 13 Hz, J = 2.4 Hz, H-H H-H H-F H-H H7), 3.87 ppm (3H, s, H8); C-NMR (CDCl , 125 MHz): 186.9 ppm (d, J = 3.7 Hz, C7), 164.8 ppm (d, J = 13 Hz, C11), 163.3 ppm (d, J = 253 Hz, C9) 142.5 ppm (C5), 136.5 ppm (C1), 133.7 ppm (C4), 132.9 ppm (d, J = 3.8 Hz, C13), 129.8 ppm (C3), 129.4 ppm (C2), 126.2 ppm (d, J = 8.8 Hz, C6), 119.6 ppm (d, J = 13 Hz, C8), 111.1 ppm (d, J = 1.25 Hz, C12), 1 1 102 ppm (d, J = 28 Hz, C10), 56.1 ppm (C14); FT-IR (KBr) 1658 cm (C=O), 1587 cm (C=C), 809 cm (Ar-Cl); MS (ESI) m/z calc for C H O FCl + Na 313; found 312.9, m/z 16 12 2 calc for C H O FCl+H 291; found 291.2. 16 12 2 1 13 Supplementary Materials: Copies of the H, C-NMR, IR, and MS spectra are available online. Author Contributions: Conceptualization, B.O.A.; methodology, B.O.A.; investigation, B.O.A., A.A. and N.B.; writing—original draft preparation, B.O.A., A.A. and N.B.; writing—review and editing, B.O.A., A.A. and N.B. All authors have read and agreed to the published version of the manuscript. Funding: This project was supported by grants from the National Institutes of Health (NIH), Na- tional Institute of General Medical Sciences (NIGMS), and IDeA Networks of Biomedical Research Excellence (INBRE), Award number: P20GM103466. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Data Availability Statement: The data presented in this study are available in the Supplementary Materials. Conflicts of Interest: The authors declare no conflict of interest. References 1. WHO. Leishmaniasis in high-burden countries: An epidemiological update based on data reported in 2014. Wkly. Epidemiol. 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