Sterol‐hydrazone derivatives as inhibitors of the fungal Δ24_sterol methyl transferase

Fungal sterols differ from vertebrate ones in the presence of an extra alkyl group at C‐24, whose insertion is catalyzed by Δ (24) ‐sterol methyl transferase (SMT). We report the syntheses of four sterol hydrazones (SH): 20‐hydrazone‐imidazol‐2‐yl‐5α‐pregnan‐3ß‐ol (H1), 20‐hydrazone‐pyridin‐2‐yl‐5α‐pregnan‐3ß‐ol (H2), 22‐hydrazone‐imidazol‐2‐yl‐5‐colen‐3ß‐ol (H3), and 22‐hydrazone‐pyridin‐2‐yl‐5‐colen‐3ß‐ol (H4), and their antiproliferative effects on the yeast phase of the fungal pathogen Paracoccidioides brasiliensis. SH inhibited in the sequence: H4 (IC 50 : 0.075 μM) >H3 (IC 50 : 0.1 μM) >H2 (IC 50 : 1 μM) = H1 (IC 50 : 1 μM). On exposure to SH, ergosterol decreased (76% ‐ 20%), lanosterol accumulated (19% – 50%), and 24‐methyl sterols were depleted, as evidence of selective SMT inhibition and functional requirement of 24‐alkyl substituents. Theoretical studies by MEP, LIP, and Isopotential Electrostatic Energy Surfaces revealed no correlation with activities. The different hybridization of nitrogen atoms in the sterol's side chain strongly increased the amount of electrons available for interaction with the positively charged S‐methyl group or the sulfur atom in S‐adenosyl methionine. The addition of a methylene group at the C‐22 of the side chain induced a more significant change in the antiproliferative effect than the introduction of a highly polar group (electron‐rich N atoms in imine and amine groups, in five‐ or six‐membered rings). These results point to the selectivity of SH as potential antifungal drugs. Source of research support: Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela