Abstract
As part of our research for new leads against human African trypanosomiasis (HAT), we report on a 3D-QSAR study for antitrypanosomal activity and cytotoxicity of aminosteroid-type alkaloids recently isolated from the African medicinal plant Holarrhena africana A. DC. (Apocynaceae), some of which are strong trypanocides against Trypanosoma brucei rhodesiense (Tbr), with low toxicity against mammalian cells. Fully optimized 3D molecular models of seventeen congeneric Holarrhena alkaloids were subjected to a comparative molecular field analysis (CoMFA). CoMFA models were obtained for both, the anti-Tbr and cytotoxic activity data. Model performance was assessed in terms of statistical characteristics (R2, Q2, and P2 for partial least squares (PLS) regression, internal cross-validation (leave-one-out), and external predictions (test set), respectively, as well as the corresponding standard deviation error in prediction (SDEP) and F-values). With R2 = 0.99, Q2 = 0.83 and P2 = 0.79 for anti-Tbr activity and R2 = 0.94, Q2 = 0.64, P2 = 0.59 for cytotoxicity against L6 rat skeletal myoblasts, both models were of good internal and external predictive power. The regression coefficients of the models representing the most prominent steric and electrostatic effects on anti-Tbr and for L6 cytotoxic activity were translated into contour maps and analyzed visually, allowing suggestions for possible modification of the aminosteroids to further increase the antitrypanosomal potency and selectivity. Very interestingly, the 3D-QSAR model established with the Holarrhena alkaloids also applied to the antitrypanosomal activity of two aminocycloartane-type compounds recently isolated by our group from Buxus sempervirens L. (Buxaceae), which indicates that these structurally similar natural products share a common structure–activity relationship (SAR) and, possibly, mechanism of action with the Holarrhena steroids. This 3D-QSAR study has thus resulted in plausible structural explanations of the antitrypanosomal activity and selectivity of aminosteroid- and aminocycloartane-type alkaloids as an interesting new class of trypanocides and may represent a starting point for lead optimization.
Highlights
Understanding the structure–activity relationships (SARs) of bioactive molecules is a crucial prerequisite for lead optimization and further drug development
The mechanism of action and biological target for the antitrypanosomal activities of these compounds are still unknown and quantitative structure–activity relationships (QSAR) studies may represent the first step towards a better understanding of their promising bioactivity
The comparative molecular field analysis (CoMFA) method, originally developed with a set of steroids [5], has frequently been applied to numerous steroids and various biological endpoints [6,7,8,9,10,11,12,13], so that it appeared straightforward to apply it to the present set of alkaloids with pregnane and pregnene scaffolds
Summary
Understanding the structure–activity relationships (SARs) of bioactive molecules is a crucial prerequisite for lead optimization and further drug development. We described some elementary structure–activity relationships, already perceived when comparing the structures and biological potency of the compounds. The mechanism of action and biological target for the antitrypanosomal activities of these compounds are still unknown and quantitative structure–activity relationships (QSAR) studies may represent the first step towards a better understanding of their promising bioactivity. The variations in substitution of the steroid core and a reasonable number of molecules in our set make it appear feasible to capture the most relevant structure–activity associations for both the antitrypanosomal as well as the cytotoxic activity using a 3D-QSAR method such as CoMFA, which could, in future studies, be used to attempt predictions for (semi-) synthetic modifications to further optimize the activity profile
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