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Synthesis of hydrazinyl–thiazole ester derivatives, in vitro trypanocidal and leishmanicidal activities

    Muhammad Haroon

    Department of Chemistry & Biochemistry, Miami University, 651 E High Street, Oxford, OH 45056, USA

    ,
    Tashfeen Akhtar

    *Author for correspondence:

    E-mail Address: tashfeenchem@must.edu.pk

    Department of Chemistry, Mirpur University of Science & Technology (MUST), 10250-Mirpur (AJK), Pakistan

    ,
    Hasnain Mehmood

    Department of Chemistry, Mirpur University of Science & Technology (MUST), 10250-Mirpur (AJK), Pakistan

    ,
    Aline C da Silva Santos

    Aggeu Magalhães Institute, Fundação Oswaldo Cruz, 50670-420, Recife, PE, Brazil

    ,
    Juliana M da Conceição

    Department of Pharmaceutical Sciences, Health Sciences Centre, Federal University of Pernambuco, 50740-520, Recife, PE, Brazil

    ,
    Graziella Leite Brondani

    Department of Pharmaceutical Sciences, Health Sciences Centre, Federal University of Pernambuco, 50740-520, Recife, PE, Brazil

    ,
    Robert da Silva Tibúrcio

    Department of Pharmaceutical Sciences, Health Sciences Centre, Federal University of Pernambuco, 50740-520, Recife, PE, Brazil

    ,
    Danilo C Galindo Bedor

    Department of Pharmaceutical Sciences, Health Sciences Centre, Federal University of Pernambuco, 50740-520, Recife, PE, Brazil

    ,
    José W Viturino da Silva

    Department of Pharmaceutical Sciences, Health Sciences Centre, Federal University of Pernambuco, 50740-520, Recife, PE, Brazil

    ,
    Policarpo A Sales Junior

    Aggeu Magalhães Institute, Fundação Oswaldo Cruz, 50670-420, Recife, PE, Brazil

    ,
    Valeria R Alves Pereira

    Aggeu Magalhães Institute, Fundação Oswaldo Cruz, 50670-420, Recife, PE, Brazil

    &
    Ana C Lima Leite

    **Author for correspondence:

    E-mail Address: ana.lleite@ufpe.br

    Department of Pharmaceutical Sciences, Health Sciences Centre, Federal University of Pernambuco, 50740-520, Recife, PE, Brazil

    Published Online:https://doi.org/10.4155/fmc-2023-0255

    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

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