Abstract/Summary

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.