title: Topliss method in the optimization of salicylic Acid derivatives as potential antimycobacterial agents.
abstract: 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 -B4 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.
authors.affiliation: Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista-UNESP, PB 502, ZIP 14801-902, Araraquara, SP, Brazil. silvam@fcfar.unesp.br
authors.forename: Márcia
authors.initials: M
authors.lastname: da Silva
authors.forename: Carla Maria Souza
authors.initials: CM
authors.lastname: Menezes
authors.forename: Elizabeth Igne
authors.initials: EI
authors.lastname: Ferreira
authors.forename: Clarice Queico Fujimura
authors.initials: CQ
authors.lastname: Leite
authors.forename: Daisy Nakamura
authors.initials: DN
authors.lastname: Sato
authors.forename: Cristiane Cardoso
authors.initials: CC
authors.lastname: Correia
authors.forename: Carolina Pereira
authors.initials: CP
authors.lastname: Pimenta
authors.forename: Kátia Cirlene Alves
authors.initials: KC
authors.lastname: Botelho
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry*; D015195:Drug Design; D008722:Methods; D008826:Microbial Sensitivity Tests; D009161:Mycobacterium / Q000187:drug effects*; D020156:Salicylic Acid / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D020156:Salicylic Acid