New indole based hybrid oxadiazole scaffolds with N-substituted acetamides: As potent anti-diabetic agents

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Novel bi‐heterocyclic benzamides were synthesized by sequentially converting 4‐(1H‐indol‐3‐yl)butanoic acid (1) into ethyl 4‐(1H‐indol‐3‐yl)butanoate (2), 4‐(1H‐indol‐3‐yl)butanohydrazide (3), and a nucleophilic 5‐[3‐(1H‐indol‐3‐yl)propyl]‐1,3,4‐oxadiazole‐2‐thiol (4). In a parallel series of reactions, various electrophiles were synthesized by reacting substituted anilines (5a–k) with 4‐(chloromethyl)benzoylchloride (6) to afford 4‐(chloromethyl)‐N‐(substituted‐phenyl)benzamides (7a–k). Finally, the nucleophilic substitution reaction of 4 was carried out with newly synthesized electrophiles, 7a–k, to acquire the targeted bi‐heterocyclic benzamides, 8a–k. The structural confirmation of all the synthesized compounds was done by IR, 1H NMR, 13C NMR, EI‐MS, and CHN analysis data. The inhibitory effects of these bi‐heterocyclic benzamides (8a–k) were evaluated against alkaline phosphatase, and all these molecules were identified as potent inhibitors relative to the standard used. The kinetics mechanism was ascribed by evaluating the Lineweaver–Burk plots, which revealed that compound 8b inhibited alkaline phosphatase non‐competitively to form an enzyme–inhibitor complex. The inhibition constant Ki calculated from Dixon plots for this compound was 1.15 μM. The computational study was in full agreement with the experimental records and these ligands exhibited good binding energy values. These molecules also exhibited mild cytotoxicity toward red blood cell membranes when analyzed through hemolysis. So, these molecules might be deliberated as nontoxic medicinal scaffolds to render normal calcification of bones and teeth.

Section: Resultsmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

“…The product was isolated by solvent extraction using chloroform (50 mL × 3). The solvent was distilled off and the required ester, 2 , was obtained as reddish brown liquid …”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Bi‐heterocyclic benzamides as alkaline phosphatase inhibitors: Mechanistic comprehensions through kinetics and computational approaches

Abbasi

Nazir

Ur-Rehman

et al. 2019

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Unveiling the chemistry of 1,3,4‐oxadiazoles and thiadiazols: A comprehensive review

Gour,

Yahya,

Shahar Yar

2023

Oxadiazoles and thiadiazoles are malleable heterocycles that have recently generated major interest in the field of medicinal chemistry. Compounds based on these moieties have versatile biological applications such as anticonvulsant, anticancer, antidiabetic, and antioxidant agents. Due to the versatile nature and stability of the oxadiazole and thiadiazole nucleus, medicinal chemists have changed the structural elements of the ring in numerous ways. These compounds have shown significant anticonvulsant effects, demonstrating their potential in the management of epileptic disorders. In this review, we have covered numerous biological pathways and in silico targeted proteins of oxadiazole and thiadiazole derivatives for treating various biological disorders. The data compiled in this article will be helpful for researchers, research scientists, and research chemists who work in the field of drug discovery and drug development.

Multitargeted inhibition of key enzymes associated with diabetes and Alzheimer's disease by 1,3,4‐oxadiazole derivatives: Synthesis, in vitro screening, and computational studies

Fatima,

Saleem,

Salar

et al. 2023

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A library of 22 derivatives of 1,3,4‐oxadiazole‐2‐thiol was synthesized, structurally characterized, and assessed for its potential to inhibit α‐amylase, α‐glucosidase, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and antioxidant activities. Most of the tested compounds demonstrated good to moderate inhibition potential; however, their activity was lower than that of the standard acarbose. Significantly, compound 3f exhibited the highest inhibition potential against α‐glucosidase and α‐amylase enzymes, with IC50 values of 18.52 ± 0.09 and 20.25 ± 1.05 µM, respectively, in comparison to the standard acarbose (12.29 ± 0.26; 15.98 ± 0.14 µM). Compounds also demonstrated varying degrees of inhibitory potential against AChE (IC50 = 9.25 ± 0.19 to 36.15 ± 0.12 µM) and BChE (IC50 = 10.06 ± 0.43 to 35.13 ± 0.12 µM) enzymes compared to the standard donepezil (IC50 = 2.01 ± 0.12; 3.12 ± 0.06 µM), as well as DPPH (IC50 = 20.98 ± 0.06 to 52.83 ± 0.12 µM) and ABTS radical scavenging activities (IC50 = 22.29 ± 0.18 to 47.98 ± 0.03 µM) in comparison to the standard ascorbic acid (IC50 = 18.12 ± 0.15; 19.19 ± 0.72). The kinetic investigations have demonstrated that the compounds exhibit competitive‐type inhibition for α‐amylase, noncompetitive‐type inhibition for α‐glucosidase and AChE, and mixed‐type inhibition for BChE. Additionally, a molecular docking study was performed on all synthetic oxadiazoles to explore the interaction details of these compounds with the active sites of the enzymes.