1,2,4-Triazine derivatives as agents for the prevention of AGE-RAGE-mediated inflammatory cascade in THP-1 monocytes: An approach to prevent inflammation-induced late diabetic complications.

INTRODUCTION: Monocytes mainly contribute to the development and progression of vascular inflammatory conditions via the M1 polarization. The elevated levels of advanced glycation end products (AGEs) in diabetic environment lead to severe inflammation, and the release of pro-inflammatory mediators. This shifts the balance towards the pro-inflammatory state of monocytes. OBJECTIVE: The current study was aimed to determine the antiglycation activity of 1,2,4-triazine derivatives, and study of their molecular basis in regulating the AGEs-mediated inflammatory responses in THP-1 monocytes. METHODS: Primarily, the antiglycation activity of a series of 1,2,4-triazine derivatives was evaluated against MGO-AGEs in vitro. The toxicity of antiglycation compounds was determined by a metabolic assay, using human hepatocyte (HepG2) and monocyte (THP-1) cell lines. DCFH-DA probe was used to evaluate the antioxidant potential of the compounds. Immunocytochemistry, Western blotting, and ELISA techniques were employed to determine the levels of pro-inflammatory markers (NF-κB, RAGE, COX-1, COX-2, and PGE2) in THP-1 monocytes under in-vitro hyperglycemic conditions. RESULTS: Results indicate that the triazine derivatives 22, and 23 were the most potent antiglycation agents among the entire series, while non-toxic to HepG2, and THP-1 cells. Both compounds inhibited the AGEs-induced upstream and downstream signaling of NADPH oxidase and inflammatory mediators p38 and NF-κß, respectively, in THP-1 monocytes. They also inhibited the induction of COX-2 and its product PGE2 by suppressing AGE-RAGE interactions. Moreover, compounds 22, and 23 reversed the AGEs-mediated suppression of COX-1 in THP-1 monocytes. CONCLUSION: In conclusion, 1,2,4-triazine derivatives 22, and 23 have the potential to suppress inflammatory responses under the diabetic environment through AGE-RAGE-NF-κß/p38 nexus in THP-1 monocytes. These findings identify triazines 22, and 23 as compelling candidates for drug development, potentially beneficial for the diabetic patients with an elevated risk of vascular complications, such as atherosclerosis.

Diphenyl-substituted triazine derivatives: synthesis, α-glucosidase inhibitory activity, kinetics and in silico studies.

Background: Diabetes mellitus (DM) is a chronic disorder, considered to be a major global health challenge in the 21st century. α-Glucosidase enzyme is a well-known drug target to treat Type II DM. Methods: A new library of biphenyl-substituted triazines was synthesized and confirmed by various spectroscopic techniques. Results: All compounds showed potent α-glucosidase inhibitory activity, with IC50 values ranging from 35.35 ± 0.34 to 564.41 ± 0.91 µM, as the standard acarbose, IC50 value of 750.7 ± 0.13 µM. Our in silico study has predicted key interactions with the enzyme's active site. Drug-likeness and absorption, distribution, metabolism, excretion and toxicity were also studied. Conclusion: This study has identified a range of potential hits against the α-glucosidase enzyme that may serve as antidiabetic agents after further investigations.

Perplexing Polyphenolics: The Isolations, Syntheses, Reappraisals, and Bioactivities of Flavonoids, Isoflavonoids, and Neoflavonoids from 2016 to 2022.

Flavonoids, isoflavonoids, neoflavonoids, and their various subcategories are polyphenolics-an extensive class of natural products. These compounds are bioactive and display multiple activities, including anticancer, antibacterial, antiviral, antioxidant, and neuroprotective activities. Thus, these compounds can serve as leads for therapeutic agents or targets for complex synthesis; they are coveted and routinely isolated, characterized, biologically evaluated, and synthesized. However, data regarding the compounds' sources, isolation procedures, structural novelties, bioactivities, and synthetic schemes are often dispersed and complex, a dilemma this review aims to address. To serve as an easily accessible guide for researchers wanting to apprise themselves of the latest advancements in this subfield, this review summarizes seventy-six (76) articles published between 2016 and 2022 that detail the isolation and characterization of two hundred and forty-nine (249) novel compounds, the total and semisyntheses of thirteen (13) compounds, and reappraisals of the structures of twenty (20) previously reported compounds and their bioactivities. This article also discusses new synthetic methods and enzymes capable of producing or modifying flavonoids, isoflavonoids, or neoflavonoids.

Substituted Benzimidazole Analogues as Potential α-Amylase Inhibitors and Radical Scavengers.

Benzimidazole scaffolds are known to have a diverse range of biological activities and found to be antidiabetic and antioxidant. In this study, a variety of arylated benzimidazoles 1-31 were synthesized. Except for compounds 1, 6, 7, and 8, all are new derivatives. All compounds were screened for α-amylase inhibitory, 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activities. In vitro screening results revealed that all molecules demonstrated significant α-amylase inhibition with IC50 values of 1.86 ± 0.08 to 3.16 ± 0.31 µM as compared to standard acarbose (IC50 = 1.46 ± 0.26 µM). However, compounds showed significant ABTS and DPPH radical scavenging potentials with IC50 values in the range of 1.37 ± 0.21 to 4.00 ± 0.10 µM for ABTS and 1.36 ± 0.09 to 3.60 ± 0.20 µM for DPPH radical scavenging activities when compared to ascorbic acid with IC50 values of 0.72 ± 0.21 and 0.73 ± 0.05 µM for ABTS and DPPH radical scavenging potentials, respectively. Structure-activity relationship (SAR) was established after critical analysis of varying substitution effects on α-amylase inhibitory and radical scavenging (ABTS and DPPH) potentials. However, molecular docking was also performed to figure out the active participation of different groups of synthetic molecules during binding with the active pocket of the α-amylase enzyme.

N-Aryl-3,4-dihydroisoquinoline Carbothioamide Analogues as Potential Urease Inhibitors.

N-Aryl-3,4-dihydroisoquinoline carbothioamide analogues 1-22 were synthesized by a simple one-step reaction protocol and subjected to in vitro urease inhibition studies for the first time. All compounds 1-22 were found active and showed significant to moderate urease inhibitory potential. Specifically, analogues 1, 2, 4, and 7 were identified to be more potent (IC50 = 11.2 ± 0.81-20.4 ± 0.22 µM) than the standard thiourea (IC50 = 21.7 ± 0.34 µM). The structure-activity relationship showed that compounds bearing electron-donating groups showed superior activity. Molecular docking study on the most active derivatives revealed a good protein-ligand interaction profile against the corresponding target with key interactions, including hydrogen bonding, hydrophobic, and π-anion interactions.

Synthesis and screening of (E)-3-(2-benzylidenehydrazinyl)-5,6-diphenyl-1,2,4-triazine analogs as novel dual inhibitors of α-amylase and α-glucosidase.

(E)-3-(2-Benzylidenehydrazinyl)-5,6-diphenyl-1,2,4-triazines analogs 1-27 were synthesized by multi-step reaction scheme and subjected to in vitro inhibitory screening against α-amylase and α-glucosidase enzymes. Out of these twenty-seven synthetic analogs, ten compounds 14-17, 19, and 21-25 are structurally new. All compounds exhibited good to moderate inhibitory potential in terms of IC50 values ranging (IC50 = 13.02 ± 0.04-46.90 ± 0.05 µM) and (IC50 = 13.09 ± 0.08-46.44 ± 0.24 µM) in comparison to standard acarbose (IC50 = 12.94 ± 0.27 µM and 10.95 ± 0.08 µM), for α-amylase and α-glucosidase, respectively. Structure-activity relationship indicated that analogs with halogen substitution(s) were found more active as compared to compounds bearing other substituents. Kinetic studies on most active α-amylase and α-glucosidase inhibitors 5, 7, 9, 15, 24, and 27, suggested non-competitive and competitive types of inhibition mechanism for α-amylase and α-glucosidase, respectively. Molecular docking studies predicted the good protein-ligand interaction (PLI) profile with key interactions such as arene-arene, H-<, <-<, and <-H etc., against the corresponding targets.

Synthesis, in vitro and in silico screening of 2-amino-4-aryl-6-(phenylthio) pyridine-3,5-dicarbonitriles as novel α-glucosidase inhibitors.

Inhibition of α-glucosidase enzyme is of prime importance for the treatment of diabetes mellitus (DM). Apart of many organic scaffolds, pyridine based compounds have previously been reported for wide range of bioactivities. The current study reports a series of pyridine based synthetic analogues for their α-glucosidase inhibitory potential assessed by in vitro, kinetics and in silico studies. For this purpose, 2-amino-4-aryl-6-(phenylthio)pyridine-3,5-dicarbonitriles 1-28 were synthesized and subjected to in vitro screening. Several analogs, including 1-3, 7, 9, 11-14, and 16 showed many folds increased inhibitory potential in comparison to the standard acarbose (IC50 = 750 ± 10 µM). Interestingly, compound 7 (IC50 = 55.6 ± 0.3 µM) exhibited thirteen-folds greater inhibition strength than the standard acarbose. Kinetic studies on most potent molecule 7 revealed a competitive type inhibitory mechanism. In silico studies have been performed to examine the binding mode of ligand (compound 7) with the active site residues of α-glucosidase enzyme.

Syntheses, in vitro α-amylase and α-glucosidase dual inhibitory activities of 4-amino-1,2,4-triazole derivatives their molecular docking and kinetic studies.

Thirty-three 4-amino-1,2,4-triazole derivatives 1-33 were synthesized by reacting 4-amino-1,2,4-triazole with a variety of benzaldehydes. The synthetic molecules were characterized via1H NMR and EI-MS spectroscopic techniques and evaluated for their anti-hyperglycemic potential. Compounds 1-33 exhibited good to moderate in vitro α-amylase and α-glucosidase inhibitory activities in the range of IC50 values 2.01 ± 0.03-6.44 ± 0.16 and 2.09 ± 0.08-6.54 ± 0.10 µM as compared to the standard acarbose (IC50 = 1.92 ± 0.17 µM) and (IC50 = 1.99 ± 0.07 µM), respectively. The limited structure-activity relationship suggested that different substitutions on aryl part of the synthetic compounds are responsible for variable activity. Kinetic study predicted that compounds 1-33 followed mixed and non-competitive type of inhibitions against α-amylase and α-glucosidase enzymes, respectively. In silico studies revealed that both triazole and aryl ring along with different substitutions were playing an important role in the binding interactions of inhibitors within the enzyme pocket. The synthetic molecules were found to have dual inhibitory potential against both enzymes thus they may serve as lead candidates for the drug development and research in the future studies.

Dihydropyridines as potential α-amylase and α-glucosidase inhibitors: Synthesis, in vitro and in silico studies.

Dihydropyridine derivatives 1-31 were synthesized via one-pot solvent free condition and screened for in vitro against α-amylase and α-glucosidase enzyme. The synthetic derivatives 1-31 showed good α-amylase inhibition in the range of IC50 = 2.21 ± 0.06-9.97 ± 0.08 µM, as compared to the standard drug acarbose (IC50 = 2.01 ± 0.1 µM) and α-glucosidase inhibition in the range of IC50 = 2.31 ± 0.09-9.9 ± 0.1 µM as compared to standard acarbose (IC50 = 2.07 ± 0.1 µM), respectively. To determine the mode of binding interactions of synthetic molecules with active sites of enzyme, molecular docking studies were also performed. Different spectroscopic techniques such as 1H, 13C NMR, EI-MS, and HREI-MS were used to characterize all the synthetic compounds.

Synthesis, in vitro α-amylase inhibitory, and radicals (DPPH & ABTS) scavenging potentials of new N-sulfonohydrazide substituted indazoles.

Over-expression of α-amylase enzyme causes hyperglycemia which lead to many physiological complications including oxidative stress, one of the most commonly associated problem with diabetes mellitus. Marketed α-amylase inhibitors such as acarbose, voglibose, and miglitol used to treat type-II diabetes mellitus, but also linked to several harmful effects. Therefore, it is essential to explore new and nontoxic antidiabetic agents with additional antioxidant properties. In this connection, a series of new N-sulfonohydrazide substituted indazoles 1-19 were synthesized by multistep reaction scheme and assessed for in vitro α-amylase inhibitory and radical (DPPH and ABTS) scavenging properties. All compounds were fully characterized by different spectroscopic techniques including 1H, 13C NMR, EI-MS, HREI-MS, ESI-MS, and HRESI-MS. Compounds showed promising α-amylase inhibitory activities (IC50 = 1.23 ±â€¯0.06-4.5 ±â€¯0.03 µM) as compared to the standard acarbose (IC50 1.20 ±â€¯0.09 µM). In addition to that all derivatives were found good to moderate scavengers of DPPH (IC50 2.01 ±â€¯0.13-5.3 ±â€¯0.11) and ABTS (IC50 = 2.34 ±â€¯0.07-5.5 ±â€¯0.07 µM) radicals, in comparison with standard ascorbic acid having scavenging activities with IC50 = 1.99 ±â€¯0.09 µM, and IC50 2.03 ±â€¯0.11 µM for DPPH and ABTS radicals. In silico molecular docking study was conducted to rationalize the binding interaction of α-amylase enzyme with ligands. Compounds were observed as mixed type inhibitors in enzyme kinetic characterization.

Synthesis, in vitro [Formula: see text]-glucosidase inhibitory activity, and in silico study of (E)-thiosemicarbazones and (E)-2-(2-(arylmethylene)hydrazinyl)-4-arylthiazole derivatives.

This study is focused on the identification of thiazole-based inhibitors for the [Formula: see text]-glucosidase enzyme. For that purpose, (E)-2-(2-(arylmethylene)hydrazinyl)-4-arylthiazole derivatives were synthesized in two steps and characterized by various spectroscopic techniques. All derivatives and intermediates were evaluated for their in vitro [Formula: see text]-glucosidase inhibitory activity. Thiosemicarbazones 20 and 35, and cyclized thiazole derivatives 2, 5-11, 13, 15, 21-24, 27-31, and 36-37 showed significant inhibitory potential in the range of [Formula: see text]-[Formula: see text] as compared to standard acarbose ([Formula: see text]). A molecular modeling study was carried out to understand the binding interactions of compounds with the active site of enzyme.

5-Acetyl-6-methyl-4-aryl-3,4-dihydropyrimidin-2(1H)-ones: As potent urease inhibitors; synthesis, in vitro screening, and molecular modeling study.

5-Acetyl-6-methyl-4-aryl-3,4-dihydropyrimidin-2(1H)-ones 1-43 were synthesized in a "one-pot" three component reaction and structurally characterized by various spectroscopic techniques such as 1H, 13C NMR, EI-MS, HREI-MS, and IR. All compounds were evaluated for their in vitro urease inhibitory activity. It is worth mentioning that except derivatives 1, 11, 12, and 14, all were found to be more potent than the standard thiourea (IC50 = 21.25 ±â€¯0.15 µM) and showed their urease inhibitory potential in the range of IC50 = 3.70 ±â€¯0.5-20.14 ±â€¯0.1 µM. Structure-activity relationship (SAR) was rationalized by looking at the varying structural features of the molecules. However, molecular modeling study was performed to confirm the binding interactions of the molecules (ligand) with the active site of enzyme.