Phenanthridine derivatives as potential HIV‑1 protease inhibitors

Abstract

In the present study, the antiviral activity of phenanthridine derivatives was assessed. In total, the inhibitory effect of eight structurally similar low-molecular-weight hydrophobic compounds on HIV-1 protease (HIVp) was investigated. HIVp is a key enzyme in the HIV-1 life cycle. Surface plasmon resonance technology was used for affinity assessment of compounds binding with either monomeric or dimeric forms of HIVp. HIVp enzyme inhibition assays with chromogenic substrate VII were also used to determine the IC 50 values. The most potent compound was 3,3,9,9-tetrameth yl-3,4,9,10-tetrahydro-2H,8H-phenanthridine-1,7-dione which binds to monomeric and dimeric forms of HIVp (apparent dissociation constant, 2-7 µM; IC 50 , 36 µМ), while possessing the most favorable Absorption, Distribution, Metabolism and Excretion parameters. Molecular docking simulations highlighted certain differences in the binding patterns of the phenanthridine derivatives with HIVp amino acid residues forming the flaps domain, monomer/monomer interfaces and the active site cavity of HIVp. Thus, it was hypothesized that the inhibitory effect of phenanthridine compounds on the enzymatic activity of HIVp may be due to restriction of substrate access to the HIVp active site.

Design, synthesis and biological evaluation of phenanthridine amide and 1,2,3-triazole analogues against Mycobacterium tuberculosis

“…Phenanthridine is one of the most prospective fused bicyclic rings that is accepted as a “drug preconception” scaffold, 6 due to its wide range of biological activities and applications in anti-cancer, 6 anti-bacterial, 7 anti-malarial, 8 anti-HIV, 9 anti-plasmodial, 10 and antitubercular agents. 11–16 Many phenanthridine derivatives are reported to have antitubercular activity.…”

“…As a result, it is critical to investigate innovative chemical entities for the treatment of drug-resistant types of this widely spread infection with minimal adverse effects. 5 Phenanthridine is one of the most prospective fused bicyclic rings that is accepted as a "drug preconception" scaffold, 6 due to its wide range of biological activities and applications in anti-cancer, 6 anti-bacterial, 7 anti-malarial, 8 anti-HIV, 9 anti-plasmodial, 10 and antitubercular agents. [11][12][13][14][15][16] Many phenanthridine derivatives are reported to have antitubercular activity.…”

Molecular Mechanics Study of Flow and Surface Influence in Ligand–Protein Association

“…For example, techniques using continuous flow biocatalysis have been developed recently to improve the efficiency of chemical synthesis, such as improved mixing, mass transfer, and automation (Planchestainer et al, 2017 ; Britton et al, 2018 ). Surface plasmon resonance (SPR), a powerful technique to measure molecular binding kinetics and thermodynamics, also utilizes flow chemistry and a continuous flow environment (Hinman et al, 2018 ; Prabowo et al, 2018 ; Ershov et al, 2020 ). However, how the flow may affect the ligand–protein association processes is unclear.…”