Synthesis, Structural Determination, and Pharmacology of Putative Dinitroaniline Antimalarials
| Autor: | Rakesh Bhatt, Alistair J. Fielding, Michael G. B. Drew, Michael J. Dascombe, Alessio del Casino, Angus Bell, Laura E. Randle, Brian J. Fennell, Fyaz M.D. Ismail, Valentina Lukinović |
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| Jazyk: | angličtina |
| Předmět: |
0301 basic medicine
Quantitative structure–activity relationship RM biology 010405 organic chemistry Stereochemistry Dimer Dinitroaniline Trifluralin General Chemistry 01 natural sciences Antiparasitic agent 0104 chemical sciences RS 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology Tubulin chemistry biology.protein Pharmacophore Isopropyl |
| ISSN: | 2365-6549 |
| Popis: | A series of novel, homologous compounds possessing the general formula N1‐Nn‐bis(2,6‐dinitro‐4‐trifluormethylphenyl)‐1,n‐diamino alkanes (where n=4, 6, 10 or 12), were designed to probe inter‐ and intra‐ binding site dimensions in malarial parasite (Plasmodium) 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 in vivo. 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 Plasmodium, 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. |
| Databáze: | OpenAIRE |
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