3D-QSAR-based design, synthesis and biological evaluation of 2,4-disubstituted quinoline derivatives as antimalarial agents

ABSTRACT

2,4-Disubstituted quinoline derivatives were designed based on a 3D-QSAR study, synthesized and evaluated for antimalarial activity. A large dataset of 178 quinoline derivatives was used to perform a 3D-QSAR study using CoMFA and CoMSIA models. PLS analysis provided statistically validated results for CoMFA (r²_ncv = 0.969, q² = 0.677, r²_cv = 0.682) and CoMSIA (r²_ncv = 0.962, q² = 0.741, r²_cv = 0.683) models. Two series of a total of 40 2,4-disubstituted quinoline derivatives were designed with amide (quinoline-4-carboxamide) and secondary amine (4-aminoquinoline) linkers at the -C4 position of the quinoline ring. For the purpose of selecting better compounds for synthesis with good pEC₅₀ values, activity prediction was carried out using CoMFA and CoMSIA models. Finally, a total of 10 2,4-disubstituted quinoline derivatives were synthesized, and screened for their antimalarial activity based on the reduction of parasitaemia. Compound #5 with amide linker and compound #19 with secondary amine linkers at the -C4 position of the quinoline ring showed maximum reductions of 64% and 57%, respectively, in the level of parasitaemia. In vivo screening assay confirmed and validated the findings of the 3D-QSAR study for the design of quinoline derivatives.

KEYWORDS:

• 3D-QSAR
• quinoline derivatives
• CoMFA
• CoMSIA
• antimalarial agents

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Acknowledgements

The authors would like to thank Nirma University, Ahmedabad, India for providing the necessary facilities.

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No potential conflict of interest was reported by the author(s).

Supplementary material

Supplemental data for this article can be accessed at: https://doi.org/10.1080/1062936X.2023.2247326

Correction Statement

This article was originally published with errors, which have now been corrected in the online version. Please see Correction (http://dx.doi.org/10.1080/1062936X.2024.2312758)

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Funding

The author(s) reported there is no funding associated with the work featured in this article.