ABSTRACT
We presented our continuing stride to optimize the second-generation NBD entry antagonist targeted to the Phe43 cavity of HIV-1 gp120. We have synthesized thirty-eight new and novel analogs of NBD-14136, earlier designed based on a CH2OH "positional switch" hypothesis, and derived a comprehensive SAR. The antiviral data confirmed that the linear alcohol towards the "N" (C4) of the thiazole ring yielded more active inhibitors than those towards the "S" (C5) of the thiazole ring. The best inhibitor, NBD-14273 (compound 13), showed both improved antiviral activity and selectivity index (SI) against HIV-1HXB2 compared to NBD-14136. We also tested NBD-14273 against a large panel of 50 HIV-1 Env-pseudotyped viruses representing clinical isolates of diverse subtypes. The overall mean data indicate that antiviral potency against these isolates improved by ~3-fold, and SI also improved ~3-fold compared to NBD-14136. This new and novel inhibitor is expected to pave the way for further optimization to a more potent and clinically relevant inhibitor against HIV-1.
Subject(s)
Anti-HIV Agents/pharmacology , CD4 Antigens/metabolism , HIV Envelope Protein gp120/drug effects , HIV Fusion Inhibitors/pharmacology , HIV-1/drug effects , Small Molecule Libraries/pharmacology , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , CD4 Antigens/chemistry , Dose-Response Relationship, Drug , Drug Design , HIV Fusion Inhibitors/chemical synthesis , HIV Fusion Inhibitors/chemistry , Microbial Sensitivity Tests , Molecular Structure , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Structure-Activity RelationshipABSTRACT
Prions are misfolded proteins involved in neurodegenerative diseases of high interest in veterinary and public health. In this work, we report the chemical space exploration around the anti-prion compound BB 0300674 in order to gain an understanding of its Structure Activity Relationships (SARs). A series of 43 novel analogues, based on four different chemical clusters, were synthetized and tested against PrPSc and mutant PrP toxicity assays. From this biological screening, two compounds (59 and 65) emerged with a 10-fold improvement in anti-prion activity compared with the initial lead compound, presenting at the same time interesting cell viability.
