Evaluation of the Multidrug Resistance Reversing Activity of Novel Imidazo[4,5-b]pyridine Derivatives.

BACKGROUND/AIM: Malignant diseases present a significant public health burden worldwide and their treatment is further complicated by the phenomenon of multidrug resistance. Derivatives of imidazopyridine exhibit several remarkable pharmacological activities and they could reverse the multidrug resistance of cancer cells due to overexpressing P-glycoprotein.

MATERIALS AND METHODS

A series of novel imidazo[4,5-b]pyridine derivatives were synthesized and their biological activities were evaluated in vitro using parental (PAR) and multidrug resistant (MDR; ABCB1-overexpressing) mouse T-lymphoma cells. The cytotoxic activity and selectivity of the tested compounds were assessed by the thiazolyl blue tetrazolium bromide (MTT) assay, the ABCB1 modulating activity was measured by rhodamine 123 accumulation assay using flow cytometry.

RESULTS

Six compounds ( and ) showed moderate-to-high cytotoxic activity on the tested cell lines, while derivative presented with promising selectivity towards the MDR cell line. Derivatives and were proven to be effective modulators of the ABCB1 multidrug efflux pump, with two compounds showing efflux pump modulatory activity at 2 μM concentration.

CONCLUSION

Based on our experimental results, compounds that showed potent activity are those with a short carbon side chain; a methoxy group on the benzene ring; a heterocyclic (triazole) side chain and the presence of an alkylated N-atom at position 4.