Synthesis, Biological Evaluation, and Molecular Docking Studies of Novel 4‐[4‐Arylpyridin‐1(4H)‐yl]benzoic Acid Derivatives as Anti‐HIV‐1 Agents

Abstract

The structural similarities between N1 substituted 1,4-dihydropyridines and the known gp41 inhibitors, NB-2 and NB-64, were considered in the current research for the design of some novel anti-HIV-1 agents. A series of novel 4-[4-arylpyridin-1(4H)-yl]benzoic acid derivatives were synthesized and after a comprehensive structural elucidation were screened for in vitro anti-HIV-1 activity. Most of the tested compounds displayed moderate to good inhibitory activity against HIV-1 growth and were evaluated for in vitro cytotoxic activity using XTT assay at the concentration of 100 μm. Among the tested compounds, 1c, 1d and 1e showed potent anti-HIV-1 activity against P24 expression at 100 μm with inhibition percentage of 84.00%, 76.42% and 80.50%, respectively. All the studied compounds possessed no significant cytotoxicity on MT-2 cell line. The binding modes of these compounds to gp41 binding site were determined through molecular docking study. Docking studies proved 1a as the most potent compound and binding maps exhibited that the activities might be attributed to the electrostatic and hydrophobic interactions and additional H-bonds with the gp41 binding site. The Lipinski's 'rule of five' and drug-likeness criteria were also calculated for the studied compounds. All derivatives obeyed the Lipinski's 'rule of five' and had drug-like features. The findings of this study suggest that novel 4-[4-arylpyridin-1(4H)-yl]benzoic acid might be a promising scaffold for the discovery and development of novel anti-HIV-1 agents.

HIV‐1 Entry Inhibitors: A Review of Experimental and Computational Studies

“…The authors believed that the presence of 2‐furyl and 2‐thienyl hetero‐aromatic substituents at the C4 position of 1,4‐dihydropyridine helps improve the anti‐HIV‐1 activity and decrease the cytotoxic effect on MT‐2 cell line. Docking studies performed in this report showed good electrostatic and hydrophobic interactions with the gp41 binding site …”

“…[ ][ ] HIV‐1 entrance inhibitors are potentially more precious among anti‐HIV medications, because these kinds of compounds can prevent transmission of HIV‐1 among individuals and can be used for prophylaxis. A variety of small molecules and peptides with different mechanisms of action have been investigated for their HIV‐1 entry inhibitory activity, among them Enfuvirtide (Fuzeon, also known as T20) and Maraviroc (MVP) are approved by FDA . Enfuvirtide an HIV‐1 CHR‐peptide‐based compound is the first HIV‐1 entry inhibitor that was approved as a drug in 2003 by FDA.…”

Design, synthesis, and in silico studies of tetrahydropyrimidine analogs as urease enzyme inhibitors

“…THPMs are provided through a Biginelli reaction including ethyl acetoacetate, aryl aldehyde, and urea. [9] Cytosine, thymine, and uracil, three important bases in nucleic acids, are pyrimidine derivatives and cytosine is existing in both RNA and DNA. [10,11] Newly, various THPMs were described to reveal antiurease activity (Figure 1).…”

Design, synthesis and evaluation of cytotoxic, antimicrobial, and anti-HIV-1 activities of new 1,2,3,4-tetrahydropyrimidine derivatives

“…Compounds 4b and 4i showed poor activity against MCF-7 cell line. It should be noted that similar compounds with ethylester moiety at C-5 position were also reported as weak cytotoxic compounds against MCF-7 cell line (34).…”

“…When transfection was complete, 800 μL of the complete medium containing the synthesized compounds was added to the cells. The culture medium containing the virus was collected 48 h after transfection and the amount of the purified virus was measured using p24 ELISA assay kit (Cell Biolabs, France) (34).…”