Terbinafine is a therapeutically used inhibitor of fungal squalene epoxidase that has prompted extensive derivatization programs for structure-activity relationship studies. In the present study, derivatives of terbinafine were synthesized that lack the central tertiary amino group but have polar substitutents at the tert-butyl residue of the side chain. Evaluation of the antifungal potential revealed that representatives of this novel structural type can also exhibit broad antifungal activity, indicating that the central amino function of allylamine antimycotics is not essential for inhibition of fungal growth. Potency appears to correlate with the polarity of the introduced functional groups, while broad antifungal activity seems to be restricted to compounds with basic substituents. The dimethylamino-substituted "carba-analog" of terbinafine (8k) showed the best antimycotic profile within the whole series.
Dedicated to Dr. G. Ohloff on the occasion of his 70th birthday (28 .IX. 94)The conformational parameters responsible for sandalwood odor were investigated by the 'active-analog approach'. The pharmacophoric (osmophoric) pattern of sandalwood-odor molecules can be outlined as three points: the OH group (point PI), a lipophilic group (point P2) 2.9-3.0 A distant from the OH group, and a bulky rigid group (point P3), represented as a dummy atom in the middle of the alicyclic system (norbornane bicycle or cyclopentene ring) or a quaternary C-atom. This concept was tested on a series of representative sandalwood-odor compounds and on some structurally similar, but odorless substances.
Derivatives of the allylamine antimycotic terbinafine (1) with varied substitution at the naphthalene ring system have been prepared, and their antifungal activity has been evaluated. In general, the potency is strongly dependent on the bulkiness of the substituent. Only hydrogen or in some cases fluorine are tolerated as substituents at positions 2-4 and 6-8 of the naphthalene moiety, whereas 5-substituents may be larger in size (F, Cl, Br, Me). Derivatives with fluorine at positions 3, 5, and 7 or chlorine at position 5 showed enhanced activity against yeasts relative to 1. This increase in sensitivity could be intensified by simultaneous introduction of two fluoro substituents at positions 5 and 7. Compound 7q demonstrated 8- to 16-fold improved potency against Aspergillus fumigatus, Candida albicans, and Candida parapsilosis.
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