Divergent synthesis and elaboration of structure activity relationship for quinoline derivatives as highly selective NTPDase inhibitor.

Quinoline derivatives have interesting biological profile. In continuation for the comprehensive evaluations of substituted quinoline derivatives against human nucleoside triphosphate diphosphohydrolases (h-NTPDases) a series of substituted quinoline derivatives (2a-g, 3a-f, 4, 5a-c, 6) was synthesized. The inhibitory activities of the synthesized compounds were evaluated against four isoenzymes of human nucleoside triphosphate diphosphohydrolases (h-NTPDases). These quinoline derivatives had IC50 (µM) values in the range of 0.20-1.75, 0.77-2.20, 0.36-5.50 and 0.90-1.82 for NTPDase1, NTPDase2, NTPDase3 and NTPDase8, respectively. The derivative 3f was the most active compound against NTPDase1 (IC50, 0.20 ± 0.02 µM) that also possessed selectivity towards NTPDase1. Similarly, derivative 3b (IC50, 0.77 ± 0.06), 2h (IC50, 0.36 ± 0.01) and 2c (IC50, 0.90 ± 0.08) displayed excellent activity corresponding to NTPDase2, NTPDase3 and NTPdase8. The compound 5c emerged as a selective inhibitor of NTPDase8. The most active compounds were then investigated to determine their mode of inhibition and finally binding interactions of the active compounds were analyzed through molecular docking studies. The obtained results strongly support the quinoline scaffold's potential as potent and selective NTPDase inhibitor.

Investigation of new quinoline derivatives as promising inhibitors of NTPDases: Synthesis, SAR analysis and molecular docking studies.

Nucleoside triphosphate diphosphohydrolases (NTPDases), an important class of ectonucleotidases, are responsible for the sequential hydrolysis of extracellular nucleotides. However, over-expression of NTPDases has been linked with various pathological diseases e.g. cancer. Thus, to treat these diseases, the inhibitors of this class of enzyme are of interest. The significance of this class of enzyme encouraged us to synthesize a new class of quinoline derivatives with the aim to find selective and potent inhibitors of NTPDases. Therefore, a mild and efficient synthetic route was established for the synthesis of quinoline derivatives. The reaction was catalyzed by molecular iodine to afford the substituted quinoline derivatives. All the synthetic derivatives (3a-3w) were evaluated for their potential to inhibit the h-NTPDase1, 2, 3 and 8. Most of the compounds were identified as dual inhibitors of h-NTPDase1 and 8 with lower effects on h-NTPDase2 and 3. Two compounds i.e.3f and 3t were identified as selective inhibitor of h-NTPDase1 whereas the compound 3s inhibited the h-NTPDase8 selectively. Moreover, the compounds 3p (IC50 = 0.23 ±â€¯0.01 µM), 3j (IC50 = 21.0 ±â€¯0.03 µM) 3d (IC50 = 5.38 ±â€¯0.21 µM) and 3c (IC50 = 1.13 ±â€¯0.04 µM) were found to be the most potent inhibitors of h-NTPDase1, 2, 3 and 8, respectively. To determine the binding interaction, molecular docking studies were also carried out.