Anuradha Singh

Design and anti-HIV activity of arylsulphonamides as non-nucleoside reverse transcriptase inhibitors

Design and anti-HIV activity of a series of arylsulphonamide derivatives as possible non-nucleoside reverse transcriptase inhibitors have been discussed. Compounds designed on the basis of Lipinski’s rule of five and having H-bond donor and acceptor sites were synthesized and screened in vitro to assess their human immunodeficiency virus type 1 reverse transcriptase inhibitory activity using TZM-bl cells. In silico studies using Discovery Studio 3.0 software showed that these molecules formed H-bonds and exhibited π–π, π–+ interactions, with amino acids in the non-nucleoside inhibitor binding pocket, and formed more stable complexes (total interaction energy in the range of (−) 47.85–(−) 77.01 kcal/mol) with human immunodeficiency virus type 1 reverse transcriptase in comparison to nevirapine and etravirine, (−) 45.79 and (−) 61.43 kcal/mol, respectively, and thus, lower EC50 values were predicted. The molecule, 4-(4-chloro-benzenesulphonyl amino)-N-(1H-indazole-5-yl)-benzamide showed significant inhibition of human immunodeficiency virus type 1 growth under in vitro conditions with EC50 value in the range of 4.89 × 10−5 μm. However, its selectivity index value was 2.45 only, which was much lower than nevirapine and etravirine. The reverse transcriptase analysis, based on luciferase reporter assay, of this compound proved its nature as non-nucleoside reverse transcriptase inhibitors. Though the molecules showed low inhibitory action against human immunodeficiency virus type 1 under in vitro conditions, the idea to develop non-nucleoside reverse transcriptase inhibitors was vindicated.

Molecular modeling, synthesis and biological evaluation of N-heteroaryl compounds as reverse transcriptase inhibitors against HIV-1.

Different N‐heteroaryl compounds bearing pyrimidine and benzimidazole moieties have been designed in silico using Discovery studio 2.5 software, synthesized and evaluated for their inhibitory activity as reverse transcriptase inhibitors against HIV‐1 replication using laboratory adapted strains HIV‐1IIIB (X4, subtype B) and HIV‐1Ada5 (R5, subtype B), and the primary isolates HIV‐1UG070 (X4, subtype D) and HIV‐1VB59 (R5, subtype C). Cell‐based assay showed that compounds were active at 1.394 μm concentrations (Selectivity Index: 1.29–38.39). The studies on structure–activity relationship clearly suggested anti‐HIV activity of pyrimidine and benzimidazole derivatives and these findings were consistent with the in vitro cell‐based experimental data. The results of molecular modeling and docking confirmed that all compounds assumed a butterfly‐like conformation and showed H‐bond, ‘π–π’ and ‘π–+’ and hydrophobic interactions within flexible non‐nucleoside inhibitor binding pocket of HIV‐1 reverse transcriptase, similar to known non‐nucleoside reverse transcriptase inhibitors, such as nevirapine. In view of the results obtained, it can be said that the chemical skeletons of N, N′‐bis‐(pyridin‐2‐yl)‐succinamide (14 and 15) and 1, 4‐bis‐benzoimidazol‐1‐yl‐butane‐1, 4‐dione (16 and 17) may be used for developing potent inhibitors of HIV‐1 replication, with suitable structure/pharmacophore modifications.

N-Heterocyclic analogues as peptide deformylase inhibitors: Molecular modeling, synthesis and antibacterial evaluation

Methods A new series of Nheterocyclic compounds has been derived from benzimidazole and pyrimidine nuclei optimized with the Discovery studio 3.0 software to investigate the interactions between the target compounds and the amino acid residues of Escherichia coli PDF Ni (PDB: ID 1G2A), and then synthesized. Further, all compounds were examined for their antibacterial activities against Gram-positive, S.viridians, and Gram-negative bacterial strains, E. coli, P. mirabilis and K. pneumoniae using the microdilution broth susceptibility test method and subjected to polynomial regression.

Synthesis, antibacterial activity, synergistic effect, cytotoxicity, docking and molecular dynamics of benzimidazole analogues

A series of 2-Cl-benzimidazole derivatives was synthesized and assessed for antibacterial activity. Antibacterial results indicated that compounds 2d, 2e, 3a, 3b, 3c, 4d and 4e showed promising activity against B. cerus, S. aureus and P. aeruginosa (MIC: 6.2 μg/mL) and excellent efficacy against E. coli (MIC: 3.1 μg/mL). Furthermore, compounds 3d and 3e displayed better activity (MIC: 3.1 μg/mL) than the reference drugs chloramphenicol and cycloheximide against gram positive and gram negative bacterial strains. The compounds 3d-e also showed better activity than the reference drug paromomycin against B. cerus and P. aeruginosa and showed similar inhibition pattern against S. aureus and E. coli. (MIC: 3.1 μg/mL). Studies on fractional inhibitory concentration (FIC) determination of compounds 1a-e, 2a-c, 4a-c and the reference antibiotic via combination approach revealed a synergistic effect as the MIC values were lowered up to 1/8th to 1/33rd of the original MIC. In-vitro cytotoxicity study indicated that 2-Cl-benzimidazole derivatives showed less toxicity than the reference used against PBM, CEM and Vero cell lines. Docking studies and MD simulations of compounds on bacterial protein (eubacterial ribosomal decoding A site, PDB: 1j7t) have been conducted to find the possible mode of action of the molecules. In silico ADMET evaluations of compounds 3d and 3e showed promising results comparable to the reference drugs used in this study.

Molecular modeling, synthesis, antibacterial and cytotoxicity evaluation of sulfonamide derivatives of benzimidazole, indazole, benzothiazole and thiazole

A new series of heterocyclic molecules bearing sulfonamide linkage has been synthesized and screened for antibacterial activity. During antibacterial screening using broath dilution method, molecules were found to be highly active (MIC value 50-3.1 µg/mL) against different human pathogens, namely B. cerus, S. aureus, E. coli and P. aeruginosa, and most effective against E. coli. A great synergistic effect was observed during determination of FIC where molecules were used in combination with reference drugs chloramphenicol and sulfamethoxazole. The MIC value of the combination - varying concentration of test compounds and ½ MIC of reference drugs or varying concentration of reference drugs and ½ MIC of test compounds, was reduced up to 1/4 or 1/32 of the original value, indicating thereby the combination was 4-32 times more potent than the test molecule. The molecules also showed low degree of cytotoxicity against PBM, CEM and VERO cell lines. The results positively indicated towards the development of lead antibacterials using the combination approach.

Computational modelling, green synthesis and biological activity of arylsulfonilamides as NNRTIs against HIV-1.

Methods Development of arylsulfonilamides as NNRTIs involved both the computational and synthetic methods. On the basis of extensive docking experiments, ten promising compounds out of 55 initially taken were synthesized using green protocols and their in vitro anti-HIV activity assessed in TZM bl cells by luciferase assay and reverse transcriptase (RT) inhibition assay against wild type HIV-1 RT.

Design, synthesis and biological evaluation on N- heteroaryl compounds as probable NNRTIs against laboratory adapted strains and the primary isolates of HIV-1

Methods Compounds designed on the basis of extensive computational studies, were finally synthesized through facile synthetic route and characterized using various chromatographic and spectral techniques. All synthesized molecules have been screened against HIV-1 using TZM bl assay and laboratory adapted strains HIV-1 IIIB (X4, subtype B), HIV-1 Ada5 (R5, Subtype B) and the primary isolates HIV-1UG070 (X4, Subtype D).

In-silico designing of acyclic nucleoside phosphonates and their anti-HIV potential

Method The object of our study is to develop newer nucleoside phosphonate analogs bearing unsaturation and modifications in heterogenous bases and prediction of their antiHIV potential. Designing is done keeping the Lipinski’s Rule of Five in focus. The diphosphates of compounds have been docked into the active site of wild type HIVRT (PDB: ID 2B6A). The forcefield of the Chemistry at Harvard Macromolecular mechanics (CHARMm) was applied to 3D models of PD HIV RT-nevirapine complex and synthesized ligands. The energy function is based on separable internal coordinate terms and pair wise non-bond interaction terms.

Novel acyclic nucleoside analogues as inhibitors of HIV-1 RT

Background Nucleoside reverse transcriptase inhibitors (NRTIs) were the first drugs introduced for treatment of human immunodeficiency virus-1 (HIV-1) infection. These NRTIs may be cyclic or acyclic analogs of natural nucleosides. Both these analogs interact at active site on HIV-RT and compete with indigenous nucleosides/ nucleotides, and thus, divert enzyme activity in manmade direction. All NRTIs follow three phosphorylation steps that convert the parent compound successively to 5’-triphosphate. These 5’-triphosphates act as alternate substrate for HIV-RT, and lead to chain termination when incorporated into the DNA chain as they don’t provide the 3’-OH function.