ANTICONVULSANT PHENYTOINERGIC PHARMACOPHORES AND ANTI-HIV ACTIVITY - PRELIMINARY EVIDENCE FOR THE DUAL REQUIREMENT OF THE 4-AMINOPHTHALIMIDE PLATFORM AND THE N-(1-ADAMANTYL) SUBSTITUTION FOR ANTIVIRAL PROPERTIES

This work is aimed at further exploring the concept that phenytoin-rel ated compounds' might present with an anti-HIV potential. We screened for anti-HIV activity, selected compounds whose structural design rest s on pharmacophores successfully shown to convey phenytoinergic antico nvulsant activity. We determined the corresponding anticonvulsant prot ective doses in mice via the ip route of administration using the maxi mal electroshock seizure test (a test in which the anticonvulsant acti vity of phenytoin is well expressed). Firstly, 4-aminophthalimide phar macophores were utilized with either N-(2,6-dimethyl)phenyl or N-(1-ad amantyl) substitutions. While the former was found to be highly potent , the latter was devoid of significant activity. Secondly, the pharmac ophores N-(2,6-dimethylphenyl)phthalimide and N-(l-adamantyl)phthalimi de were compared for antiviral (antiHIV-1 and antiHIV-2) properties in CEM (human T-lymphocyte) cells infected with HIV-1 or HIV-2 strains. Various phthalimide C-4-substitutions (H, NO2, NH2, Cl, CH3, OCH3, COO H) of these pharmacophores were studied. From this set of experiments, 4-amino-N-(1-adamantyl)phthalimide emerged with EC50 (effective conce ntration-50) values of 16 and 27 mu M against HIV-1 and HIV-2, respect ively. The CC50 (cytostatic concentration-50) of this compound was 30 mu M. Thirdly, the N-(2,6-dimethylphenyl) and N-(l-adamantyl) substitu tions of the 4-aminobenzamide pharmacophore (another known phenytoiner gic anticonvulsant platform) were shown to be devoid of anti-HIV activ ities. A similar negative result was obtained for amantadine. Taken as a whole, the present data indicate that both the 4-aminophthalimide p harmacophore and N-(l-adamantyl) substitutions are required for anti-H IV properties. Molecular modeling studies further provide clues for th is dual requirement. (C) 1998 Elsevier Science Inc.