Synthesis, Structural Determination, and Pharmacology of Putative Dinitroaniline Antimalarials

del Casino, Alessio, Lukinovic, Valentina, Bhatt, Rakesh, Randle, Laura E ORCID: 0000-0002-7881-2979, Dascombe, Michael J, Fennell, Brian J, Drew, Michael GB, Bell, Angus, Fielding, Alistair J and Ismail, Fyaz MD (2018) Synthesis, Structural Determination, and Pharmacology of Putative Dinitroaniline Antimalarials. CHEMISTRYSELECT, 3 (26). pp. 7572-7580.

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Official URL: http://dx.doi.org/10.1002/slct.201801723

Abstract

<jats:title>Abstract</jats:title><jats:p>A series of novel, homologous compounds possessing the general formula <jats:italic>N</jats:italic><jats:sup><jats:italic>1</jats:italic></jats:sup>‐<jats:italic>N</jats:italic><jats:sup><jats:italic>n</jats:italic></jats:sup>‐bis(2,6‐dinitro‐4‐trifluormethylphenyl)‐1,<jats:italic>n</jats:italic>‐diamino alkanes (where <jats:italic>n</jats:italic>=4, 6, 10 or 12), were designed to probe inter‐ and intra‐ binding site dimensions in malarial parasite (<jats:italic>Plasmodium</jats:italic>) tubulin. Various crystal structures, including chloralin and trifluralin, an isopropyl dimer, and 2,6‐dinitro‐4‐trifluoromethyl‐phenylamine, were determined. Dinitroanilines, when soluble, were evaluated both in culture and <jats:italic>in</jats:italic> <jats:italic>vivo</jats:italic>. Trifluralin was up to 2‐fold more active than chloralin against cultured parasites. The isopropyl dimer was water soluble (>5 mM) and revealed activity superior to that of chloralin in culture. The effects of selected dinitroanilines upon the mitotic microtubular structures of <jats:italic>Plasmodium</jats:italic>, the putative target of these dinitroanilines, were also determined. Electronic properties of the molecules were calculated using DFT (B3LYP/6‐31+G* level) to ascertain whether incorporation of such a pharmacophore could allow both QSAR and rational development of more selectively toxic antiparasitic agents.</jats:p>

Item Type:	Article
Uncontrolled Keywords:	antimalarial, chloralin, trifluralin, DFT, X-ray
Depositing User:	Symplectic Admin
Date Deposited:	03 Dec 2019 10:00
Last Modified:	19 Sep 2023 00:28
DOI:	10.1002/slct.201801723
Open Access URL:	http://researchonline.ljmu.ac.uk/id/eprint/9016/
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3064584