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Structure–activity relationship of a series of 1,2-dihydroquinoline analogues and binding mode with Vibrio cholerae dihydrofolate reductase

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Abstract

Cholera is a reemerging disease caused by Vibrio cholerae that can occasion severe dehydration and death if it is not appropriately treated. The irrational use of antibiotics has led to emergence and dissemination of resistant strains; thus, the development of new antibiotics is required. The aim of this study was to establish a structure–activity relationship analysis of a series of 1,2-dihydroquinoline analogues described in the literature as dihydrofolate reductase (DHFR) inhibitors and evaluate their binding mode. Herein, some stereoelectronic properties were found to be correlated with the antibacterial activity such as molecular weight, molecular area, volume, ovality, polar surface area and highest occupied molecular orbital (HOMO) energy, besides HOMO location and the electronic distribution profile. A three-dimensional model of V. cholerae DHFR was constructed using Swiss Model Server, and molecular docking of the most potent and less potent 1,2-dihydroquinoline analogues of the series was carried out using AutoDock 4.2 program. The results showed a similar binding mode of the most potent inhibitors with the antibiotic trimethoprim, and some interactions with the DHFR seemed to be important as hydrogen bonds with E28, van der Waals contacts with F32, M51 and hydrophobic interactions with the pocket comprised of residues Q29, G52, K53 and L54. Therefore, our study provides new insights into inhibition of V. cholerae DHFR which may be used to guide the rational design of new antibiotic agents.

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Acknowledgments

The Brazilian agencies: National Counsel of Technological and Scientific Development—(Conselho Nacional de Desenvolvimento Científico e Tecnológico, CNPq). Vítor Won-Held Rabelo was supported by a scholarship from PIBIC/CNPq.

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  1. Laboratório de Modelagem Molecular e Pesquisa em Ciências Farmacêuticas, LaMCiFar, Universidade Federal do Rio de Janeiro, Campus Macaé Professor Aloísio Teixeira, Macaé, RJ, 27965-045, Brazil

    Vítor W. Rabelo & Paula A. Abreu

  2. Universidade Federal do Rio de Janeiro, Campus Macaé Professor Aloísio Teixeira, Macaé, RJ, 27930-560, Brazil

    Thienne F. Sampaio, Lívia D. Duarte & Desirée H. B. Lopes

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  1. Vítor W. Rabelo
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  2. Thienne F. Sampaio
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Correspondence to Paula A. Abreu.

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Rabelo, V.W., Sampaio, T.F., Duarte, L.D. et al. Structure–activity relationship of a series of 1,2-dihydroquinoline analogues and binding mode with Vibrio cholerae dihydrofolate reductase. Med Chem Res 25, 1524–1537 (2016). https://doi.org/10.1007/s00044-016-1583-1

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