Design, Synthesis, and Antiviral Activity of the Thiazole Positional Isomers of a Potent HIV-1 Entry Inhibitor NBD-14270.

The envelope glycoprotein gp120 of human immunodeficiency virus type 1 (HIV-1) plays a critical role in virus entry to the cells by binding to the host cellular protein CD4. Earlier, we reported the design and discovery of a series of highly potent small-molecule entry antagonists containing a thiazole ring (Scaffold A). Since this thiazole ring connected with an ethyl amide linkage represents the molecule's flexible part, we decided to explore substituting Scaffold A with two other positional isomers of the thiazole ring (Scaffold B and C) to evaluate their effect on the antiviral potency and cellular toxicity. Here we report the novel synthesis of two sets of positional thiazole isomers of the NBD-14270 by retrosynthetic analysis approach, their anti-HIV-1 activity, cellular toxicity, and structure-activity relationships. The study revealed that Scaffold A provided the best HIV-1 inhibitors with higher potency and better selectivity index (SI).

Design of gp120 HIV-1 entry inhibitors by scaffold hopping via isosteric replacements.

We present the development of alternative scaffolds and validation of their synthetic pathways as a tool for the exploration of new HIV gp120 inhibitors based on the recently discovered inhibitor of this class, NBD-14136. The new synthetic routes were based on isosteric replacements of the amine and acid precursors required for the synthesis of NBD-14136, guided by molecular modeling and chemical feasibility analysis. To ensure that these synthetic tools and new scaffolds had the potential for further exploration, we eventually tested few representative compounds from each newly designed scaffold against the gp120 inhibition assay and cell viability assays.

Preclinical Optimization of gp120 Entry Antagonists as anti-HIV-1 Agents with Improved Cytotoxicity and ADME Properties through Rational Design, Synthesis, and Antiviral Evaluation.

We previously reported a milestone in the optimization of NBD-11021, an HIV-1 gp120 antagonist, by developing a new and novel analogue, NBD-14189 (Ref1), which showed antiviral activity against HIV-1HXB2, with a half maximal inhibitory concentration of 89 nM. However, cytotoxicity remained high, and the absorption, distribution, metabolism, and excretion (ADME) data showed relatively poor aqueous solubility. To optimize these properties, we replaced the phenyl ring in the compound with a pyridine ring and synthesized a set of 48 novel compounds. One of the new analogues, NBD-14270 (8), showed a marked improvement in cytotoxicity, with 3-fold and 58-fold improvements in selectivity index value compared with that of Ref1 and NBD-11021, respectively. Furthermore, the in vitro ADME data clearly showed improvements in aqueous solubility and other properties compared with those for Ref1. The data for 8 indicated that the pyridine scaffold is a good bioisostere for phenyl, allowing the further optimization of this molecule.