Molecular hybridization yielded phenyl linked oxadiazole-benzohydrazones hybrids 6-35 and were evaluated for their antileishmanial potentials. Compound 10, a 3,4-dihydroxy analog with IC50 value of 0.95 ± 0.01 μM, was found to be the most potent antileishmanial agent (7 times more active) than the standard drug pentamidine (IC50 = 7.02 ± 0.09 μM). The current series 6-35 conceded in the identification of thirteen (13) potent antileishmanial compounds with the IC50 values ranging between 0.95 ± 0.01-78.6 ± 1.78 μM. Molecular docking analysis against pteridine reductase (PTR1) were also performed to probe the mode of action. Selectivity index showed that compounds with higher number of hydroxyl groups have low selectivity index. Theoretical stereochemical assignment was also done for certain derivatives by using density functional calculations.
In search of potent urease inhibitor indole analogues (1-22) were synthesized and evaluated for their urease inhibitory potential. All analogues (1-22) showed a variable degree of inhibitory interaction potential having IC50 value ranging between 0.60 ± 0.05 to 30.90 ± 0.90 µM when compared with standard thiourea having IC50 value 21.86 ± 0.90 µM. Among the synthesized analogues, the compounds 1, 2, 3, 5, 6, 8, 12, 14, 18, 20 and 22 having IC50 value 3.10 ± 0.10, 1.20 ± 0.10, 4.60 ± 0.10, 0.60 ± 0.05, 5.30 ± 0.20, 2.50 ± 0.10, 7.50 ± 0.20, 3.90 ± 0.10, 3.90 ± 0.10, 2.30 ± 0.05 and 0.90 ± 0.05 µM respectively were found many fold better than the standard thiourea. All other analogues showed better urease interaction inhibition. Structure activity relationship (SAR) has been established for all analogues containing different substituents on the phenyl ring. To understand the binding interaction of most active analogues with enzyme active site docking study were performed.Communicated by Ramaswamy H. Sarma.
We have synthesized benzo[d]oxazole derivatives (1-21) through a multistep reaction. Alteration in the structure of derivatives was brought in the last step via using various substituted aromatic aldehydes. In search of an anti-Alzheimer agent, all derivatives were evaluated against acetylcholinesterase and butyrylcholinesterase enzyme under positive control of standard drug donepezil (IC50 = 0.016 ± 0.12 and 4.5 ± 0.11 µM) respectively. In case of acetylcholinesterase enzyme inhibition, derivatives 8, 9 and 18 (IC50 = 0.50 ± 0.01, 0.90 ± 0.05 and 0.3 ± 0.05 µM) showed very promising inhibitory potentials. While in case of butyrylcholinesterase enzyme inhibition, most of the derivatives like 6, 8, 9, 13, 15, 18 and 19 (IC50 = 2.70 ± 0.10, 2.60 ± 0.10, 2.20 ± 0.10, 4.25 ± 0.10, 3.30 ± 0.10, 0.96 ± 0.05 and 3.20 ± 0.10 µM) displayed better inhibitory potential than donepezil. Moreover, derivative 18 is the most potent one among the series in both inhibitions. The binding interaction of derivatives with the active gorge of the enzyme was confirmed via a docking study. Furthermore, the binding interaction between derivatives and the active site of enzymes was correlated through the SAR study. Structures of all derivatives were confirmed through spectroscopic techniques such as 1H-NMR, 13C-NMR and HREI-MS, respectively.Communicated by Ramaswamy H. Sarma.
Trillium govanianum is a high-value medicinal herb, having multifunctional traditional and culinary uses. The present investigation was carried out to evaluate the phytochemical, biological and toxicological parameters of the T. govanianum Wall. ex D. Don (Family: Trilliaceae) roots collected from Azad Kashmir, Pakistan. Phytochemical profiling was achieved by determining total bioactive contents (total phenolic and flavonoid contents) and UHPLC-MS analysis. For biological evaluation, antioxidant activities (DPPH, ABTS, FRAP, CUPRAC, phosphomolybdenum, and metal chelation assays) and enzyme inhibition activities (against AChE, BChE, glucosidase, amylase, and tyrosinase) were performed. Moreover, cytotoxicity was assessed against three human carcinoma cell lines (MDA-MB-231, CaSki, and DU-145). The tested extract was found to contain higher total phenolics (7.56 mg GAE/g dry extract) as compared to flavonoid contents (0.45 mg RE/g dry extract). Likewise, for the antioxidant activity, higher CUPRAC activity was noted with 39.84 mg TE/g dry extract values. In the case of enzyme assays, higher activity was pointed out against the cholinesterase, glucosidase and tyrosinase enzymes. The plant extract displayed significant cytotoxicity against the cell lines examined. Moreover, the in-silico studies highlighted the interaction between the important phytochemicals and tested enzymes. To conclude, the assessed biological activity and the existence of bioactive phytochemicals in the studied plant extract may pave the way for the development of novel pharmaceuticals.
Dihydropyrimidones 1-37 were synthesized via a 'one-pot' three component reaction according to well-known Biginelli reaction by utilizing Cu(NO3)2·3H2O as catalyst, and screened for their in vitro β-glucuronidase inhibitory activity. It is worth mentioning that amongst the active molecules, compounds 8 (IC50=28.16±.056μM), 9 (IC50=18.16±0.41μM), 10 (IC50=22.14±0.43μM), 13 (IC50=34.16±0.65μM), 14 (IC50=17.60±0.35μM), 15 (IC50=15.19±0.30μM), 16 (IC50=27.16±0.48μM), 17 (IC50=48.16±1.06μM), 22 (IC50=40.16±0.85μM), 23 (IC50=44.16±0.86μM), 24 (IC50=47.16±0.92μM), 25 (IC50=18.19±0.34μM), 26 (IC50=33.14±0.68μM), 27 (IC50=44.16±0.94μM), 28 (IC50=24.16±0.50μM), 29 (IC50=34.24±0.47μM), 31 (IC50=14.11±0.21μM) and 32 (IC50=9.38±0.15μM) found to be more potent than the standard d-saccharic acid 1,4-lactone (IC50=48.4±1.25μM). Molecular docking study was conducted to establish the structure-activity relationship (SAR) which demonstrated that a number of structural features of dihydropyrimidone derivatives were involved to exhibit the inhibitory potential. All compounds were characterized by spectroscopic techniques such as (1)H, (13)C NMR, EIMS and HREI-MS.
In an effort to design and synthesize a new class of α-glucosidase inhibitor, we synthesized benzothiazole hybrid having benzohydrazide moiety (5). Compound 5 was reacted with various substituted aryl aldehyde to generate a small library of compounds 6-35. Synthesis of compounds was confirmed by the spectral information. These compounds were screened for their α-glucosidase activity. They showed a varying degree of α-glucosidase inhibition with IC50 values ranging between 5.31 and 53.34 μM. Compounds 6, 7, 9-16, 19, 21-30, 32-35 showed superior activity as compared to standard acarbose (IC50 = 906 ± 6.3 μM). This has identified a new class of α-glucosidase inhibitors. The predicted physico-chemical properties indicated the drug appropriateness for most of these compounds, as they obey Lipinski's rule of five (RO5). A hybrid B3LYP density functional theory (DFT) was employed for energy, minimization of 3D structures for all synthetic compounds using 6-311 + G(d,p) basis sets followed by molecular docking to explore their interactions with human intestinal C- and N-terminal domains of α-glucosidase. All compounds bind to the prospective allosteric site of the C- terminal domain, and consequently, may be considered as mixed inhibitors. It was hypothesized that both the dipole moment and H-bond interactions govern the biological activation of these compounds.
A series of thiobarbituric acid derivatives 1-27 were synthesized and evaluated for their urease inhibitory potential. Exciting results were obtained from the screening of these compounds 1-27. Compounds 5, 7, 8, 11, 16, 17, 22, 23 and 24 showed excellent urease inhibition with IC50 values 18.1 ± 0.52, 16.0 ± 0.45, 16.0 ± 0.22, 14.3 ± 0.27, 6.7 ± 0.27, 10.6 ± 0.17, 19.2 ± 0.29, 18.2 ± 0.76 and 1.61 ± 0.18 μM, respectively, much better than the standard urease inhibitor thiourea (IC₅₀=21 ± 0.11 μM). Compound 3, 4, 10, and 26 exhibited comparable activities to the standard with IC₅₀ values 21.4 ± 1.04 and 21.5 ± 0.61 μM, 22.8 ± 0.32, 25.2 ± 0.63, respectively. However the remaining compounds also showed prominent inhibitory potential The structure-activity relationship was established for these compounds. This study identified a novel class of urease inhibitors. The structures of all compounds were confirmed through spectroscopic techniques such as EI-MS and (1)H NMR.
A series of thirty (30) thiazole analogs were prepared, characterized by (1)H NMR, (13)C NMR and EI-MS and evaluated for Acetylcholinesterase and butyrylcholinesterase inhibitory potential. All analogs exhibited varied butyrylcholinesterase inhibitory activity with IC50 value ranging between 1.59±0.01 and 389.25±1.75μM when compared with the standard eserine (IC50, 0.85±0.0001μM). Analogs 15, 7, 12, 9, 14, 1, 30 with IC50 values 1.59±0.01, 1.77±0.01, 6.21±0.01, 7.56±0.01, 8.46±0.01, 14.81±0.32 and 16.54±0.21μM respectively showed excellent inhibitory potential. Seven analogs 15, 20, 19, 24, 28, 30 and 25 exhibited good acetylcholinesterase inhibitory potential with IC50 values 21.3±0.50, 35.3±0.64, 36.6±0.70, 44.81±0.81, 46.36±0.84, 48.2±0.06 and 48.72±0.91μM respectively. All other analogs also exhibited well to moderate enzyme inhibition. The binding mode of these compounds was confirmed through molecular docking.
Benzimidazole analogs 1-27 were synthesized, characterized by EI-MS and (1)HNMR and their α-glucosidase inhibitory activities were found out experimentally. Compound 25, 19, 10 and 20 have best inhibitory activities with IC50 values 5.30±0.10, 16.10±0.10, 25.36±0.14 and 29.75±0.19 respectively against α-glucosidase. Compound 6 and 12 has no inhibitory activity against α-glucosidase enzyme among the series. Further studies showed that the compounds are not showing any cytotoxicity effect. The docking studies of the compounds as well as the experimental activities of the compounds correlated well. From the molecular docking studies, it was observed that the top ranked conformation of all the compounds fit well in the active site of the homology model of α-glucosidase.
6-Chloro-2-Aryl-1H-imidazo[4,5-b]pyridine derivatives 1-26 were synthesized and characterized by various spectroscopic techniques. All these derivatives were evaluated for their antiglycation, antioxidant and β-glucuronidase potential followed their docking studies. In antiglycation assay, compound 2 (IC50=240.10±2.50μM) and 4 (IC50=240.30±2.90μM) was found to be most active compound of this series, while compounds 3 (IC50=260.10±2.50μM), 6 (IC50=290.60±3.60μM), 13 (IC50=288.20±3.00μM) and 26 (IC50=292.10±3.20μM) also showed better activities than the standard rutin (IC50=294.50±1.50μM). In antioxidant assay, compound 1 (IC50=69.45±0.25μM), 2 (IC50=58.10±2.50μM), 3 (IC50=74.25±1.10μM), and 4 (IC50=72.50±3.30μM) showed good activities. In β-glucuronidase activity, compounds 3 (IC50=29.25±0.50μM), compound 1 (IC50=30.10±0.60μM) and compound 4 (IC50=46.10±1.10μM) showed a significant activity as compared to than standard D-Saccharic acid 1,4-lactonec (IC50=48.50±1.25μM) and their interaction with the enzyme was confirm by docking studies.
A library of novel 2,5-disubtituted-1,3,4-oxadiazoles with benzimidazole backbone (3a-3r) was synthesized and evaluated for their potential as β-glucuronidase inhibitors. Several compounds such as 3a-3d, 3e-3j, 3l-3o, 3q and 3r showed excellent inhibitory potentials much better than the standard (IC50=48.4±1.25μM: d-saccharic acid 1,4-lactone). All the synthesized compounds were characterized satisfactorily by using different spectroscopic methods. We further evaluated the interaction of the active compounds and the enzyme active site with the help of docking studies.
The synthetic indole Mannich bases 1-13 have been investigated for their ability to modulate immune responses measured in vitro. These activities were based on monitoring their affects on T-lymphocyte proliferation, reactive oxygen species (ROS), IL (interleukin)-2, IL-4, and nitric oxide production. Compound 5 was found to be the most potent immunomodulator in this context. Four of the synthesized compounds, 5, 11, 12, and 13, have significant potent inhibitory effects on T-cell proliferation, IL-4, and nitric oxide production. However, none of the thirteen indole compounds exerted any activity against ROS production.
Isatin base Schiff bases (1-20) were synthesized, characterized by (1)H NMR and EI/MS and evaluated for α-glucosidase inhibitory potential. Out of these twenty (20) compounds only six analogs showed potent α-glucosidase inhibitory potential with IC50 value ranging in between 2.2±0.25 and 83.5±1.0μM when compared with the standard acarbose (IC50=840±1.73μM). Among the series compound 2 having IC50 value (18.3±0.56μM), 9 (83.5±1.0μM), 11 (3.3±0.25μM), 12 (2.2±0.25μM), 14 (11.8±0.15μM), and 20 (3.0±0.15μM) showed excellent inhibitory potential many fold better than the standard acarbose. The binding interactions of these active analogs were confirmed through molecular docking.
Benzotriazoles (4-6) were synthesized which were further reacted with different substituted benzoic acids and phenacyl bromides to synthesize benzotriazole derivatives (7-40). The synthetic compounds (7-40) were characterized via different spectroscopic techniques including EI-MS, HREI-MS, 1H-, and 13C NMR. These molecules were examined for their anti-hyperglycemic potential hence were evaluated for α-glucosidase and α-amylase inhibitory activities. All benzotriazoles displayed moderate to good inhibitory activity in the range of IC50 values of 2.00-5.6 and 2.04-5.72 μM against α-glucosidase and α-amylase enzymes, respectively. The synthetic compounds were divided into two categories "A" and "B", in order to understand the structure-activity relationship. Compounds 25 (IC50 = 2.41 ± 1.31 μM), (IC50 = 2.5 ± 1.21 μM), 36 (IC50 = 2.12 ± 1.35 μM), (IC50 = 2.21 ± 1.08 μM), and 37 (IC50 = 2.00 ± 1.22 μM), (IC50 = 2.04 ± 1.4 μM) with chloro substitution/s at aryl ring were found to be most active against α-glucosidase and α-amylase enzymes. Molecular docking studies on all compounds were performed which revealed that chloro substitutions are playing a pivotal role in the binding interactions. The enzyme inhibition mode was also studied and the kinetic studies revealed that the synthetic molecules have shown competitive mode of inhibition against α-amylase and non-competitive mode of inhibition against α-glucosidase enzyme.
The current study describes the discovery of novel inhibitors of α-glucosidase and α-amylase enzymes. For that purpose, new hybrid analogs of N-hydrazinecarbothioamide substituted indazoles 4-18 were synthesized and fully characterized by EI-MS, FAB-MS, HRFAB-MS, 1H-, and 13C NMR spectroscopic techniques. Stereochemistry of the imine double bond was established by NOESY measurements. All derivatives 4-18 with their intermediates 1-3, were evaluated for in vitro α-glucosidase and α-amylase enzyme inhibition. It is worth mentioning that all synthetic compounds showed good inhibition potential in the range of 1.54 ± 0.02-4.89 ± 0.02 µM for α-glucosidase and for α-amylase 1.42 ± 0.04-4.5 ± 0.18 µM in comparison with the standard acarbose (IC50 value of 1.36 ± 0.01 µM). In silico studies were carried out to rationalize the mode of binding interaction of ligands with the active site of enzymes. Moreover, enzyme inhibitory kinetic characterization was also performed to understand the mechanism of enzyme inhibition.
A series of twenty-six analogs of benzimidazole based oxadiazole have been synthesized and evaluated against alpha-glycosidase enzyme. Most the analogs showed excellent to good inhibitory potential. Among the screened analogs, analog 1, 2, 3 and 14 with IC50 values 4.6 ± 0.1, 9.50 ± 0.3, 2.6 ± 0.1 and 9.30 ± 0.4 µM respectively showedexcellent inhibitory potential than reference drug acarbose (IC50 = 38.45 ± 0.80 µM). Some of the analogs like 19, 21, 22 and 23 with methyl and methoxy substituent on phenyl ring show hydrophobic interaction and were found with no inhibitory potential. The binding interactions between synthesized analogs and ligands protein were confirmed through molecular docking study. Various spectroscopic techniques like 1H NMR, 13C NMR, and EI-MS were used for characterization of all synthesized analogs. These derivatives were synthesized by simple mode of synthesis like heterocyclic ring formation.
A variety of dihydroquinazolin-4(1H)-one derivatives (1-37) were synthesized via "one-pot" three-component reaction scheme by treating aniline and different aromatic aldehydes with isatoic anhydride in the presence of acetic acid. Chemical structures of compounds were deduced by different spectroscopic techniques including EI-MS, HREI-MS, 1H-, and 13C-NMR. Compounds were subjected to α-amylase and α-glucosidase inhibitory activities. A number of derivatives exhibited significant to moderate inhibition potential against α-amylase (IC50 = 23.33 ± 0.02-88.65 ± 0.23 μM) and α-glucosidase (IC50 = 25.01 ± 0.12-89.99 ± 0.09 μM) enzymes, respectively. Results were compared with the standard acarbose (IC50 = 17.08 ± 0.07 μM for α-amylase and IC50 = 17.67 ± 0.09 μM for α-glucosidase). Structure-activity relationship (SAR) was rationalized by analyzing the substituents effects on inhibitory potential. Kinetic studies were implemented to find the mode of inhibition by compounds which revealed competitive inhibition for α-amylase and non-competitive inhibition for α-glucosidase. However, in silico study identified several important binding interactions of ligands (synthetic analogues) with the active site of both enzymes.
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 ± 0.06-4.5 ± 0.03 µM) as compared to the standard acarbose (IC50 1.20 ± 0.09 µM). In addition to that all derivatives were found good to moderate scavengers of DPPH (IC50 2.01 ± 0.13-5.3 ± 0.11) and ABTS (IC50 = 2.34 ± 0.07-5.5 ± 0.07 µM) radicals, in comparison with standard ascorbic acid having scavenging activities with IC50 = 1.99 ± 0.09 µM, and IC50 2.03 ± 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.
Apoptotic cell death is the cause of the loss of insulin-producing β-cells in all forms of diabetes mellitus. The identification of small molecules capable of protecting cytokine-induced apoptosis could form the basis of useful therapeutic interventions. Here in, we present the discovery and synthesis of new benzimidazole derivatives, capable of rescuing pancreatic β-cells from cytokine-induced apoptosis. Three hydrazone derivatives of benzimidazole significantly increased the cellular ATP levels, reduced caspase-3 activity, reduced nitrite production and increased glucose-stimulated insulin secretion in the presence of proinflammatory cytokines. These findings suggest that these compounds may protect β-cells from the harmful effects of cytokines and may serve as candidates for therapeutic intervention for diabetes.