Design, synthesis and activity against drug-resistant bacteria evaluation of C-20, C-23 modified 5-O-mycaminosyltylonolide derivatives.

With the increasing incidence of antibiotic resistance, there is an urgent need to develop new antibiotics with excellent activity against drug-resistant bacteria. Three novel series of tylosin semisynthetic derivatives were designed, synthesized and evaluated for their antibacterial activities against various Gram-positive and Gram-negative bacteria. Among these derivatives, compound C-2 demonstrated potent antibacterial activity against both gram-positive and gram negative bacteria, and non mutagenic. More importantly, compound C-2 displayed high antimicrobial potency against Gram-positive bacteria in a murine model, and was found to be more efficient than tildipirosin. Thus, compound C-2 had great potential as a promising lead compound for the treatment of bacterial infection.

Novel indazole derivatives as potent apoptotic antiproliferative agents by multi-targeted mechanism: Synthesis and biological evaluation.

Indazole is a significant class of heterocyclic compounds with a wide range of biological activity. We display here the synthesis and biological evaluation of a novel series of indazole derivatives 6a-v, which are differently substituted at the 6-position of the indazole moiety. The antiproliferative activity of compounds 6a-v was tested against four human cancer cell lines, using the MTT assay and doxorubicin as the reference drug. Compounds 6f, 6i, 6j, 6 s, and 6n were the most effective synthesized derivatives, with GI50 values of 0.77, 0.86, 1.05, 1.05, and 1.07 µM, respectively, against the 4 cell lines, in comparison to the control doxorubicin (GI50 = 1.10 µM). Compounds 6f, 6i, 6j, and 6 s the most potent derivatives as antiproliferative agents, displayed the utmost inhibitory activity against EGFR, and CDK2 and c-Met. Compounds 6f, 6n, and 6 s induced apoptosis through cytochrome C overexpression and activation of the intrinsic apoptotic pathway generated by the investigated compounds.

New 1,2,4-oxadiazole/pyrrolidine hybrids as topoisomerase IV and DNA gyrase inhibitors with promising antibacterial activity.

A series of hybridized pyrrolidine compounds with a 1,2,4-oxadiazole moiety were synthesized to develop effective molecules against the enzymes DNA gyrase and topoisomerase IV (Topo IV). Compounds 8-20 were developed based on a previously disclosed series of compounds from our lab, but with small structural modifications in the hopes of increasing the compounds' biological activity. In comparison to novobiocin, with IC50 = 170 nM, the findings of the DNA gyrase inhibitory assay revealed that compounds 16 and 17 were the most potent of all synthesized derivatives, with IC50 values of 180 and 210 nM, respectively. Compound 17 had the strongest inhibitory effect against Escherichia coli Topo IV of all the synthesized compounds, with an IC50 value of 13 µM, which was comparable to novobiocin (IC50 = 11 µM). Therefore, hybrids 16 and 17 appeared to be potential dual-target inhibitors. In the minimal inhibitory concentration (MIC) assays, compound 17 outperformed ciprofloxacin against E. coli, with an MIC of 55 ng/ml, compared to 60 ng/ml for ciprofloxacin. Finally, the docking study, along with the in vitro experiments, supports our promising approach to effectively develop potent leads for further optimization as dual DNA gyrase and Topo IV inhibitors.

Novel indazole skeleton derivatives containing 1,2,3-triazole as potential anti-prostate cancer drugs.

In this study, a novel batch of indazole containing 1,2,3-triazole agents were designed and synthesized. The antiproliferative activity of target compounds in four human cancer cells, PC-3 (human prostate cancer cell), MCF-7 (human breast cancer cell), HepG-2 (human hepatoma cell) and MGC-803 (human gastric cancer cell), was evaluated by thiazole blue (MTT). In the antiproliferative activity screening, we were surprised to find that most compounds have specific cytotoxicity to PC-3 cancer cells. In particular, 9a has an IC50 value of 4.42 ± 0.06 µmol/L against PC-3 cell. Cloning experiments showed that 9a could inhibit the formation of PC-3 cancer cell clone in a dose-dependent manner. Through cell cycle arrest experiment, we found that compound 9a can block the cell cycle in G2/M phase and inhibit cell proliferation. Finally, by evaluating the safety of compound 9a, we noticed that it showed fairly good safety both in vivo and in vitro. Overall, based on the biological activity evaluation and safety, analogue 9a can be viewed as a potential lead compound for further development of novel anti-prostate cancer drug.