A Ligand-Based Approach to Lead Optimization of N, Nʹ-Substituted Diamines for Leishmanicidal Activity

Abstract

Several N, N-substituted diamines such as putrescine and N-monoalkylated derivatives have demonstrated potential as lead compounds against Leishmania donovani at submicromolar levels. There is a need to refine available diamines for enhanced leishmanicidal activity. A 3D-QSAR by Comparative molecular field analysis (CoMFA) on a series of tested diamines for their activities against L. donovani was conducted to understand better the mechanism of action and SARs of the compounds. The model was constructed with AM1 energy minimized conformers of the training set compounds (n=20) by the PLS algorithm method, cross-validated by the method of leave-one-out (LOO), and externally validated using the test set compounds (n=5). A robust model with high predictability of untested compounds was obtained for 2PC (latent variables). The coefficients of determinations for PLS regression R2, internal cross-validation, Q2 and external prediction P2 were 0.97 (SDEC=0.095), 0.82 (SDEP=0.102) and 0.73 (SDEP=0.115) respectively with F-value 618.8 for 2PC. The model coefficients graphically translated into contour maps showed regions where steric (62 %) and electrostatic (38 %) properties influence the leishmanicidal activity of the compounds. In addition to the optimum chain length (n=4), a steric effect at position 4 alone or combined with the electrostatic effect at position 3 of the diamine backbone significantly enhanced the leishmanicidal activity. It could further be explored for even higher activity. The model supported the empirical data, which identified N, N'-substituted diamine as the scaffold for leishmanicidal activities and further provided insights for further optimization of the lead compound.