As part of our research for new leads against human African trypanosomiasis (HAT),\nwe report on a 3D-QSAR study for antitrypanosomal activity and cytotoxicity of aminosteroid-type\nalkaloids recently isolated from the African medicinal plant Holarrhena africana A. DC. (Apocynaceae),\nsome of which are strong trypanocides against Trypanosoma brucei rhodesiense (Tbr), with low toxicity\nagainst mammalian cells. Fully optimized 3D molecular models of seventeen congeneric Holarrhena\nalkaloids were subjected to a comparative molecular field analysis (CoMFA). CoMFA models were\nobtained for both, the anti-Tbr and cytotoxic activity data. Model performance was assessed in\nterms of statistical characteristics (R2, Q2, and P2 for partial least squares (PLS) regression, internal\ncross-validation (leave-one-out), and external predictions (test set), respectively, as well as the\ncorresponding standard deviation error in prediction (SDEP) and F-values). With R2 = 0.99, Q2 = 0.83\nand P2 = 0.79 for anti-Tbr activity and R2 = 0.94, Q2 = 0.64, P2 = 0.59 for cytotoxicity against L6 rat\nskeletal myoblasts, both models were of good internal and external predictive power. The regression\ncoefficients of the models representing the most prominent steric and electrostatic effects on anti-Tbr\nand for L6 cytotoxic activity were translated into contour maps and analyzed visually, allowing\nsuggestions for possible modification of the aminosteroids to further increase the antitrypanosomal\npotency and selectivity. Very interestingly, the 3D-QSAR model established with the Holarrhena\nalkaloids also applied to the antitrypanosomal activity of two aminocycloartane-type compounds\nrecently isolated by our group from Buxus sempervirens L. (Buxaceae), which indicates that these\nstructurally similar natural products share a common structureââ?¬â??activity relationship (SAR) and,\npossibly, mechanism of action with the Holarrhena steroids. This 3D-QSAR study has thus resulted in\nplausible structural explanations of the antitrypanosomal activity and selectivity of aminosteroidand\naminocycloartane-type alkaloids as an interesting new class of trypanocides and may represent\na starting point for lead optimization.
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