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Topliss Method in the Optimization of Salicylic Acid Derivatives as Potential Antimycobacterial Agents
Author(s) -
Silva Márcia da,
Menezes Carla Maria Souza,
Ferreira Elizabeth Igne,
Leite Clarice Queico Fujimura,
Sato Daisy Nakamura,
Correia Cristiane Cardoso,
Pimenta Carolina Pereira,
Botelho Kátia Cirlene Alves
Publication year - 2008
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2007.00621.x
Subject(s) - antimycobacterial , chemistry , partition coefficient , salicylic acid , computational chemistry , stereochemistry , molecular descriptor , acid dissociation constant , quantitative structure–activity relationship , combinatorial chemistry , organic chemistry , mycobacterium tuberculosis , biochemistry , aqueous solution , medicine , tuberculosis , pathology
The Topliss method was used to guide a synthetic path in support of drug discovery efforts toward the identification of potent antimycobacterial agents. Salicylic acid and its derivatives, p ‐chloro, p ‐methoxy, and m ‐chlorosalicylic acid, exemplify a series of synthetic compounds whose minimum inhibitory concentrations for a strain of Mycobacterium were determined and compared to those of the reference drug, p ‐aminosalicylic acid. Several physicochemical descriptors (including Hammett’s sigma constant, ionization constant, dipole moment, Hansch constant, calculated partition coefficient, Sterimol‐ L and ‐B 4 and molecular volume) were considered to elucidate structure–activity relationships. Molecular electrostatic potential and molecular dipole moment maps were also calculated using the AM1 semi‐empirical method. Among the new derivatives, m ‐chlorosalicylic acid showed the lowest minimum inhibitory concentration. The overall results suggest that both physicochemical properties and electronic features may influence the biological activity of this series of antimycobacterial agents and thus should be considered in designing new p ‐aminosalicylic acid analogs.