Natural Product Based Green Synthesis Of Heterocyclic Analogs As Antidiabetic, Antibacterial And Antioxidant Agents: A Combined Experimental And Computational Study

Abstract

Heterocyclic compounds and their analogs possess a broad spectrum of antidiabetic and antibacterial properties, which block postprandial hyperglycemia, and bacterial growth owing to their structural features and the generation of antioxidation products. They have a broad range of therapeutic potential with the ability to regulate the activity of numerous metabolic enzymes. In this study, a greener and more efficient approach has been developed to synthesize a novel series of thiazole-pyrazoline Schiff base hybrids, thiazolo[3,2-α] pyrimidine and heterocyclic C5- curcuminoid analogs using ZnO nanoparticle and ultrasonic irradiation assisted protocol affords good to excellent yields (78.3-96.9%) with improved reaction time. All the synthesized compounds were characterized using a combination of physicochemical parameters and spectroscopic techniques (UV-visible, 1H-NMR, and 13C-NMR). Among the synthesized compounds, 81, 83, 93, 94, 96, 98, 100, 108, 111, and 116 showed good activities against P. aeruginosa with mean inhibition zone of 13.33±0.58, 17.33±0.58, 11.00  1.00, 12.00  1.00, 14.67±0.58, 12.33±0.58, 10.67±1.15, 17.67± 0.57, 14.33± 0.57 and 23.33±00 mm diameter, respectively, at 500 μg/mL compared to amoxicillin (15.00±1.00, 12.33±0.58, and 13.75±1.83 mm, respectively) at same concentration. While, compounds 78, 81, 83, 94, 96, 100, 108, and 111 showed good activities against E. coli with mean inhibition zone of 12.00±1.00, 13.33±0.58, 17.00±1.00, 12.33  1.15, 12.67±0.58, 12.00±1.00, 13.00± 0.57, and 19.66±00 mm diameter, respectively, at 500 μg/mL compared to amoxicillin (14.67±0.58, 13.33±1.15, and 12.87±1.41 mm, respectively) at same dose. While, compounds, 80, and 99 showed good activities against S. aureus with mean inhibition zone of 11  1.00, 12.00  1.73 at 250 μg/mL where as compound, 112 exhibited 11.33±0.57 mm diameter at 500 μg/mL, compared to amoxicillin (14  0.01, 16.33  0.58, and 10.75±1.83 mm, respectively). Compounds 77, 78 and 80 showed good activities against S. pyogenes with mean inhibition zone of 18.33  0.58, 17.00±1.00 and 22.33±1.53 mm diameter, respectively, at 250 μg/mL compared to amoxicillin (29.67±2.52 mm). Compounds 80, 94, 111 displayed a higher binding affinities of -8.3, -7.9, -7.5 aginst Penicillin binding proteins (PBPs) and compounds 83, 96, 111 displayed a higher binding affinities of -7.6, -8.3, -8.3 Kcal/mol with β-lactamases producing bacterial strains, compared to amoxicillin (-7.2 and -7.9 Kcal/mol, respectively), these results are in good agreement with the in vitro antibacterial activities. In vitro testing for antidiabetic potential on α-amylase enzyme revealed that compounds 80, 81, 82, 83, 94, 98, 99, 111, and 116 with IC50 values of 6.90, 6.74, 6.67, 6.80, 6.56, 6.80, 6.75, 7.59 and 4.08 µg/mL, respectively have comparable to potent inhibitory activities with reference drug, acarbose (IC50= 4.42, 4.42 and 8.0 µg/mL, respectively). The obtained results revealed that, both the biological activities and in silico computational results revealed that compounds 81, 83, 94, 96, 98, 100, 111, and 116 are good antidiabetic agents against α-amylase enzymes and antibacterial agents against P. aeruginosa and E. coli. On the other hand, compounds 80, 81, 95, and 112 were found to be promising antibacterial, against S. aureus, and antioxidant agents. Compounds 80, 99, and 108 displayed significant inhibition of DPPH (IC50= 4.63, 9.48, and 2.44 μg/mL) compared to ascorbic acid (IC50 = 3.21 μg/mL), and compounds 80, 99, and 116 displayed 80.01±0.07, 76.28 ± 0.12, and 89.92±0.42% inhibition of peroxide formation suggesting its potential in preventing the formation of lipid peroxides, respectively. The results of the ADMET study showed that all synthesized compounds obeyed Lipinski's rule of five, good oral drug-likeness and drug-score properties without toxic effects to become orally active molecules. Moreover, the molecular docking studies of the most active compounds showed stronger binding interactions and they are in good agreement with their in vitro biological activities as well as with in silico ADMET profiles, demonstrating promising anti-diabetic properties as well as moderate to strong antibacterial and free radical scavenging activities that may also assist decrease lipid profiles. According to our findings, an efficient synthesis of natural product base heterocyclic compounds via greener protocols of ZnO nanoparticles and ultrasonic-aided approachs are preferable due to increased yields, time savings, and achievement of environmentally friendly reactions, which makes it a useful and eco friendly strategy compared to the conventional method. Hence, the present study revealed that the synthesized compounds appear to become valuable lead molecules for rational drug design.