title: Design, biologic evaluation, and SAR of novel pseudo-peptide incorporating benzheterocycles as HIV-1 protease inhibitors.
abstract: 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 P(2) ligands were synthesized. Prolonged chain linking the benzhereocycle to the carbonyl group resulted in partial loss of binding affinities. Introduction of a small alkyl substituent with appropriate size to the -CH2- of P(1)-P(2) linkage as a side chain resulted in improved inhibitory potency, and in this study, isopropyl was the best side chain. Replacement of the isobutyl substituent at P(1)'group with phenyl substituent decreased the inhibitory potency. One of the most potent inhibitor, compound 23 showing high affinity to HIV-1 protease with an IC(50) value of 5 nM, also exhibited good anti-SIV activity (EC(50) = 0.8 microM) with low toxicity (TC(50) > 100 microM). The flexible docking of inhibitor 23 to HIV-1 protease active site rationalized the interactions with protease.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100083, China.
authors.forename: Meizi
authors.initials: M
authors.lastname: He
authors.forename: Hang
authors.initials: H
authors.lastname: Zhang
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Yao
authors.forename: Michael
authors.initials: M
authors.lastname: Eckart
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Zuo
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020134:Catalytic Domain; D002460:Cell Line; D003198:Computer Simulation; D015195:Drug Design; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000882:Haplorhini; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D010455:Peptides / Q000737:chemistry; D015301:Retroviruses, Simian / Q000187:drug effects; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry
chemical_list: D001583:Benzoxazoles; D017320:HIV Protease Inhibitors; D006571:Heterocyclic Compounds; D010455:Peptides; D013449:Sulfonamides; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1