phenanthrenes and Tuberculosis

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) based on three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were conducted on a series (44 compounds) of diaryloxy-methano-phenanthrene derivatives as potent antitubercular agents. The best predictions were obtained with a CoMFA standard model (q (2)=0.625, r (2)=0.994) and with CoMSIA combined steric, electrostatic, and hydrophobic fields (q (2)=0.486, r (2)=0.986). Both models were validated by a test set of seven compounds and gave satisfactory predictive r (2) values of 0.999 and 0.745, respectively. CoMFA and CoMSIA contour maps were used to analyze the structural features of the ligands to account for the activity in terms of positively contributing physicochemical properties: steric, electrostatic, and hydrophobic fields. The information obtained from CoMFA and CoMSIA 3-D contour maps can be used for further design of phenanthrene-based analogs as anti-TB agents. The resulting contour maps, produced by the best CoMFA and CoMSIA models, were used to identify the structural features relevant to the biological activity in this series of analogs. Further analysis of these interaction-field contour maps also showed a high level of internal consistency. This study suggests that introduction of bulky and highly electronegative groups on the basic amino side chain along with decreasing steric bulk and electronegativity on the phenanthrene ring might be suitable for designing better antitubercular agents.

Topics: Antitubercular Agents; Binding Sites; Chemical Phenomena; Chemistry, Pharmaceutical; Chemistry, Physical; Computer Simulation; Drug Design; Humans; Models, Chemical; Models, Molecular; Molecular Conformation; Phenanthrenes; Protein Binding; Quantitative Structure-Activity Relationship; Static Electricity; Tuberculosis

A new series of diaryloxy methano phenanthrenes were prepared through tertiary-aminoalkylations of [(methoxy-phenyl)-phenanthren-9-yl-methyl]-phenols obtained from Friedel-Crafts alkylations on (methoxy-phenyl)-phenanthren-9-yl-methanols. These series of compounds were evaluated against Mycobacterium tuberculosis H37Rv and showed the desired activity in the range of 6.25 microg/mL in vitro. One of the compound 12j protects the mice from the challenge of M. tuberculosis in vivo, as 30% of the mice were survived at treatment of 50 mg/kg body weight.

Topics: Animals; Antitubercular Agents; Female; Mice; Mycobacterium tuberculosis; Phenanthrenes; Tuberculosis

Topics: Animals; Carbon Dioxide; Cortisone; Female; Guinea Pigs; Hypersensitivity; Lipoproteins; Mycobacterium; Phagocytosis; Phenanthrenes; Tuberculosis

Topics: Antitubercular Agents; Chelating Agents; Chromium; Copper; Iron; Mycobacterium tuberculosis; Naphthalenes; Naphthols; Phenanthrenes; Tuberculosis