Imidazopyridine linked triazoles as tubulin inhibitors,effectively triggering apoptosis in lung cancer cell line

A library of new imidazopyridine linked triazole hybrid conjugates (8a-r) were designed, synthesized and evaluated for their cytotoxicity against four cancer cell lines namely, human lung (A549), human prostate (DU-145), human colon (HCT-116) and breast (MDA-MB 231) cancer. These conjugates exhibited good to moderate activity against the tested human cancer cell lines. Two of the conjugates (8g and 8j) showed significant antitumor activity against human lung cancer cell line (A549) with IC₅₀ values of 0.51 µM and 0.63 µM respectively. Flow cytometry analysis revealed that these conjugates arrested the cell cycle at G₂/M phase in human lung cancer cell line (A549). Immune-histochemistry and tubulin polymerization assay suggest inhibition of tubulin. Hoechst staining, annexin V and DNA fragmentation by tunnel assay suggested that these compounds induce cell death by apoptosis. Overall, the current study demonstrates that the synthesis of imidazopyridine linked triazole conjugates as promising anticancer agents causing G₂/M arrest and apoptotic-inducing ability.     

Identification of an imidazopyridine scaffold to generate potent and selective TYK2 inhibitors that demonstrate activity in an in vivo psoriasis model

Herein we report identification of an imidazopyridine class of potent and selective TYK2 inhibitors, exemplified by prototype 6, through constraint of the rotatable amide bond connecting the pyridine and aryl rings of compound 1. Further optimization led to generation of compound 30 that potently inhibits the TYK2 enzyme and the IL-23 pathway in cells, exhibits selectivity against cellular JAK2 activity, and has good pharmacokinetic properties. In mice, compound 30 demonstrated dose-dependent reduction of IL-17 production in a PK/PD model as well as in an imiquimod-induced psoriasis model. In this efficacy model, the IL-17 decrease was accompanied by a reduction of ear thickness indicating the potential of TYK2 inhibition as a therapeutic approach for psoriasis patients.     

Imidazopyridine‐Based Inhibitors of Glycogen Synthase Kinase 3: Synthesis and Evaluation of Amide Isostere Replacements of the Carboxamide Scaffold

In this study, we explored the effect of bioisostere replacement in a series of glycogen synthase kinase 3 (GSK3) inhibitors based on the imidazopyridine core. The synthesis and biological evaluation of a number of novel sulfonamide, 1,2,4‐oxadiazole, and thiazole derivates as amide bioisosteres, as well as a computational rationalization of the obtained results are reported.     

Imidazopyridyl compounds as aldosterone synthase inhibitors

The inhibition of aldosterone synthase (CYP11B2) may be an effective treatment of hypertension and heart failure, among other ailments. Previously reported benzimidazole CYP11B2 inhibitors led the way for bioisosteric imidazopyridines that are both potent and selective over CYP11B1.     

Potent bicyclic inhibitors of malarial cGMP-dependent protein kinase: approaches to combining improvements in cell potency,selectivity and structural novelty

Focussed studies on imidazopyridine inhibitors of Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG) have significantly advanced the series towards desirable in vitro property space. LLE-based approaches towards combining improvements in cell potency, key physicochemical parameters and structural novelty are described, and a structure-based design hypothesis relating to substituent regiochemistry has directed efforts towards key examples with well-balanced potency, ADME and kinase selectivity profiles.