Remarkable Inhibitory Potential Research Articles

Synthesis, Characterization, and Evaluation of Tetrazole Derivatives with Pyrrole‐2,5‐Dione Moieties as Urease Inhibitors: Exploring Structure‐Activity Relationships and Computational Insights

AbstractA series of Tetrazole derivatives containing pyrrole‐2,5‐dione groups (5 a–e) were synthesized and comprehensively characterized using HRMS, FT‐IR, and 1H−, 13C‐NMR spectroscopic techniques. These compounds were evaluated for their ability to inhibit urease activity in vitro, demonstrating remarkable inhibitory potential with IC50 values ranging from 4.325±1 to 18.28±1 μM, surpassing the standard thiourea (IC50=17.386±1 μM). Notably, compounds 5 b (IC50=4.325±1 μM), 5 e (IC50=7.411±1 μM), 5 c (IC50=9.313±1 μM), and 5 a (IC50=10.46±1 μM) exhibited notably higher activity compared to the standard thiourea. In our exploration of the structure‐activity relationship (SAR), we investigated the impact of differently substituted aryl rings on inhibitory potential. Our results highlight the crucial role of substituent positioning on the aryl ring, independent of the nature of the substituents. Additionally, computational studies were conducted on all compounds, supporting our experimental findings. Molecular docking simulations revealed a strong correlation between biological evaluation results and computational predictions, affirming the promising inhibitory activity of the compounds.

Synthesis, physico‐chemical characterization and theoretical exploration of some 2,4,5‐triaryl imidazole derivatives

AbstractA series of six 2, 4, 5‐triarylimidazole (IM‐1 to IM‐6) have been prepared by the multi‐component condensation reaction involving benzil, substituted salicylaldehyde and NH4OAc under solvent free condition by using unconventional CuB4O7 catalyst. The compounds were characterized using various analytical and spectroscopic techniques. Furthermore, DFT studies such as optimization of gas phase structure, HOMO‐LUMO energies, Molecular electrostatic potential, NLO properties of these compounds have been investigated. In‐silico molecular docking study of 2, 4, 5‐triarylimidazole derivatives (IM‐1 to IM‐6) have been carried out to ascertain the inhibitory potential of these molecules against a diabetic protein (PDB ID 1IR3). The study showed that the these compounds have remarkable inhibitory potential against the protein 1IR3 with binding energy (ΔG) values for the compounds (IM‐1 to IM‐6) −8.7, −8.4, −8.8, −8.0, −8.9 and −7.8 kcal/mol respectively. In addition, the pharmacokinetic properties (ADMET) of the compounds (IM‐1 to IM‐6) have also been studied.

Synthesis, α-Glucosidase and β-Galactosidase Inhibitory Potentials and Molecular Docking of Some Novel Benzofuran-Pyridazine Derivatives

A novel series of benzofuran-pyridazine derivatives have been synthesized and characterized by different spectroscopic techniques including FT-IR, 1H-NMR, 13C-NMR, and ESI-MS spectrometry. All synthesized compounds were evaluated in vitro for their antidiabetic activity against α-glucosidase and β-galactosidase enzymes. All derivatives (3a-3h) and (4a-4b) showed a remarkable inhibitory potential greater than 89% against α-glucosidase enzyme compared to standard acarbose (42.50%), and compounds 3 b and 4a exhibited significant inhibitory potential against β-galactosidase enzyme with 50.33% and 57.67% respectively, compared to standard Queretin (52.00%). A molecular docking study was conducted to understand the binding interactions of the compounds with the active site of the α-glucosidase enzyme.

Therapeutic potential of reserpine in metabolic syndrome: An evidence based study

Reserpine is as old as the scientific diagnosis of hypertension. For many years’ clinicians have used it for the treatment of high blood pressure, but with the passage of time and introduction of new anti-hypertensive drugs, the usage of reserpine has gone down drastically most probably due to poorly understood mechanism of action and multiple misleading adverse effects precisely due to high dosing of reserpine. With an aim to elucidate the specific mechanism of action, we screened reserpine against various targets associated with regulation of blood pressure. Surprisingly reserpine showed remarkable inhibitory potential for soluble epoxide hydrolase an enzyme responsible for pathophysiology of not only hypertension but also hyperlipidemia, diabetes and inflammation collectively known as metabolic syndrome. The in-silico, in-vitro and in-vivo results showed that reserpine has the ability to treat metabolic syndrome effectively by inhibiting soluble epoxide hydrolase.

Potentially Postbiotic-Containing Preservative to Extend the Use-By Date of Raw Chicken Sausages and Semifinished Chicken Products

This study aimed to evaluate the use of potentially postbiotic-containing preservative (PPCP), produced in a semiculture fermentation system with Lacticaseibacillus paracasei DTA 83 and Saccharomyces cerevisiae var. boulardii 17, to extend the use-by date of raw chicken sausages and semifinished chicken products. Microorganisms associated with the spoilage of chicken products were stimulated to grow by pair incubation of the products at two different temperatures and with collection at different times. The turbidity method was performed to evaluate the microbial susceptibility to PPCP. PPCP was added in chicken products to obtain an in situ partial inhibitory effect on spoilage microorganisms to extend the use-by date. The in vitro trial showed total inhibition of the microbial growth by adding above 3.0% of PPCP. Although this concentration showed a remarkable inhibitory potential, its addition can severely impact the formulation cost. Thus, the application of doses with partial microbial inhibition may be a suitable strategy for the use of PPCP in chicken products. The results revealed that cold chain management and couse of PPCP in chicken products extended the proposed use-by date, suggesting an alternative food preservation technology for the use of naturally derived compounds.

Chemical composition, antioxidant and antimicrobial activities of Himalayan Fraxinus micrantha Lingelsh leaf extract

The present investigation determines the phytochemical analysis, antioxidant and antibacterial potential of methanol extract of Himalayan Fraxinus micrantha (Lingelsh) leaves. Chemical analysis of extract revealed the presence of fifty five compounds. The extract was strongly characterised by tyrosol, esculetin, β-sitosterin, l-(+)-ascorbic acid 2,6-dihexadecanoate, (Z,Z)-6,9-cis-3,4-epoxy nonadecadiene as main components (62.6%). The F. micrantha extract presents IC50, 43.93 µg/ml and 68.90 µg/ml using DPPH and H2O2 scavenging assay, respectively. The antibacterial activity of F. micrantha was evaluated for five microorganisms showed that the extract had a remarkable inhibitory potential with a mean zone diameter of inhibition ranging from 11 to 22 mm. The MIC of the extracts ranged from 7.8 to 250 µg/ml and MBC value range 31.25 to 125 µg/ml. F. micrantha showed significant antibacterial activity against B. subtilis (22 mm, ZOI) with MIC and MBC values 7.8 and 31.25 µg/ml respectively.

Therapeutic potential of labdane diterpene isolated from Alpinia nigra: detailed hemato-compatibility and antimicrobial studies

(E)-labda-8(17), 12-diene-15,16-dial has been isolated from the seeds of Alpinia nigra that is unsuitable for oral administration and evident from in silico studies. The present investigation therefore deals with understanding the effect of this compound on RBCs for intravenous administration. No prominent hemolytic effect of compound at a concentration of ≤0.4 mg/ml was found whereas higher concentrations perforated RBC membrane. The molecule showed remarkable inhibitory potential against Gram negative bacteria (concentration ≥0.025 mg/ml) causing cell lysis. In case of pathogenic yeast Candida albicans although growth was inhibited (concentration ≥ 0.0025 mg/ml), growth kinetic study revealed that the diterpene significantly delayed fungal growth (concentration 0.005–0.020 mg/ml) by preventing substrate uptake and was able to extend its lag phase in a dose-dependent manner. This study tries to unveil the mechanism of action of this diterpene on microorganisms with differential cell wall compositions.

In Silico and 3D QSAR Studies of Natural Based Derivatives as Xanthine Oxidase Inhibitors.

A large number of disorders and their symptoms emerge from deficiency or overproduction of specific metabolites has drawn the attention for the discovery of new therapeutic agents for the treatment of disorders. Various approaches such as computational drug design have provided the new methodology for the selection and evaluation of target protein and the lead compound mechanistically. For instance, the overproduction of xanthine oxidase causes the accumulation of uric acid which can prompt gout. In the present study we critically discussed the various techniques such as 3-D QSAR and molecular docking for the study of the natural based xanthine oxidase inhibitors with their mechanistic insight into the interaction of xanthine oxidase and various natural leads. The computational studies of deferent natural compounds were discussed as a result the flavonoids, anthraquinones, xanthones shown the remarkable inhibitory potential for xanthine oxidase inhibition moreover the flavonoids such as hesperidin and rutin were found as promising candidates for further exploration.

Rational Approaches, Design Strategies, Structure Activity Relationship and Mechanistic Insights for Esterase Inhibitors.

Esterase is an enzyme that splits esters into an acid and alcohol. Varieties of esterases are present in human body to control diverse set of cellular processes and execute their specific functions. It can be seen that any increase in metabolites produced by these enzymes lead to severe pathological conditions like Alzheimer disease, hypercholesterolemia etc. Objective: Numerous esterase inhibitors have been developed and reported by the researchers around the globe, but not systematically summarized yet. Therefore, this assemblage focuses on various reported esterase inhibitors during recent past with detailed account of the design strategies employed for the synthesis of novel drug entities. The article also highlights the structure activity relationship along with mechanistic insights revealed during the biological evaluation of inhibitors as esterase inhibition. The interactions with the amino acid residues responsible for esterase inhibitory potential of molecules have also been discussed. This compilation will be of great interest for the researchers working in the area of esterase inhibitors. Rivastigmine derivatives (44-53), tacrine-piperazine hybrid (136), coumarin-benzofuran derivative (169), coumarin-benzylpiperidine hybrid (181) and phenylcinnamide derivative (220) found to be exerting cholinesterase inhibition with IC50 below the range of 1 nM. Whereas, flavone (258) has displayed anticholesterol esterase potential below 1 nM. Benzil like derivative, (273) has also been designed and reported to possess remarkable inhibitory potential (IC50 < 1 nM) against carboxylesterase. These representative results place them in forefront as potential future drug candidates to further develop potent and specific esterase inhibitors.

Phytochemicals and anti-aging potentials of the extracts from Lagerstroemia speciosa and Lagerstroemia floribunda

Skin aging is caused by oxidative stress and the enhanced activation of proteolytic enzymes. Inhibition of these mechanisms by natural plants might be a promising approach to prevent skin aging. The flowers of Lagerstroemia speciosa and Lagerstroemia floribunda are unused parts of agricultural products. They have been reported to possess antioxidant activity and inhibitory properties against matrix metalloproteinase enzymes. In the present study, the ethanolic flowers extracts of L. speciosa and L. floribunda were studied for their total phenolic, flavonoid, and anthocyanin contents, and antioxidant properties. Additionally, the active compounds were identified using high performance liquid chromatography (HPLC). The extracts were also evaluated for their inhibitory effects against hyaluronidase, elastase and tyrosinase. Finally, the extracts were investigated for their protective effects on hydrogen peroxide-induced oxidative stress in human keratinocytes. Results showed that antioxidant activities of the flowers extracts of L. speciosa and L. floribunda were equal to that of ascorbic acid. Both plants also inhibited hyaluronidase, elastase and tyrosinase activity. In addition, these flower extracts showed remarkable inhibitory potential against hyaluronidase, which was higher than that of the standard oleanolic acid. Furthermore, these extracts were found to inhibit hydrogen peroxide-induced cell death in human keratinocytes. L. speciosa extract exhibited higher antioxidant properties, enzymatic inhibitory activities and cytoprotective effects compared with that of L. floribunda. HPLC analysis had revealed that ellagic acid, epicatechin gallate, and quercetin were the major compounds in both extracts, but with higher contents in L. speciosa than in L. floribunda. Taken together, the results suggest that these flower extracts can be considered as new natural sources to be potentially used as anti-aging ingredients in skin care formulations.

2-(chromon-3-yl)imidazole derivatives as potential antimicrobial agents: synthesis, biological evaluation and molecular docking studies.

A series of novel 2-(chromon-3-yl)-4,5-diphenyl-1H-imidazoles (4a-h) were synthesized by one pot condensation of substituted 3-formylchromones (1a-h), benzil (2) and ammonium acetate (3) in refluxing acetic acid at 110 °C under N2 atmosphere. Allylation of compounds 4a-h with allyl bromide in the presence of fused K2CO3 furnished N-allyl-2-(chromon-3-yl)-4,5-diphenyl-1H-imidazoles (6a-h). The synthesized compounds were characterized spectroscopically and evaluated for in vitro antimicrobial activity against various pathogenic bacterial and fungal strains by disc diffusion method. Compounds bearing electron withdrawing substituents such as bromo (4f) showed significant inhibitory activity against S. cerevisiae (MIC 1.4 μg/ml) and 4g containing chloro substituent, displayed more inhibitory potential against C. albicans (MIC 1.5), as compared to the standard drugs. Compounds 6a and 4c exhibit remarkable inhibitory potential against B. subtilis with MIC 0.98 and 1.23, respectively. The time kill assay for active compound 6a was performed by viable cell count (VCC) method to elucidate the microbicidal nature of 2-(chromon-3-yl)imidazoles. A molecular docking study of most active compounds with target 'lanosterol 14α-demethylase' (CYP51) was performed to unravel the mode of antifungal action.

Dual inhibition of nitric oxide and prostaglandin E2 production by polysubstituted 2-aminopyrimidines

The present in vitro experiments demonstrate inhibitory effects of polysubstituted 2-aminopyrimidines on high output production of nitric oxide (NO) and prostaglandin E2 (PGE2) stimulated by interferon-γ and lipopolysaccharide (LPS) in peritoneal macrophages of mouse and rat origin. PGE2 production was inhibited also in LPS-activated human peripheral blood mononuclear cells. A tight dependence of the suppressive activities on chemical structure of pyrimidines was observed. Derivatives containing hydroxyl groups at the C-4 and C-6 positions of pyrimidine ring were devoid of any influence on NO and PGE2. Remarkable inhibitory potential was acquired by the replacement of hydroxyl groups with chlorine, the 4,6-dichloro derivatives being more effective than the monochloro analogues. The effects were further intensified by modification of the amino group at the C-2 position, changing it to the (N,N-dimethylamino)methyleneamino or the formamido ones. There was no substantial difference in the expression of NO-inhibitory effects among derivatives containing distinct types of substituents at the C-5 position (hydrogen, methyl, ethyl, propyl, butyl, phenyl, and benzyl). In contrast to NO, larger substituents then methyl were required to inhibit PGE2 production. Overall, no significant correlation between the extent of NO and PGE2 suppression was observed. The IC50s of derivatives with the strongest effects on both NO and PGE2 were within the range of 2–10 μM. Their NO-inhibitory potential of pyrimidines was stronger than that of non-steroidal anti-inflammatory drugs (NSAIDs) aspirin and indomethacin. The PGE2-inhibitory effectiveness of pyrimidines was about the same as that of aspirin, but weaker as compared to indomethacin. The NO- and PGE2-inhibitory activity of tested pyrimidines has been found associated with decreased expression of iNOS mRNA and COX-2 mRNA, respectively, and with post-translation interactions. Selected NO-/PGE2-inhibitory derivatives decreased severity of intestinal inflammation in murine model of ulcerative colitis.

An Investigation of the Growth Inhibitory Capacity of Several Medicinal Plants From Iran on Tumor Cell Lines

Background:Traditional herbal medicine is a valuable resource that provides new drugs for cancer treatment. Objectives:In this study we aim to screen and investigate the in vitro anti-tumor activities of ten species of plants commonly grown in Southern Iran. Materials and Methods:We used the MTT colorimetric assay to evaluate the cytotoxic activities of the methanol extracts of these plants on various tumor cell lines. The IC50 was calculated as a scale for this evaluation.Results:Satureja bachtiarica, Satureja hortensis, Thymus vulgaris, Thymus daenensis and Mentha lonigfolia showed the inhibitoriest effects on Jurkat cells with > 80% inhibition at 200 µg/mL. Satureja hortensis (IC50: 66.7 µg/mL) was the most effective. These plants also strongly inhibited K562 cell growth; Satureja bachtiarica (IC50: 28.3 µg/mL), Satureja hortensis (IC50: 52 µg/mL) and Thymus vulgaris (IC50: 87 µg/mL) were the most effective extracts. Cichorium intybus, Rheum ribes, Alhagi pseudalhagi and Glycyrrihza glabra also showed notable effects on the leukemia cell lines. The Raji cell line was mostly inhibited by Satureja bachtiarica and Thymus vulgaris with approximately 40% inhibition at 200µg/ml. The influence of these extracts on solid tumor cell lines was not strong. Fen cells were mostly affected by Glycyrrihza glabra (IC50: 182 µg/mL) and HeLa cells by Satureja hortensis (31.6% growth inhibitory effect at 200 µg/mL).Conclusions:Leukemic cell lines were more sensitive to the extracts than the solid tumor cell lines; Satureja hortensis, Satureja bachtiarica, Thymus vulgaris, Thymus daenensis and Mentha lonigfolia showed remarkable inhibitory potential.

Design, synthesis and evaluation of 2,4-diarylpyrano[3,2-c]chromen-5(4H)-one as a new class of non-purine xanthine oxidase inhibitors

Keeping in view the recent success of molecular hybridization technique in drug design, 2,4-diarylpyrano[3,2-c]chromen-5(4H)-ones as conjugates of coumarins and chalcones have been designed and synthesized in the present study. The catalytic efficiency of various Lewis acids for the synthesis of designed conjugates under neat conditions was investigated, and SiO2 (200–400 mesh)-ZnCl2 was optimized as the best catalyst among the tested ones. The conjugates were evaluated for in-vitro xanthine oxidase activity. The results of the in-vitro assay were quite promising as some conjugates were endowed with remarkable inhibitory potential against the enzyme. HV-8, 11 and 12 were found to be high-potent inhibitors with HV-11 (the most potent inhibitor) possessing an IC50 value of 2.21 µM. The most active conjugate HV-11 was evaluated for the type of inhibition and was found to be a mixed type inhibitor. The compliance of some selected conjugates to the Lipinski rule was also calculated.

Purification, Physicochemical Characterization, and Bioactivities of Polysaccharides from Puerh Tea

Two fractions of polysaccharides, named PTPS-1 and PTPS-2, was extracted and purified from puerh tea by Sephacryl S-300 column chromatography. The physicochemical properties of these two polysaccharides were investigated by high-performance liquid chromatography (HPLC), Fourier Transform IR spectra, scanning electron microscope (SEM) and atomic force microscope (AFM). Analysis of chemical compositions (protein, neutral sugars, uronic acid and monosaccharide composition) suggested that they were both kinds of acid heteropolysaccharides bound with protein, and contained seven monosaccharides with different molar ratio. Meanwhile, evaluation of antioxidant activities by in vitro assays of DPPH, ABTS and FRAP showed that PTPS-1 demonstrated stronger antioxidant ability than PTPS-2. Similarly, PTPS-1 exhibited remarkable inhibitory potential on α-glycosidase in vitro, significantly stronger than that of PTPS-2 and acarbose. Moreover, the results from animal test indicated PTPS-1 possessed significant inhibition on postprandial hyperglycemia in diabetic mice compared with the model group.

ChemInform Abstract: Rational Approaches, Design Strategies, Structure Activity Relationship and Mechanistic Insights for Anticancer Hybrids

AbstractReview: 534 refs.

The remarkable efficiency of a Pin-II proteinase inhibitor sans two conserved disulfide bonds is due to enhanced flexibility and hydrogen bond density in the reactive site loop

Capsicum annuum (L.) expresses diverse potato type II family proteinase inhibitors comprising of inhibitory repeat domain (IRD) as basic functional unit. Most IRDs contain eight conserved cysteines forming four disulfide bonds, which are indispensible for their stability and activity. We investigated the functional significance of evolutionary variations in IRDs and their role in mediating interaction between the inhibitor and cognate proteinase. Among the 18 IRDs encoded by C. annuum, IRD-7, -9, and -12 were selected for further characterization on the basis of variation in their reactive site loop, number of conserved cysteine residues, and higher theoretical ΔGbind for interaction with Helicoverpa armigera trypsin. Moreover, inhibition kinetics showed that IRD-9, despite loss of some of the disulfide bonds, was a more potent proteinase inhibitor among the three selected IRDs. Molecular dynamic simulations revealed that serine residues in the place of cysteines at seventh and eighth positions of IRD-9 resulted in an increase in the density of intramolecular hydrogen bonds and reactive site loop flexibility. Results of the serine residues chemical modification also supported this observation and provided a possible explanation for the remarkable inhibitory potential of IRD-9. Furthermore, this natural variant among IRDs showed special attributes like stability to proteolysis and synergistic inhibitory effect on other IRDs. It is likely that IRDs have coevolved selective specialization of their structure and function as a response towards specific insect proteases they encountered. Understanding the molecular mechanism of pest protease–plant proteinaceous inhibitor interaction will help in developing effective pest control strategies.An animated interactive 3D complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:39