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.

Keywords:

• 1,2,3-Triazole
• isooxazoline
• isoxazole
• antileishmanial activity
• molecular dynamics

Acknowledgements

The author JP-DJ acknowledges the Ministry of Education, Science and Technological Development of the Republic of Serbia for the support (Grant No. 451-03-9/2021-14/200026). S. Goumri-Said thank the office of research at Alfaisal University in Saudi Arabia for funding this research work through internal project number C20431.

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.