Relationships between Molecular Properties and Antimycobacterial Activities of Steroids

Progesterone ( 1 ), cholesterol ( 2 ), stigmasterol ( 3 ), ergosterol endoperoxide ( 4 ), sitosterol ( 5 ), betulin ( 6 ), fusidic acid ( 7 ), chondrilasterol ( 8 ), and ergosterol ( 9 ) have been evaluated against Mycobacterium tuberculosis H37Rv. The maximum antimycobacterial activity seemed to depend on hydrophobicity and the type of substituents on the phytyl moiety on steroidal backbone. The variation in activity was rationalized using quantitative structure-activity relationship (QSAR) models based on several molecular descriptors including van der Waals surface area (VDW A ), van der Waals volume (VDW v ), polarizability, dipole moment, logP, and the differences between the Highest Occupied Molecular Orbital and the Lowest Unoccupied Molecular Orbital (HOMO-LUMO gap). The proposed QSAR models could be developed to predict the antimycobacterial activity of structurally similar steroids and to create a priority list for testing so that time, money, and effort can be focused on the potentially most promising steroids. The implications of QSAR data for the rational design of new antituberculosis agents are discussed. Because mycobacteria degrade steroids to progesterone-type compounds, unambiguous assignments of the high-field proton ( 1 H) and carbon-13 ( 13 C) NMR data of progesterone ( 1 ) were achieved through a combination of modern one- and two-dimensional (2D) NMR techniques.