Rational design, synthesis and biological evaluation of novel HIV-1 protease inhibitors containing 2-phenylacetamide derivatives as P2 ligands with potent activity against DRV-Resistant HIV-1 variants.

A novel kind of potent HIV-1 protease inhibitors, containing diverse hydroxyphenylacetic acids as the P2-ligands and 4-substituted phenyl sulfonamides as the P2' ligands, were designed, synthesized and evaluated in this work. Majority of the target compounds exhibited good to excellent activity against HIV-1 protease with IC50 values below 200 nM. In particular, compound 18d with a 2-(3,4-dihydroxyphenyl) acetamide as the P2 ligand and a 4- methoxybenzene sulfonamide P2' ligand exhibited inhibitory activity IC50 value of 0.54 nM, which was better than that of the positive control darunavir (DRV). More importantly, no significant decline of the potency against HIV-1DRVRS (DRV-resistant mutation) and HIV-1NL4_3 variant (wild type) for 18d was detected. The molecular docking study of 18d with HIV-1 protease (PDB-ID: 1T3R, www.rcsb.org) revealed possible binding mode with the HIV-1 protease. These results suggested the validity of introducing phenol-derived moieties into the P2 ligand and deserve further optimization which was of great value for future discovery of novel HIV-1 protease.

Synthesis, Molecular Docking and Biological Evaluation of 2-Aryloxy-N-Phenylacetamide and N'-(2-Aryloxyoxyacetyl) Benzohydrazide Derivatives as Potential Antibacterial Agents.

A new class of 2-aryloxy-N-phenylacetamide and N'-(2-aryloxyoxyacetyl) benzohydrazide derivatives with different active moieties were synthesized and screened for their antibacterial activity. Structural characterization of synthesized compounds was performed using HR-MS, 1 H-NMR, and 13 C-NMR spectral data. Amongst the synthesized compounds, 4-{2-[2-(2-chloroacetamido)phenoxy]acetamido}-3-nitrobenzoic acid (3h) and 2-chloro-N-(2-{2-[2-(2-chlorobenzoyl)hydrazinyl]-2-oxoethoxy}phenyl)acetamide (3o) have shown good antibacterial activity against a selected panel of bacteria. Besides, compounds also exhibited bactericidal activity against P. aeruginosa (3h, 0.69 µg/mL) and S. aureus (3o, 0.62 µg/mL) as evident by MBC and time-kill kinetics studies. In silico molecular docking and ADMET properties of newly synthesized compounds revealed that compounds could be considered as promising antibacterial agents.

Benzohydrazide and Phenylacetamide Scaffolds: New Putative ParE Inhibitors.

Antibacterial resistance (ABR) is a major life-threatening problem worldwide. Rampant dissemination of ABR always exemplified the need for the discovery of novel compounds. However, to circumvent the disease, a molecular target is required, which will lead to the death of the bacteria when acted upon by a compound. One group of enzymes that have proved to be an effective target for druggable candidates is bacterial DNA topoisomerases (DNA gyrase and ParE). In our present work, phenylacetamide and benzohydrazides derivatives were screened for their antibacterial activity against a selected panel of pathogens. The tested compounds displayed significant antibacterial activity with MIC values ranging from 0.64 to 5.65 µg/mL. Amongst 29 title compounds, compounds 5 and 21 exhibited more potent and selective inhibitory activity against Escherichia coli with MIC values at 0.64 and 0.67 µg/mL, respectively, and MBC at onefold MIC. Furthermore, compounds exhibited a post-antibiotic effect of 2 h at 1× MIC in comparison to ciprofloxacin and gentamicin. These compounds also demonstrated the concentration-dependent bactericidal activity against E. coli and synergized with FDA-approved drugs. The compounds are screened for their enzyme inhibitory activity against E. coli ParE, whose IC50 values range from 0.27 to 2.80 µg/mL. Gratifyingly, compounds, namely 8 and 25 belonging to the phenylacetamide series, were found to inhibit ParE enzyme with IC50 values of 0.27 and 0.28 µg/mL, respectively. In addition, compounds were benign to Vero cells and displayed a promising selectivity index (169.0629-951.7240). Moreover, compounds 1, 7, 8, 21, 24, and 25 (IC50: <1 and Selectivity index: >200) exhibited potent activity in reducing the E. coli biofilm in comparison with ciprofloxacin, erythromycin, and ampicillin. These astonishing results suggest the potential utilization of phenylacetamide and benzohydrazides derivatives as promising ParE inhibitors for treating bacterial infections.

2-(4-Fluorophenyl)-N-phenylacetamide Derivatives as Anticancer Agents: Synthesis and In-vitro Cytotoxicity Evaluation.

Cancer is a major global problem and is the second leading cause of mortality in the developed countries.Resistance to current chemotherapeutics and high incidence of adverse effects are the two principal reasons for developing new anticancer agents. Phenylacetamide derivatives can act as potential anticancer agents. Synthesis and screening of 2-(4-Fluorophenyl)- N-phenylacetamide derivatives in present study showed that these compounds act as potent anticancer agents especially against PC3(prostate carcinoma) cell line. Compounds 2a-2c with nitro moiety demonstrated a higher cytotoxic effect than compounds 2d-2f with methoxy moiety. All compounds in this series exhibited lower activity than imatinib as reference drug. Compounds 2b (IC50 = 52 µM) and 2c (IC50 = 80 µM) were the most active compounds against PC3 cell line in comparison with imatinib(IC50 = 40 µM). Compound 2c (IC50 = 100 µM) with p-nitro substituent was the most active compound compared to imatinib(IC50 = 98 µM) in MCF-7 cell line.