Structural elucidation, molecular docking, α-amylase and α-glucosidase inhibition studies of 5-amino-nicotinic acid derivatives

Abstract

In this study, 5-amino-nicotinic acid derivatives (1-13) have been designed and synthesized to evaluate their inhibitory potential against α-amylase and α-glucosidase enzymes. The synthesized compounds (1-13) exhibited promising α-amylase and α-glucosidase activities. IC 50 values for α-amylase activity ranged between 12.17 ± 0.14 to 37.33 ± 0.02 µg/mL ± SEM while for α-glucosidase activity the IC 50 values were ranged between 12.01 ± 0.09 to 38.01 ± 0.12 µg/mL ± SEM. In particular, compounds 2 and 4-8 demonstrated significant inhibitory activities against α-amylase and α-glucosidase and the inhibitory potential of these compounds was comparable to the standard acarbose (10.98 ± 0.03 and 10.79 ± 0.17 µg/mL ± SEM, respectively). In addition, the impact of substituent on the inhibitory potential of these compounds was assessed to establish structure activity relationships. Studies in molecular simulations were conducted to better comprehend the binding properties of the compounds. All the synthesized compounds were extensively characterized with modern spectroscopic methods including 1 H-NMR, 13 C-NMR, FTIR, HR-MS and elemental analysis.

Trifluoromethylated Flavonoid-Based Isoxazoles as Antidiabetic and Anti-Obesity Agents: Synthesis, In Vitro α-Amylase Inhibitory Activity, Molecular Docking and Structure–Activity Relationship Analysis

“…By comparing the structures and activities of the synthesized molecules, compounds 3b-d, halogenated in the para position of the phenyl group attached to the isoxazole ring, displayed significant efficacy (PI= 85.4 ± 0.9%-94.7 ± 1.2%at 50 µM) and potency (IC 50 = 12.6 ± 0.2 µM-14.6 ± 0.3 µM) in inhibiting the α-amylase enzyme. This finding is in good agreement with the literature, showing that the presence of halogen atoms (F, Cl, or Br) in the structure was essential for a potent α-amylase inhibition [49,50]. In addition, the structure-activity relationship study allowed us to conclude that more inductive attractor (−I) and mesomeric donor (+M) effects increase the α-amylase inhibitory efficacy and potency (activity of the fluorinated derivative 3b (R 1 = F, R 2 = H; PI = 94.7 ± 1.2% at 50 µM; IC 50 = 12.6 ± 0.2 µM) is higher than that of the chlorinated derivative 3c (R 1 = Cl, R 2 = H; PI = 87.1 ± 0.7% at 50 µM; IC 50 = 14.4 ± 0.2 µM), followed by the brominated derivative 3d (R 1 = Br, R 2 = H; PI = 85.4 ± 0.9% at 50 µM; IC 50 = 14.6 ± 0.3 µM)), in accordance with previous studies [4,49].…”

“…This finding is in good agreement with the literature, showing that the presence of halogen atoms (F, Cl, or Br) in the structure was essential for a potent α-amylase inhibition [49,50]. In addition, the structure-activity relationship study allowed us to conclude that more inductive attractor (−I) and mesomeric donor (+M) effects increase the α-amylase inhibitory efficacy and potency (activity of the fluorinated derivative 3b (R 1 = F, R 2 = H; PI = 94.7 ± 1.2% at 50 µM; IC 50 = 12.6 ± 0.2 µM) is higher than that of the chlorinated derivative 3c (R 1 = Cl, R 2 = H; PI = 87.1 ± 0.7% at 50 µM; IC 50 = 14.4 ± 0.2 µM), followed by the brominated derivative 3d (R 1 = Br, R 2 = H; PI = 85.4 ± 0.9% at 50 µM; IC 50 = 14.6 ± 0.3 µM)), in accordance with previous studies [4,49]. It is evident that the α-amylase inhibition increases with the inductive attractor (−I) and mesomeric donor (+M) effects of halogen atoms.…”

“…The compound 3h (R 1 = OMe, R 2 = H), bearing a para-methoxy group, exhibited interesting α-amylase inhibitory activity, with an efficacy of 93.5 ± 1.1% at 50 µM and an IC 50 value of 13.3 ± 0.2 µM. This finding is consistent with previous results [49]. Moreover, the compound 3i (R 1 = O-n-Bu, R 2 = H; IC 50 = 15.6 ± 0.2 µM; PI= 79.4 ± 1.0% at 50 µM), bearing a para-substituted butoxy group, perceived a lower activity than that of the para-methoxylated compound 3h.…”

“…Likewise, it should be noted that the compound 3g (R 1 = NO 2 , R 2 = H), bearing a para-nitro group, revealed sufficient efficacy (PI = 74.7 ± 0.3%at 50 µM) and potency (IC 50 = 18.1 ± 0.3 µM) to inhibit the α-amylase enzyme, consistent with the results of Nawaz et al (2020) [49]. The activity of this molecule may be due to the inductive attracting effect (−I) of the nitro group.…”

“…This fluorinated moiety was found to be indispensable in many important drugs, including fluphenazine (antipsychotic, anticancer) [45], leflunomide (antirheumatic) [43], celecoxib (COX-2 selective inhibitor) [46], fluoxetine (antidepressant) [47], and fluazinam (fungicide) [48]. One review of the literature mentions that trifluoromethylated 5-amino-nicotinic acid has been reported to exhibit promising α-amylase activity [49]. In addition, the chlorinated hybrid pyrazole-thiazole molecules were found to be good inhibitors of the α-amylase enzyme [50], which also indicates the importance of the chlorine atom in α-amylase inhibitory structures.…”