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Novel 3-chloro-6-nitro-1H-indazole derivatives as promising antileishmanial candidates: synthesis, biological activity, and molecular modelling studies.

ABSTRACT: An efficient pathway was disclosed for the synthesis of 3-chloro-6-nitro-1H-indazole derivatives by 1,3-dipolar cycloaddition on dipolarophile compounds 2 and 3. Faced the problem of separation of two regioisomers, a click chemistry method has allowed us to obtain regioisomers of triazole-1,4 with good yields from 82 to 90% were employed. Also, the antileishmanial biological potency of the compounds was achieved using an MTT assay that reported compound 13 as a promising growth inhibitor of Leishmania major. Molecular docking demonstrated highly stable binding with the Leishmania trypanothione reductase enzyme and produced a network of hydrophobic and hydrophilic interactions. Molecular dynamics simulations were performed for TryR-13 complex to understand its structural and intermolecular affinity stability in a biological environment. The studied complex remained in good equilibrium with a structure deviation of ∼1-3 Å. MM/GBSA binding free energies illustrated the high stability of TryR-13 complex. The studied compounds are promising leads for structural optimisation to enhance the antileishmanial activity.

SUBMITTER: Mohamed Abdelahi MM

PROVIDER: S-EPMC8667887 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Novel 3-chloro-6-nitro-1H-indazole derivatives as promising antileishmanial candidates: synthesis, biological activity, and molecular modelling studies.

Mohamed Abdelahi Mohamed Mokhtar MM El Bakri Youness Y Lai Chin-Hung CH Subramani Karthikeyan K Anouar El Hassane EH Ahmad Sajjad S Benchidmi Mohammed M Mague Joel T JT Popović-Djordjević Jelena J Goumri-Said Souraya S

Journal of enzyme inhibition and medicinal chemistry 20221201 1

An efficient pathway was disclosed for the synthesis of 3-chloro-6-nitro-1H-indazole derivatives by 1,3-dipolar cycloaddition on dipolarophile compounds 2 and 3. Faced the problem of separation of two regioisomers, a click chemistry method has allowed us to obtain regioisomers of triazole-1,4 with good yields from 82 to 90% were employed. Also, the antileishmanial biological potency of the compounds was achieved using an MTT assay that reported compound 13 as a promis ...[more]

PMID: 34894940

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Project description:Leishmaniasis is a parasitic disease caused by protozoan organisms belonging to the Leishmania genus, affecting many individuals worldwide, with the burden surpassing one million cases. This disease leads to considerable morbidity and mortality, predominantly within tropical and subtropical regions. The current therapeutic options for leishmaniasis are far from ideal, as they fail to achieve a level of efficacy that can be deemed universally effective. The primary drawbacks of existing treatments include severe side effects, substantial toxicity, high financial costs, extended treatment regimens, and the discomfort associated with injectable forms of administration. Additionally, the growing issue of drug resistance presents a formidable challenge, further complicating disease management and control efforts. In light of these limitations, developing new therapeutic agents that can effectively disrupt the parasite's life cycle at multiple stages is of paramount importance. This study endeavors to address this critical need by focusing on the design and synthesis of a series of novel compounds. Fifteen derivatives incorporating the nitrochromene pharmacophore were meticulously synthesized using the Henry reaction. After synthesizing these derivatives, a comprehensive evaluation of their biological activity against L. tropica was undertaken. This assessment employed both in vitro techniques to directly observe the compounds' effects on the parasite and in silico methods, specifically molecular docking studies, to predict and analyze the interaction between the synthesized compounds and various target proteins of the parasite. The dual approach of combining experimental and computational methods aims to provide a robust understanding of the compounds' mechanisms of action and their potential as effective anti-leishmanial agents. This integrative strategy not only enhances the reliability of the findings but also offers valuable insights that could guide future drug development efforts in combating leishmaniasis.

Dataset Information

Novel 3-chloro-6-nitro-1H-indazole derivatives as promising antileishmanial candidates: synthesis, biological activity, and molecular modelling studies.

Publications

Novel 3-chloro-6-nitro-1<i>H</i>-indazole derivatives as promising antileishmanial candidates: synthesis, biological activity, and molecular modelling studies.

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