Novel N-quaternary coumarin-3-yl-imidazo[1,2-a]pyridines as fluorescent hybrids: Their synthesis and biological evaluation in cancer cells

Abstract

Hybrid coumarin-3-yl-imidazo[1,2-a]pyridines were used to synthesize novel derivatives of quaternary salts 5a-c and 6a,b, employing ethyl iodide and benzyl bromide as alkylating agents. The molecular patterns of Total Polar Surface Area (TPSA) coincide with substituent polarity at positions 6 or 7, along with the substituent at the quaternary N. Notably, most polar molecules contain an amino group at position 7, followed by those substituted with −OMe at position 6. Conversely, molecules lacking substituents are the least polar. Despite existing as salts, the polarity of the compounds does not experience a substantial increase. Nonetheless, solubility experiences a notable decrease, particularly for the 6a-c series, due to the potent hydrophobic effect of the benzyl substituent at the N position. A similar phenomenon is observed with the ethyl substituent in the 5a-c series, albeit with a less pronounced hydrophobic impact. To assess the effect of the quaternary hybrid coumarin-3-yl-imidazo[1,2-a]pyridines on proliferation, both breast (MDA-MB-231) and prostate (PC3) cancer cell lines were utilized. The biological assessment of these cancer cell lines demonstrated that compounds 4a, 4c, and 5c exhibit noteworthy antiproliferative effects on MDA-MB-231 (Inhibitory concentration at 50 % (IC₅₀) values of 2.27 µM, 3.76 µM, and 0.113 µM, respectively) and PC3 (IC₅₀ values of 1.03 µM, 0.527 µM, and 0.888 µM, respectively). Furthermore, these same structures demonstrated substantial fluorescence emissions localized within the cytoplasm. Additionally, compounds decreased the G2/M phase of the cell cycle and increased the SubG1 phase. These findings suggest that these novel hybrids have promising applications in cancer treatment.