Exploring antiviral potency of N-1 substituted pyrimidines against HIV-1 and other DNA/RNA viruses: Design, synthesis, characterization, ADMET analysis, docking, molecular dynamics and biological activity

A novel series of pyrimidine derivatives, bearing modified benzimidazoles at N-1 position, has been designed, synthesized and screened as NNRTIs against HIV and as broad-spectrum antiviral agents. The molecules were screened against different HIV targets using molecular docking experiment. The docking results indicated that the molecules interacted well with the residues Lys101, Tyr181, Tyr188, Trp229, Phe227 and Tyr318 present in NNIBP of HIV-RT protein, formed quite stable complexes and, thus, behaved as probable NNRTIs. Among these compounds, 2b and 4b showed anti-HIV activity with IC50 values as 6.65 µg/mL (SI = 15.50) and 15.82 µg/mL (SI = 14.26), respectively. Similarly, compound 1a showed inhibitory property against coxsackie virus B4 and compound 3b against different viruses. Molecular dynamics simulation results unequivocally demonstrated the higher stability of the complex HIV-RT:2b than the HIV-RT:nevirapine complex. The MM/PBSA-based binding free energy (-) 114.92 kJ/mol of HIV-RT:2b complex in comparison to that of HIV-RT:nevirapine complex (-) 88.33 kJ/mol, further demonstrated the higher binding strength of 2b and thus, established the potential of compound 2b as a lead molecule as an HIV-RT inhibitor. [Display omitted] •New pyrimidine derivatives bearing modified benzimidazoles synthesized as antivirals against HIV-1 and different DNA/RNA viruses.•MTT assay was used to determine the cytotoxicity of pyrimidine derivatives.•Compound 2b and 4b showed anti-HIV activity with SI values as 15.50 and 14.26, respectively.•Compound 3b found to be active against different DNA/RNA viruses.•Compound 1a exhibited antiviral activity against coxsackie virus B4.•Molecular dynamics simulation studies confirmed the stability of ligand-protein complex of compound 2b within hydrophobic pocket of HIV-RT.