Bioinspired imidazo[1,2-a:4,5-c']dipyridines with dual antiproliferative and anti-migrative properties in human cancer cells: The SAR investigation.

Herein, we report the design, synthesis and evaluation of novel bioinspired imidazo[1,2-a:4,5c']dipyridines. The structural optimization identified four anti-proliferative compounds. Compounds 11, 18, 19 and 20 exhibited excellent anticancer activities in vitro with IC50 of 0.4-5 µM against three human cancer cell lines (MDA-MB-468, MDA-MB-435s and MDA-MB-231). These four compounds induced apoptosis in MDA-MB-231 cells in a dose-dependent manner, targeting different apoptotic proteins expression: 11 increased the expression of pro-apoptotic Bax protein while 18-20 reduced the level of anti-apoptotic Bcl-2 protein. Compounds 18 and 19 also reduced MDA-MB-231 cells proliferation as measured by Ki-67 staining. Furthermore, compounds were also tested for the ability to inhibit cell migration in the highly aggressive human MDA-MB-435s cell line. Six compounds of this series (8, 15, 18, 22, 23, 24) inhibited cell migration by 41-50% while four compounds (20, 25, 27, 30) inhibited the migration by 53-62% in wound-healing experiments. Interestingly, compound 20 presented both antiproliferative and anti-migration activities and might be a promising anti-metastatic agent for cancer treatment.

Discovery of imidazo[1,2-a]pyridine-based anthelmintic targeting cholinergic receptors of Haemonchus contortus.

We report the synthesis of a series of imidazo[1,2-a]pyridine-based molecules as anthelmintic against the livestock parasite Haemonchus contortus. The molecules were tested by using Larval Paralysis Test (LPT), in order to target ionic channels, as most of the prominent marketed anthelminthics present such mechanism of action. The most active compound (5e) displayed paralysis on H. contortus stage 3 larvae until 31.25 µM. Effect of 5e on H. contortus cholinergic receptors (L-AChR1 and 2) was characterized via electrophysiological measurement and a rare antagonist mode of action was unveiled.

Synthesis and evaluation of the anticoccidial activity of trifluoropyrido[1,2-a]pyrimidin-2-one derivatives.

Screening of our chemical library to discover new molecules exhibiting in vitro activity against the invasion of host cells by Eimeria tenella revealed a lead compound with an IC50 of 15µM. Structure-activity relationship studies were conducted with 34 newly synthesized compounds to identify more active molecules and enhance in vitro activity against the parasite. Four compounds were more effective in inhibiting MDBK cell invasion in vitro than the lead compound.

Development of new highly potent imidazo[1,2-b]pyridazines targeting Toxoplasma gondii calcium-dependent protein kinase 1.

Using a structure-based design approach, we have developed a new series of imidazo[1,2-b]pyridazines, targeting the calcium-dependent protein kinase-1 (CDPK1) from Toxoplasma gondii. Twenty derivatives were thus synthesized. Structure-activity relationships and docking studies confirmed the binding mode of these inhibitors within the ATP binding pocket of TgCDPK1. Two lead compounds (16a and 16f) were then identified, which were able to block TgCDPK1 enzymatic activity at low nanomolar concentrations, with a good selectivity profile against a panel of mammalian kinases. The potential of these inhibitors was confirmed in vitro on T. gondii growth, with EC50 values of 100 nM and 70 nM, respectively. These best candidates also displayed low toxicity to mammalian cells and were selected for further in vivo investigations on murine model of acute toxoplasmosis.