Design, biologic evaluation, and SAR of novel pseudo-peptide incorporating benzheterocycles as HIV-1 protease inhibitors.

摘要: A series of novel HIV-1 protease inhibitors based on the (hydroxyethylamino)-sulfonamide isostere incorporating substituted phenyls and benzheterocycle derivatives bearing rich hydrogen bonding acceptors as P2 ligands were synthesized. Prolonged chain linking benzhereocycle to carbonyl group resulted in partial loss binding affinities. Introduction a small alkyl substituent with appropriate size -CH2- P1-P2 linkage side improved inhibitory potency, this study, isopropyl was best chain. Replacement isobutyl at P1′group phenyl decreased potency. One most potent inhibitor, compound 23 showing high affinity an IC50 value 5 nm, also exhibited good anti-SIV activity (EC50 = 0.8 μm) low toxicity (TC50 > 100 μm). The flexible docking inhibitor active site rationalized interactions protease.