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Background: Medication used to treat Type 2 diabetes by decreasing the absorption of carbohydrates in the intestine consists of α-glucosidase inhibitors. Polyhydroquinoline derivatives have attracted interest as excellent antidiabetic agents. Methods: Polyhydroquinoline derivatives ( 1-17 ) were synthesized and tested for in vitro α-glucosidase inhibitory activity. Results: All the synthesized compounds exhibited excellent to good inhibitory activity, having IC 50 values from 1.23 ± 0.03 to 73.85 ± 0.61 μM, compared with the standard drug, acarbose. The binding mechanism of these derivatives with α-glucosidase was deduced by docking studies and indicated that a slight variation in the orientation of compounds, affects their binding capability. Conclusion: In order to find new antidiabetic drugs, this study has discovered prospective lead candidates.

Inhibiting α-glucosidase is a reliable method for reducing blood sugar levels in diabetic individuals. Several novel chromen-linked hydrazine carbothioamide (3a-r) were designed and synthesized by condensation of chromone-3-carbaldehyde with a variety of substituted thiosemicarbazides. The structures of these new analogues were elucidated through various advanced spectroscopic techniques ( 1 H NMR, 13 C NMR, and ESI-MS). The resulted compounds were screened for α-glucosidase inhibitory potential and all the compounds (3a-r) exhibited potent inhibition of α-glucosidase with IC 50 values ranging 0.29-53.70 µM. Among them compounds 3c, 3f, 3h, and 3r displayed the highest α-glucosidase inhibitor capability with IC 50 values of 1.50, 1.28, 1.08, and 0.29 µM, respectively. Structure-activity relationship showed that different substituted groups are responsible for the variation in the α-glucosidase inhibition. The kinetics studies of the most active inhibitor (3r) were performed, to investigate the mode of inhibition and dissociation constants (Ki), that indicated a competitive inhibitor with Ki value of 1.47 ± 0.31 µM. Furthermore, molecular docking studies was performed to reveal the possible interactions, such as H-bonding, or π-π stacking, with the key residues of α-glucosidase. Docking analysis revealed the importance of hydrazine carbothioamide moiety of compounds in the attachment of ligands with the crucial residues of α-glucosidase. The estimated pharmacokinetic, physicochemical, and drug likeness properties of compounds 3a-r reflects that these molecules have acceptable range of these properties., (© 2023 Wiley Periodicals LLC.)

Bis-Schiff's base derivatives of 4-nitroacetophenone (1-18) were synthesized in good yields by reacting hydrazone of 4-nitroacetophenone with substituted aldehydes and ketones with catalytic amount of acetic acid. The structures of synthesized products (1-18) were deduced with the help of spectroscopic techniques like 1 H NMR, 13 C NMR and HR-ESIMS. The synthesized bis-Schiff's bases were assessed for their α-glucosidase inhibitory activity where compound 4 (IC 50  = 2.79 ± 0.04 µM), 1 (IC 50  = 9.76 ± 0.31 µM), 6 (IC 50  = 11.37 ± 0.20 µM), 17 (IC 50  = 14.10 ± 0.12 µM), 14 (IC 50  = 17.21 ± 0.28 µM), and 8 (IC 50  = 20.73 ± 0.53 µM), showed a very high potential for inhibition of α-glucosidase. Compounds 11, 15, 16, 2, 18, 7, and 5 showed significant inhibition against alpha-glucosidase with IC 50 values 22.98 ± 0.34, 24.45 ± 0.53, 27.31 ± 0.29, 40.56 ± 0.60, 41.58 ± 0.47, 46.53 ± 0.76, and 47.46 ± 0.89 µM, respectively. Furthermore, compound 10 (IC 50  = 52.63 ± 0.74 µM), 12 (IC 50  = 70.80 ± 3.59 µM), 3 (IC 50  = 82.68 ± 0.69 µM), 13 (IC 50  = 88.89 ± 4.25 µM), and 9 (IC 50  = 94.58 ± 0.86 µM) showed moderate activity towards the inhibition of α-glucosidase enzyme. All these compounds were compared with acarbose (IC 50  = 875.75 ± 1.24 µM) as a standard α-glucosidase inhibitor. Molecular docking was used to know the molecular bases of such high activities against α-glucosidase. High docking scores were recorded implying significant interactions between the active compounds and amino acid residues of the active site of α-glucosidase., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Diabetes mellitus, a progressive chronic disease, characterized by the abnormal carbohydrate metabolism is associated with severe health complications including long term dysfunction or failure of several organs, cardiovascular and micro-angiopathic problems (neuropathy, nephropathy, retinopathy). Despite the existence of diverse chemical structural libraries of α-glucosidase inhibitors, the limited diabetic treatment due to the adverse side effects such as abdominal distention, flatulence, diarrhoea, and liver damage associated with these inhibitors encourage the medicinal research community to design and develop new and potent inhibitors of α-glucosidase with better pharmacokinetic properties. In this perspective, we demonstrate the successful integration of common functional groups (ketone & ester) in one combined pharmacophore which is favorable for the formation of hydrogen bonds and other weaker interactions with the target proteins. These keto ester derivatives were screened for their α-glucosidase inhibition potential and the in vitro results revealed compound 3c as the highly active inhibitor with an IC 50 value of 12.4 ± 0.16 μM compared to acarbose (IC 50  = 942 ± 0.74 μM). This inhibition potency was ~76-fold higher than acarbose. Other potent compounds were 3f (IC 50  = 28.0 ± 0.28 μM), 3h (IC 50  = 33.9 ± 0.09 μM), 3g (IC 50  = 34.1 ± 0.04 μM), and 3d (IC 50  = 76.5 ± 2.0 μM). In addition, the emerging use of carbonic anhydrase inhibitors for the treatment of diabetic retinopathy (a leading cause of vision loss) prompted us to screen the keto ester derivatives for the inhibition of carbonic anhydrase-II. Compound 3b was found significantly active against carbonic anhydrase-II with an IC 50 of 16.5 ± 0.92 μM (acetazolamide; IC 50  = 18.2 ± 1.23 μM). Compound 3a also exhibited comparable potency with an IC 50 value of 18.9 ± 1.08 μM. Several structure-activity relationship analyses depicted the influence of the substitution pattern on both the aromatic rings. Molecular docking analysis revealed the formation of several H-bonding interactions through the ester carbonyl and the nitro oxygens of 3c with the side chains of His348, Arg212 and His279 in the active pocket of α-glucosidase whereas 3b interacted with His95, -OH of Thr197, Thr198 and WAT462 in the active site of carbonic anhydrase-II. Furthermore, evaluation of ADME properties suggests the safer pharmacological profile of the tested derivatives., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Fourteen triterpene acids, viz., three tirucallane-type ( 1 - 3 ), eight ursane-type ( 4 - 11 ), two oleanane-type ( 12 , 13 ) and one lupane type ( 21 ), along with boswellic aldehyde ( 14 ), α-amyrine ( 15 ), epi-amyrine ( 16 ), straight chain acid ( 17 ), sesquiterpene ( 19 ) and two cembrane-type diterpenes ( 18 , 20 ) were isolated, first time, from the methanol extract of Boswellia elongata resin. Compound ( 1 ) was isolated for first time as a natural product, while the remaining compounds ( 2 ‒ 21 ) were reported for first time from B. elongata. The structures of all compounds were confirmed by advanced spectroscopic techniques including mass spectrometry and also by comparison with the reported literature. Eight compounds ( 1 - 5, 11, 19 and 20 ) were further screened for in vitro α-glucosidase inhibitory activity. Compounds 3 - 5 and 11 showed significant activity against α-glucosidase with IC 50 values ranging from 9.9-56.8 μM. Compound 4 (IC 50 = 9.9 ± 0.48 μM) demonstrated higher inhibition followed by 11 (IC 50 = 14.9 ± 1.31 μM), 5 (IC 50 = 20.9 ± 0.05 μM) and 3 (IC 50 = 56.8 ± 1.30 μM), indicating that carboxylic acid play a key role in α-glucosidase inhibition. Kinetics studies on the active compounds 3 - 5 and 11 were carried out to investigate their mechanism (mode of inhibition and dissociation constants K i ). All compounds were found to be non-competitive inhibitors with K i values in the range of 7.05 ± 0.17-51.15 ± 0.25 µM. Moreover, in silico docking was performed to search the allosteric hotspot for ligand binding which is targeted by our active compounds investigates the binding mode of active compounds and it was identified that compounds preferentially bind in the allosteric binding sites of α-glucosidase. The results obtained from docking study suggested that the carboxylic group is responsible for their biologic activities. Furthermore, the α-glucosidase inhibitory potential of the active compounds is reported here for the first time.

Diabetes is a non-communicable disease, which occurs either due to the lack of insulin or the inability of the human body to recognize it. The recent data indicates an increase in the trend of people diagnosed with Type 2 diabetes mellitus (T2DM). α-Glucosidase inhibitors are known to reduce the impact of carbohydrates on blood glucose level and prevent the digestion of carbohydrates. α-glucosidase inhibitors hold great potential for the treatment of T2DM. In search of better α-glucosidase inhibitors, a series of novel (R)-4-fluorophenyl-1H-1,2,3-triazole derivatives were synthesized (6 and 8a-n) and evaluated for their α-glucosidase inhibitory activity in vitro. All new compounds were characterized by 1 H NMR, 13 C NMR, 19 F NMR, ESI-MS, and where applicable by single crystal X-ray diffraction (8 m). A preliminary structure-activity relationship suggested that the presence of 1H-1,2,3-triazole ring in (R)-4-fluorophenyl-1H-1,2,3-triazole derivatives has remarkable contribution in the overall activity. Molecular docking studies were carried out to investigate the binding mode of compounds within the active site of the α-glucosidase enzyme. Docking results are in complete agreement with the experimental finding. This study unravelled a new class of triazole derivatives with α-glucosidase inhibitory activity., (Copyright © 2019 Elsevier Inc. All rights reserved.)