Hydrophobic Pocket Occupation Design of Difluoro-Biphenyl-Diarylpyrimidines as Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors: from N-Alkylation to Methyl Hopping on the Pyrimidine Ring

Abstract

Considering the non-ideal metabolic stability of the difuloro-biphenyl-diarylpyrimidine lead compound 4, a series of novel alkylated difuloro-biphenyl-diarylpyrimidines were structure-based designed and synthesized as non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs). Introducing alkyl or substituted alkyl groups on the linker region (consist of V179, Y181, E138 residues) to block the potential metabolic sensitive sites obtained twenty-two derviatives. Among them, compound 12a with N-methyl group displayed excellent HIV-1 inhibitory activity (EC 50 = 6.16 nM), moreover, a significant improvement in the selectivity (SI = 24,069) compared with existing drugs (NVP, SI > 72; ETR, SI > 1159; EFV, SI > 1600). Finally, the methyl group was hopped to the central pyrimidine ring in order to occupy the small linker region and maintain the water-mediated hydrogen bond observed in the binding of compound 4 with RT. The resulting compound 16y exhibited an improved HIV-1 inhibitory activity (EC 50 = 1.37 nM) and much lower cytotoxicity with the SI > 208,333). In addition, compound 16y possessed nanomolar activity toward multiple single-mutant virus strains except Y188L. For the metabolic stability, compound 16y have a better stability in human liver microsomes (T 1/2 = 138 min, Cl int = 5.0 μL/min/mg) than compounds 4 (T 1/2 = 44 min, Cl int = 16 μL/min/mg). No apparent in vivo acute toxicity was observed in 16y-treated female, and especially pregnant mice. The molecular docking studies predicted the binding modes of 16y with RT, and the methyl group was displayed as occupying effect in the hydrophobic pocket, explaining the activity differences for 16y and the precursor 12a. This series of alkylated compounds with highly potency and safety represent promising lead template for future discovery.

Crystallography-Guided Optimizations of the Keap1–Nrf2 Inhibitors on the Solvent Exposed Region: From Symmetric to Asymmetric Naphthalenesulfonamides

“…Suitable solubility was considered to be an essential characteristic of great importance for drug candidates . The salification strategy was confirmed to benefit the solubilities. − We selected compound 6k with the best in vitro activity and evaluated the water solubility of its different salt forms (Table ). The free 6k possessed a solubility of 902.3 μg/mL at pH 2.0, which was about 20-fold higher than that of NXPZ-2 ( S = 47.5 μg/mL).…”

Improving Druggability of Novel Diarylpyrimidine NNRTIs by a Fragment-Based Replacement Strategy: From Biphenyl-DAPYs to Heteroaromatic-Biphenyl-DAPYs

“…HIV-1 RT (PDB entry: 2ZD1) was mutated and minimized by Schrödinger BioLuminate. The protein preparation followed a standard protocol: (1) addition of missing hydrogen atoms to the X-ray structure, (2) removal of all crystallographic water (except 465), (3) assignment of ionizable state to each titrable groups by PropKa, and (4) energy minimization using OPLS-AA 2005 force field to optimize all hydrogen-bonding networks. ,,,− The docking study was performed using Glide. The small molecule, taking from the PDB structures, was redocked into its corresponding protein structure at the Standard Precision (SP) without the need of any constraints.…”

Contemporary Medicinal Chemistry Strategies for the Discovery and Development of Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors

“…Afterward, a series of non-dimethylphenyl DAPYs were identified to overcome the high cytotoxicity of 48 , and the most active 3,5-difluorobiphenyl derivative, 49 , showed prominent inhibitory activity and no apparent cytotoxicity . Further addition of a methyl group to the central scaffold yielded compound 50 with better in vitro metabolic stability . In addition, a variety of aromatic heterocycles were introduced on the terminal benzonitrile of 49 by using the fragment-based replacement strategy, leading to the identification of compound 51 bearing a pyridinyl group with excellent druggability (Table ).…”

“…128 Further addition of a methyl group to the central scaffold yielded compound 50 with better in vitro metabolic stability. 129 In addition, a variety of aromatic heterocycles were introduced on the terminal benzonitrile of 49 by using the fragment-based replacement strategy, leading to the identification of compound 51 bearing a pyridinyl group with excellent druggability (Table 5). 130 4.3.…”