Functional Roles of Azoles Motif in Anti-HIV Agents

Peng      Zhan; Dongyue      Li; Xuwang      Chen; Xinyong      Liu; Erik      De Clercq

Abstract

Currently, there has been considerable interest in the discovery of original molecules with broad-spectrum anti- HIV activity and favourable pharmacokinetic profiles, to be used as an alternative to the approved anti-HIV/AIDS drugs, should they fail as therapeutics. Five-membered azole heterocycles represent an important class of lead structures for novel anti-HIV drug development. They can serve as versatile building blocks to introduce different new functional groups, (i) as scaffolds to anchor these groups into the optimal space for interactions with the target, (ii) as basic pharmacophore elements to make hydrogen bonds or hydrophobic interaction for facilitating the spatial filling at the binding site, (iii) as ester surrogates to improve metabolic stability, or (iv) as pharmacophoric motif of metal coordination to coordinate metal ions (i.e. magnesium) within the active site of target (i.e. integrase). This article will summarize recent progress in the development of some azoles derivatives that inhibit the replication of HIV-1 and will illustrate the possible functional role(s) of the azole motif in the search for new anti-HIV drugs.

Keywords: Heterocycle, azoles, HIV, AIDS, biological activity, acquired immune deficiency syndrome (AIDS), antiretroviral drugs, morbidity, mortality, long-term drug, pharmacokinetic, pyrazole, thiadiazole, oxadiazole, amino acid, bioisosteres, azole rings, hydrogen bonds, non-nucleoside, drug-resistant viruses, mutations, orthogonal, benzene, carbonyl group, potency, X-ray crystallography, aromatic side chains, bioavailability, physico-chemical properties, Aromatic, heterocyclic thiazolyl, strains, ester, blood plasma, bioisosters, thioesters, orientation, Metal Coordination, pharmacophore, novel orally, heteroaromatic carboxylic acid, DNA, Peptide Bond Isostere, efficacy, Ritonavir, antagonist, biochemistry, chemoinformatics, chemogenomics, optimization, azole-based antiviral agents