Isobenzofurans as conformationally constrained miconazole analogs with improved antifungal potency

• Published in: Journal of medicinal chemistry 1992-10, Vol.35 (22), p.4221-4229
• Main Authors: Lovey, Raymond G, Elliott, Arthur J, Kaminski, James J, Loebenberg, David, Parmegiani, Raulo M, Rane, D. F, Girijavallabhan, Viyyoor M, Pike, Russel E, Guzik, Henry
• Format: Article
• Language: English
• Subjects: Animals; Antifungal Agents - chemical synthesis; Antifungal Agents - pharmacology; Benzofurans - chemical synthesis; Benzofurans - pharmacology; Candida; Candidiasis - drug therapy; Chemistry; Computer Simulation; Cricetinae; Exact sciences and technology; Female; Guinea Pigs; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Mice; Miconazole - analogs & derivatives; Miconazole - chemical synthesis; Miconazole - pharmacology; Microbial Sensitivity Tests; Models, Molecular; Molecular Conformation; Organic chemistry; Preparations and properties; Structure-Activity Relationship; Tinea - drug therapy
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00100a030

A series of halogen-substituted isobenzofuran analogues was synthesized, which represented conformationally constrained analogues of miconazole (1). In vitro and in vivo topical antifungal activity against both dermatophytes and Candida species varied widely, but 13c proved to be significantly superior to both 1 and clotrimazole against a vaginal Candida infection in hamsters, while 13b was significantly more active than 1 against a a topical Trichophyton infection in guinea pigs. None of the compounds were orally active. When the most direct analogue of 1 proved to be among the least active, a molecular modeling study was done using 1, the two active analogues 13b and 13c, and the inactive analogue 13a. All four compounds possessed skeletally similar conformations either at or energetically readily accessible from the global minimum energy conformations. This common conformation of the inactive analogue 13a, however, occupies unique molecular volume space associated with two chlorine atoms, which must also present unique electrostatic properties at the receptor. The conformation-activity relationships discussed may contribute toward deduction of additional structural requirements for pharmacophore optimization and more efficacious antifungal drugs.