Issue 26, 2024

Designing novel anti-plasmodial quinoline–furanone hybrids: computational insights, synthesis, and biological evaluation targeting Plasmodium falciparum lactate dehydrogenase

Abstract

To combat resistance against current antimalarials, modifying key pharmacophores and exploring novel parasite-specific drug targets remained one of the key drug design strategies. The resistance to quinoline-based antimalarials arises often due to the efflux of the drug. Hence, the development of newer agents containing bulkier pharmacophores will enable medicinal chemists to counteract drug resistance. In view of this, herein we designed bulkier quinoline–furanone hybrids. Initially, virtual drug-likeness and ADMET screening were conducted to optimize physicochemical properties followed by docking of the hybrids against the Plasmodium falciparum lactate dehydrogenase (PfLDH) enzyme. The most potent hybrids that emerged from the computational screening were synthesized and screened for their bioactivity against the resistant strain of Plasmodium through Schizont Maturation Inhibition assays. Among the compounds tested, 5g and 6e demonstrated the best activity, with IC50 values similar to chloroquine (CQ), and 5g exhibited superior LDH inhibition compared to CQ. Compounds 5f, 7a, and 7f showed IC50 values comparable to CQ and moderate LDH inhibition. Structure–activity relationship (SAR) analysis revealed that halogen substitutions, particularly Br and Cl, enhanced antimalarial activity, while strong electron-withdrawing (–NO2) or -donating (–OH) groups led to diminished activity. Additionally, bulkier aromatic substitutions were favoured for antimalarial activity and LDH inhibition. The investigation successfully found potent anti-plasmodial quinoline–furanone hybrids, demonstrating promising prospects for combating malaria.

Graphical abstract: Designing novel anti-plasmodial quinoline–furanone hybrids: computational insights, synthesis, and biological evaluation targeting Plasmodium falciparum lactate dehydrogenase

Supplementary files

Article information

Article type
Paper
Submitted
08 Mar 2024
Accepted
04 Jun 2024
First published
12 Jun 2024
This article is Open Access
Creative Commons BY-NC license

RSC Adv., 2024,14, 18764-18776

Designing novel anti-plasmodial quinoline–furanone hybrids: computational insights, synthesis, and biological evaluation targeting Plasmodium falciparum lactate dehydrogenase

D. Choudhary, P. Rani, N. K. Rangra, G. K. Gupta, S. L. Khokra, R. R. Bhandare and A. B. Shaik, RSC Adv., 2024, 14, 18764 DOI: 10.1039/D4RA01804D

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