Antimicrobial Activity of Nitrogen-Containing 5-α-Androstane Derivatives: In Silico and Experimental Studies

We evaluated the antimicrobial activity of thirty-one nitrogen-containing 5-α-androstane derivatives in silico using computer program PASS (Prediction of Activity Spectra for Substances) and freely available PASS-based web applications (such as Way2Drug). Antibacterial activity was predicted for 27 out of 31 molecules; antifungal activity was predicted for 25 out of 31 compounds. The results of experiments, which we conducted to study the antimicrobial activity, are in agreement with the predictions. All compounds were found to be active with MIC (Minimum Inhibitory Concentration) and MBC (Minimum Bactericidal Concentration) values in the range of 0.0005–0.6 mg/mL. The activity of all studied 5-α-androstane derivatives exceeded or was equal to those of Streptomycin and, except for the 3β-hydroxy-17α-aza-d-homo-5α-androstane-17-one, all molecules were more active than Ampicillin. Activity against the resistant strains of E. coli, P. aeruginosa, and methicillin-resistant Staphylococcus aureus was also shown in experiments. Antifungal activity was determined with MIC and MFC (Minimum Fungicidal Concentration) values varying from 0.007 to 0.6 mg/mL. Most of the compounds were found to be more potent than the reference drugs Bifonazole and Ketoconazole. According to the results of docking studies, the putative targets for antibacterial and antifungal activity are UDP-N-acetylenolpyruvoylglucosamine reductase and 14-α-demethylase, respectively. In silico assessments of the acute rodent toxicity and cytotoxicity obtained using GUSAR (General Unrestricted Structure-Activity Relationships) and CLC-Pred (Cell Line Cytotoxicity Predictor) web-services were low for the majority of compounds under study, which contributes to the chances for those compounds to advance in the development.

Computational modeling of distribution coefficients and their correlations with pharmacokinetic properties of 17α-picolyl and 17(E)-picolinylidene androstane derivatives

The present study describes the computational modeling of distribution coefficient (logD) of 17?-picolyl and 17(E)-picolinylidene androstane derivatives, as a group of compounds with significant anticancer activities. The determination of logD is practically important for estimation and prediction of pharmacokinetic and pharmacodynamic behavior of compounds in a living organism and it is related to blood-brain barrier permeability, skin permeability, gastrointestinal absorption, binding to plasma proteins, etc. These features are crucial for the determination of potential drug candidates as well. The results presented in this study include determination of pH versus logD profiles, pH versus molecular charge profiles and determination of isoelectric point of eleven 17?- picolyl androstane derivatives and thirteen 17(E)-picolinylidene androstane derivatives. Since the pH of the organism differs depending on the organ (for example, the pH of the blood is significantly different from the pH of the stomach), these profiles are significant because they indicate in what form the molecule will exist and how it will be distributed between different phases at certain pH value. The influence of tautomerization and resonance was taken into account during the modeling of logD parameters. Eventually, the correlations between logD values and specific absorption, distribution, metabolism, and excretion (ADME) properties, such as human intestinal absorption (HIA) and permeability of heterogeneous human epithelial colorectal adenocarcinoma cells (Caco-2), were determined.

Evaluation of A-ring fused pyridine d-modified androstane derivatives for antiproliferative and aldo–keto reductase 1C3 inhibitory activity

New A-ring pyridine fused androstanes in d-homo lactone, 17α-picolyl or 17(E)-picolinylidene series were synthesized and validated.