Synthesis of hydrazinyl–thiazole ester derivatives, in vitro trypanocidal and leishmanicidal activities
Abstract
Aim: To synthesize novel more potent trypanocidal and leishmanicidal agents. Methods: Hantzsch’s synthetic strategy was used to synthesize 1,3-thiazole-4-carboxylates and their N-benzylated derivatives. Results: 28 new thiazole-carboxylates and their N-benzylated derivatives were established to test their trypanocidal and leishmanicidal activities. From both series, compounds 3b, 4f, 4g, 4j and 4n exhibited a better or comparable trypanocidal profile to benznidazole. Among all tested compounds, 4n was found to be the most potent and was better than benznidazole. Conclusion: Further variation of substituents around 1,3-thiazole-4-carboxylates and or hydrazinyl moiety may assist in establishing better and more potent trypanocidal and leishmanicidal agents.
Plain language summary
Chagas disease and leishmaniasis are neglected tropical diseases. Herein, 28 1,3-thiazoles have been synthesized from thiosemicarbazones in a rapid, efficient and cost-effective manner. In vitro assays were performed against intracellular amastigotes of Trypanosoma cruzi (T. cruzi) and promastigotes and intracellular amastigote forms of Leishmania infantum (L. infantum) and Leishmania amazonensis (L. amazonensis). Some of the 1,3-thiazole-4-carboxylates inhibited the amastigote form of T. cruzi without affecting macrophage viability, compound 4n being the most potent and better than benznidazole. Our synthesized compounds exhibited promising activity against T. cruzi, thus broadening options for scaffold and lead compound optimization. Concerning the leishmanicidal activity, compound 4g was the best prototype in terms of potency and selectivity. Compounds 4g and 3m showed moderate selectivity and potency against intracellular amastigotes of L. amazonensis and L. infantum, respectively.
Synthesis of thiazole-based derivatives by Hantzsch's approach and their trypanocidal and leishmanicidal activities.
Graphical abstract
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. . Trypanosomatids are much more than just trypanosomes: clues from the expanded family tree. Trends Parasitol. 6(34), 466–480 (2018).
- 2. World Health Organization. The NTD road map: together towards 2030. who.int/neglected_diseases/diseases/ • WHO report about neglected tropical diseases.
- 3. . A profile of research on the parasitic trypanosomatids and the diseases they cause. PLOS Negl. Trop. Dis. 1(16), e0010040 (2022).
- 4. . Biological factors that impinge on Chagas disease drug development. Parasitology 14(144), 1871–1880 (2017).
- 5. . Current advances in drug discovery for Chagas disease. Eur. J. Med. Chem. 155, 824–838 (2018). • Review about discovery of different drugs/derivatives for Chagas disease.
- 6. A practical green synthesis and biological evaluation of benzimidazoles against two neglected tropical diseases: Chagas and leishmaniasis. Curr. Med. Chem. 24(41), 4714–4725 (2017).
- 7. . Heterocycles in the treatment of neglected tropical diseases. Curr. Med. Chem. 3(28), 472–495 (2021). • Very important review about the applications of different heterocycles for the treatment of neglected tropical diseases.
- 8. Benzopyrazine-based small molecule inhibitors as trypanocidal and leishmanicidal agents: green synthesis, in vitro, and in silico evaluations. Front. Chem. 9, 725892 (2021).
- 9. Design, synthesis and in vitro trypanocidal and leishmanicidal activities of 2-(2-arylidene)hydrazono-4-oxothiazolidine-5-acetic acid derivatives. ChemistrySelect 45(4), 13163–13172 (2019). •• Inspired us to establish more potent trypanocidal and leishmanicidal agents.
- 10. The design, synthesis, and in vitro trypanocidal and leishmanicidal activities of 1,3-thiazole and 4-thiazolidinone ester derivatives. RSC Adv. 4(11), 2487–2500 (2021). •• Helped us to establish more accurate structure–activity relationships for trypanocidal and leishmanicidal targets.
- 11. Synthesis, antioxidant, antimicrobial and antiviral docking studies of ethyl 2-(2-(arylidene)hydrazinyl)thiazole-4-carboxylates. Z. Naturforsch. C. J. Biosci. 11–12(76), 467–480 (2021). •• Helped us to synthesize our current thiazole derivatives.
- 12. . Synthesis, spectroscopic characterization and crystallographic behavior of ethyl 2-(4-methyl-(2-benzylidenehydrazinyl))thiazole-4-carboxylate: experimental and theoretical (DFT) studies. J. Mol. Struct. 1167, 154–160 (2018).
- 13. Synthesis, spectroscopic, SC-XRD characterizations and DFT based studies of ethyl 2-(substituted-(2-benzylidenehydrazinyl))thiazole-4-carboxylate derivatives. J. Mol. Struct. 1187, 164–171 (2019).
- 14. Aryl thiosemicarbazones: in vitro and immunomodulatory activities against L. amazonensis. Exp. Parasitol. 177, 57–65 (2017).
- 15. Synthesis, spectroscopic characterization, single crystal XRD, Hirshfeld surface analysis and theoretical studies (DFT) of 4-adamantyl-(2-(substitutedbenzylidene)hydrazinyl)thiazoles. J. Mol. Struct. 1267, 133620 (2022).
- 16. Synthesis, characterization and DFT calculated properties of electron-rich hydrazinylthiazoles: experimental and computational synergy. J. Mol. Struct. 1245, 131043 (2021).
- 17. Synthesis, crystal structure, Hirshfeld surface investigation and comparative DFT studies of ethyl 2-[2-(2-nitrobenzylidene)hydrazinyl]thiazole-4-carboxylate. BMC Chem. 16, 18 (2022).
- 18. Synthesis, crystal structure, spectroscopic, electronic and nonlinear optical properties of potent thiazole based derivatives: joint experimental and computational insight. J. Mol. Struct. 1202, 127354 (2020).
- 19. Design, and synthesis of selectively anticancer 4-cyanophenyl substituted thiazol-2-ylhydrazones. RSC Adv. 12, 34126 (2022). •• Helped us to establish our current derivatives via Hantzsch’s synthetic strategy.
- 20. Alkyl 2-(2-(arylidene)alkylhydrazinyl)thiazole-4-carboxylates: synthesis, acetyl cholinesterase inhibition and docking studies. J. Mol. Struct. 1245, 131063 (2021).
- 21. Synthesis and in silico docking studies of ethyl 2-(2-arylidene-1-alkylhydrazinyl)thiazole-4-carboxylates as antiglycating agents. Chem. Biodivers. 19, e202100581 (2022). •• Helped us to develop N-benzyalted thiazole-4-carboxylates.
- 22. . Efficient technique for screening drugs for activity against Trypanosoma cruzi using parasites expressing beta-galactosidase. Antimicrob. Agents Chemother. 40, 2592–2597 (1996).
- 23. In vitro and in vivo experimental models for drug screening and development for Chagas disease. Mem. Inst. Oswaldo Cruz 105, 233–238 (2010).
- 24. Structural improvement of new thiazolyl-isatin derivatives produces potent and selective trypanocidal and leishmanicidal compounds. Chem. Biol. Interact. 345, 109561 (2021).