Discovery of potent HIV‐1 non‐nucleoside reverse transcriptase inhibitors by exploring the structure–activity relationship of solvent‐exposed regions I

Abstract

Two novel series of human immunodeficiency virus‐1 (HIV‐1) non‐nucleoside reverse transcriptase inhibitors (NNRTIs) bearing a thiophene[3,2‐d]pyrimidine scaffold and sulfonamide linker in the right wing have been identified, which demonstrated activity against the wild‐type (WT) HIV‐1 strain in MT‐4 cells with inhibitory concentrations ranging from micromolar to submicromolar. Especially, against the mutant strains K103N and E138K, most compounds exhibited more potent activity than against WT HIV‐1. Compound 7 (EC50 = 0.014, 0.031 μM) achieved the most potent activity against the two mutants, being more effective than that of nevirapine (NVP, EC50 = 7.572, 0.190 μM) and comparable to that of etravirine (ETV, EC50 = 0.004, 0.014 μM). Molecular docking experiments on the novel analogs have also suggested that the extensive network of main chain hydrogen bonds are important in the binding mode, which may provide valuable insights for further optimization.

Structure‐based non‐nucleoside inhibitor design: Developing inhibitors that are effective against resistant mutants

“…Thus, there is a need to develop new NNRTIs, particularly new compounds that will be broadly effective against the known NNRTI‐resistant mutants. In an effort to seek improved solubility and bioavailability, others have reported the development of RPV analogs that have different modifications of the moieties that are linked to the pyrimidine core (Huang et al., 2019; Kang, Wang, et al, 2019; Kang, Zhang, et al, 2019; Liu et al., 2016). We have focused primarily on increasing the potency of RPV analogs against resistant strains of HIV.…”

Development of Machine Learning Models and the Discovery of a New Antiviral Compound against Yellow Fever Virus

“…Further investigation of the target for this molecule is ongoing while preliminary data suggest the compound is not active against the protease or polymerase for YFV (data not shown). Sulfonamides are a well-known class of drugs with antiviral activity, for example there are recent articles for HBV, HIV, and HCV . The dearth of new molecules for YFV as well as very little current research activity provides a unique opportunity to pursue this hit further.…”

Thienopyrimidine: A Promising Scaffold to Access Anti-Infective Agents

“…Similarly, diaminocyclohexane derivatives 91e and 91f showed a slight decrease in anti-HIV1 activity (EC 50 = 7.1 and 10 nM, respectively) [88]. A diaminophenyl group at position 2 caused a loss of potency, with EC 50 s 10-fold weaker than etravirine (91g vs. ETV) [89]. Finally, various amino-cycloalkyl groups were introduced at position 2.…”

“…10 nM, respectively) [88]. A diaminophenyl group at position 2 caused a loss of potency, with EC50s 10-fold weaker than etravirine (91g vs ETV) [89]. Finally, various amino-cycloalkyl groups were introduced at position 2.…”