Synthesis and evaluation of novel almazole D analogs as anticancer agents.

Novel almazole D-amide conjugates, esters, and N-alkylated analogs were synthesized and investigated for their anticancer activity against seven cancer cell lines. Among the series, compounds 5g and 5m showed significant anticancer activities against multiple cell lines with moderate selectivity indices. Compound 5g had IC50 values of 5.86 ± 0.31, 9.94 ± 0.06, 12.74 ± 0.12, and 9.40 ± 0.03 µM against the B16-F10, DU145, HeLa, and LC-540 cell lines, respectively, while compound 5m showed IC50 values of 6.35 ± 0.09, 9.17 ± 0.11, 9.00 ± 0.011, 19.65 ± 0.63, 8.13 ± 0.04, and 11.56 ± 0.01 µM against B16-F10, DU145, HeLa, HepG2, LC-540, and SK-BR-3 cells, respectively. Compared to almazole D, which only showed significant activity against B16-F10 cells (IC50 = 9.05 ± 0.008 µM), the synthesized analogs showed improved anticancer activity against multiple cell lines. The kinase inhibition assay coupled with the docking studies revealed that epidermal growth factor receptor (EGFR) kinase inhibition via interaction with amino acid residue T790 on the EGFR is one of the possible mechanisms by which 5g exerts its anticancer potential. The ADMET prediction and drug-likeness of the analogs project the synthesized analogs as promising agents, which can be further developed for application in cancer therapy.

Nitazoxanide potentiates linezolid against linezolid-resistant Staphylococcus aureus in vitro and in vivo.

BACKGROUND: Antimicrobial resistance is a growing menace, claiming millions of lives all over the world. In this context, drug repurposing is one approach gaining interest as a suitable alternative to conventional drug discovery and development. METHODS: Whole-cell assays were used to screen FDA-approved drugs to identify novel antimicrobial agents active against bacterial pathogens. Following identification of nitazoxanide, its various characteristics, such as antimicrobial activity against MDR isolates, time-kill kinetics, ability to synergize with approved drugs, antibiofilm activity and ability to generate resistance in Staphylococcus aureus, were determined, followed by determination of its in vivo potential against MDR S. aureus. RESULTS: Nitazoxanide demonstrated a potent in vitro antistaphylococcal profile, including equipotent activity against clinical drug-resistant S. aureus and Enterococcus spp. Nitazoxanide exhibited concentration-dependent killing, significantly eradicated preformed S. aureus biofilm and S. aureus did not generate resistance to it. Nitazoxanide strongly synergized with linezolid both in vitro and in vivo against linezolid-susceptible and -resistant S. aureus, displaying superior activity to untreated control and drug-alone treatment groups. CONCLUSIONS: Nitazoxanide can be utilized in combination with linezolid against infections caused by linezolid-resistant S. aureus as it exhibits strong synergism in vitro and in vivo.

3-Aryl-substituted imidazo[1,2-a]pyridines as antituberculosis agents.

Novel inhibitors are needed to tackle tuberculosis. Herein, we report the 3-aryl-substituted imidazo[1,2-a]pyridines as potent antituberculosis agents. A small library of 3-aryl-substituted imidazo[1,2-a]pyridines was synthesized using direct arylation, followed by nitro reduction and finally Pd-catalyzed C-N coupling reactions. The compounds thus obtained were evaluated against Mycobacterium tuberculosis H37Rv. Compound 26 was identified as an antituberculosis lead with a minimum inhibitory concentration of 2.3 µg/ml against M. tuberculosis H37Rv. This compound showed a selectivity index of 35. The docking of 26 in the active site of the M. tuberculosis cytochrome bc1 complex cytochrome b subunit (Mtb QcrB) revealed key π-π interactions of compound 26 with the Tyr389 and Trp312 residues of Mtb QcrB.