2,4,5-Trisubstituted Pyrimidines as Potent HIV-1 NNRTIs: Rational Design, Synthesis, Activity Evaluation, and Crystallographic Studies

Abstract

There is an urgent unmet medical need for novel human immunodeficiency virus type 1 (HIV-1) inhibitors that are effective against a variety of NNRTI-resistance mutations. We report our research efforts aimed at discovering a novel chemotype of anti-HIV-1 agents with improved potency against a variety of NNRTI-resistance mutations in this paper. Structural modifications of the lead K-5a2 led to the identification of a potent inhibitor 16c. 16c yielded highly potent anti-HIV-1 activities and improved resistance profiles compared with the approved drug etravirine. The co-crystal structure revealed the key role of the water networks surrounding the NNIBP for binding and for resilience against resistance mutations, while suggesting further extension of 16c toward the NNRTI-adjacent site as a lead development strategy. Furthermore, 16c demonstrated favorable pharmacokinetic and safety properties, suggesting the potential of 16c as a promising anti-HIV-1 drug candidate.

Structure-Based Design and Discovery of Pyridyl-Bearing Fused Bicyclic HIV-1 Inhibitors: Synthesis, Biological Characterization, and Molecular Modeling Studies

“… a EC 50 : concentration of compound required to achieve 50% protection of MT-4 cell cultures against HIV-1-induced cytotoxicity, as determined by the MTT method. b CC 50 : concentration required to reduce the viability of mock-infected cell cultures by 50%, as determined by the MTT method. c SI: selectivity index, the ratio of CC 50 /EC 50 . d Calculated using the free online software Molinspiration (). e X1: ≥1 or <1. f CV: cyanovinyl. g Used for comparison. The data were obtained from the same laboratory using the same method (Prof. Christophe Pannecouque, Rega Institute for Medical Research, KU Leuven, Belgium) h Used for comparison.…”

“… g Used for comparison. The data were obtained from the same laboratory using the same method (Prof. Christophe Pannecouque, Rega Institute for Medical Research, KU Leuven, Belgium) …”

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

“…With the great advantages of heterocycles in mind, introducing heterocycles into the biphenyl-DAPYs is proposed to improve the physical properties, metabolic stability, and toxicity of small-molecule candidates. , Based on previous structure–activity relationship (SAR) studies, 4-cyanophenyl was considered to be an important moiety in antiviral activities. , As shown in Figure , this fragment is located in the highly conserved W229 hydrophobic pocket, where it could be replaced by different aromatic rings. Moreover, the NNRTI binding site is considered flexible and inducible to accommodate an additional heteroaryl ring . Thus, in the present study, five- and six-membered unsaturated heterocycles as classical or unclassical bioisosterisms for 4-cyanophenyl were investigated to explore the inhibitory activities, SAR, and their druggability properties (water solubility, metabolic stability, oral bioavailability, CYP inhibition, and toxicity).…”

Newly Emerging Strategies in Antiviral Drug Discovery: Dedicated to Prof. Dr. Erik De Clercq on Occasion of His 80th Anniversary

“…Undoubtedly, our endeavors and most achievements in antiviral drug research field have continuously benefited from the inspiration of these articles and his direct guidance. Our long-term close cooperation with Professor Erik De Clercq culminated in the discovery of several antiviral drug candidates for further preclinical studies or clinical trials [ 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 ]. On the occasion of his 80th anniversary, on behalf of our whole research group, we would like to extend our sincere gratitude and best wishes to Professor Erik De Clercq.…”