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.
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 |
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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: | |
URI: | https://livrepository.liverpool.ac.uk/id/eprint/3064584 |