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Isobenzofurans as conformationally constrained miconazole analogs with improved antifungal potency

Isobenzofurans as conformationally constrained miconazole analogs with improved antifungal potency. Lovey, Raymond G.; Elliott, Arthur J.; Kaminski, James J.; Loebenberg, David; Parmegiani, Raulo M. 34824-58-3 which is the cas registry number of some chemical is mentioned.; Rane, D. F.; Girijavallabhan, Viyyoor M.; Pike, Russel E.; Guzik, Henry; et al. (Schering-Plough Res. Inst., Bloomfield, NJ 07003, USA). J. Med. Chem., 35(22), 4221-9 (English) 1992. CODEN: JMCMAR. ISSN: 0022-2623. DOCUMENT TYPE: Journal CA Section: 28 (Heterocyclic Compounds (More Than One Hetero Atom)) Section cross-reference(s): 10 A series of halogen-substituted isobenzofuran analogs I (R, R1 = H, Cl; R2 = H, Cl, F; R3 = H, Cl, F, Ph; Z = CH, N) was synthesized, which represented conformationally constrained analogs to miconazole (II). In vitro and in vivo topical antifungal activity against both dermatophytes and Candida species varied widely, but I (R = R1 = H, R2 = R3 = Cl, Z = CH) (III) proved to be significantly superior to both II and clotrimazole against a vaginal Candida infection in hamsters, while I (R-R2 = H, R3 = Cl, Z = CH) (IV) was significantly more active than II against a a topical Trichophyton infection in guinea pigs. None of the compds. were orally active. When the most direct analog of II proved to be among the least active, a mol. modeling study was done using II, the two active analogs IV and III, and the inactive analog I (R-R3 = Cl). All four compds. possessed skeletally similar conformations either at or energetically readily accessible from the global min. energy conformations. This common conformation of the inactive analog I (R-R3 = Cl), however, occupies unique mol. vol. space assocd. with two chlorine atoms, which must also present unique electrostatic properties at the receptor. The conformation-activity relationships discussed may contribute toward deduction of addnl. structural requirements for pharmacophore optimization and more efficacious antifungal drugs. .