Larvicidal activity, molecular docking, and molecular dynamics studies of 7-(trifluoromethyl)indolizine derivatives against Anopheles arabiensis

Harshada Rambaboo Singh; Priya Tiwari; Pran Kishore Deb; Gourav Rakshit; Prasenjit Maity; Viresh Mohanlall; Raquel M Gleiser; Katharigatta N Venugopala; Sandeep Chandrashekharappa

doi:10.1007/s11030-024-10994-7

Larvicidal activity, molecular docking, and molecular dynamics studies of 7-(trifluoromethyl)indolizine derivatives against Anopheles arabiensis

Mol Divers. 2024 Oct 8. doi: 10.1007/s11030-024-10994-7. Online ahead of print.

Authors

Harshada Rambaboo Singh¹, Priya Tiwari¹, Pran Kishore Deb², Gourav Rakshit³, Prasenjit Maity³, Viresh Mohanlall⁴, Raquel M Gleiser⁵, Katharigatta N Venugopala^{4

6}, Sandeep Chandrashekharappa⁷

Affiliations

¹ Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research Raebareli, Near CRPF Base Camp, Transit Campus, Bijnor-Sisendi Road, Sarojini Nagar, Lucknow, UP, 226002, India.
² Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology (BIT), Mesra, Ranchi, Jharkhand, 835215, India. prankishoredeb@bitmesra.ac.in.
³ Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology (BIT), Mesra, Ranchi, Jharkhand, 835215, India.
⁴ Department of Biotechnology and Food Science, Faculty of Applied Sciences, Durban University of Technology, Durban, 4000, South Africa.
⁵ CREAN-IMBIV (UNC-CONICET), Universidad Nacional de Cordoba, Av. Valparaiso s.n., and FCEFyN, Av. V. Sarsfield 299, 5000, Cordoba, Argentina.
⁶ Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, 31982, Al-Ahsa, Saudi Arabia.
⁷ Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research Raebareli, Near CRPF Base Camp, Transit Campus, Bijnor-Sisendi Road, Sarojini Nagar, Lucknow, UP, 226002, India. c.sandeep@niperraebareli.edu.in.

PMID: 39377893
DOI: 10.1007/s11030-024-10994-7

Abstract

A novel series of 7-(trifluoromethyl)indolizine derivatives (4a-4n) was synthesized using a 1,3-Dipolar cycloaddition reaction. Structure elucidation of the synthesized compounds was done using various spectroscopic techniques. Compounds were assessed for their larvicidal activity against Anopheles arabiensis. Exposure of Anopheles arabiensis larvae to a series of 7-(trifluoromethyl)indolizine at 4 µg/mL for 24 and 48 h resulted in moderate to high larval mortality rates. Among them, compounds 4b, 4a, 4g, and 4m exhibited the most promising larvicidal activities, with mortality rates of 94.4%, 93.3%, 80.00%, and 85.6%, respectively, compared to controls, Acetone and Temephos. The structural activity relationship analysis of the evaluated compounds revealed that substitution with halogens or electron-withdrawing groups (CN, F, Cl, Br) at the para position of the benzoyl group is crucial for achieving promising larvicidal activity. Molecular docking studies were carried out involving six potential larvicidal target proteins to predict how the tested compounds might work. Compounds 4a and 4b showed strong binding to the Mosquito Juvenile Hormone-Binding Protein (5V13). Molecular dynamics (MD) simulations confirmed the stability of the protein-ligand complexes over the simulation period, reinforcing the reliability of the docking results. Compounds 4a and 4b also exhibited favourable ADMET profiles, showing high oral bioavailability, good permeability, moderate distribution, low plasma protein binding, sufficient metabolic stability, efficient renal clearance and low toxicity. Given the crucial role of Juvenile Hormone in regulating gene expression and developmental pathways through receptor interactions, compounds 4a and 4b show promise as inhibitors of this protein. Inhibiting this process could hinder larval growth and reproduction, presenting a promising approach for early-stage mosquito larvicidal activity. Therefore, compounds 4a and 4b represent lead candidates for further optimization and the development of new larvicidal agents.

Keywords: Anopheles arabiensis; Characterization; Indolizine; Larvicidal activity; Malaria; Mosquito Juvenile Hormone-Binding Protein; Synthesis.