3D QSAR on a library of heterocyclic diamidine derivatives with antiparasitic activity

African trypanosomes, Trypanosoma brucei rhodesiense (TBR) and Trypanosoma brucei gambiense (TBG), affect hundreds of thousands of lives in tropical regions of the world. The toxicity of the diamidine pentamidine, an effective drug against TBG, necessitates the design of better drugs. An orally effective prodrug of the diamidine, furamidine (DB75), presently scheduled for phase III clinical trials, has excellent activity against TBG with toxicity lower than that of pentamidine. As part of an effort to develop additional and improved diamidines against African trypanosomes, CoMFA and CoMSIA 3D QSAR analyses have been conducted with furamidine and a set of 25 other structurally related compounds. Two different alignment strategies, based on a putative kinetoplast DNA minor groove target, were used. Due to conserved electrostatic properties across the Compounds, models that used only steric and electronic properties did not perform well in predicting biological results. An extended CoMSIA model with additional descriptors for hydrophobic, donor, and acceptor properties had good predictive ability with a q(2) = 0.699 r(2) = 0.974, SEE, standard error of estimate = 0.1, and F = 120.04. The results have been used as a guide to design Compounds that, potentially, have better activity against African trypanosomes. (c) 2006 Elsevier Ltd. All rights reserved.