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Ethnopharmacological Relevance: Nyctanthes arbor-tristis Linn. has been used by Ayruvedic physicians for the cure of different diseases including ulcers, gastric and inflammatory diseases., Aim of the Study: To isolate and identify compounds from this source and investigate their therapeutic potential for the treatment of gastric ulcer and related disorders., Material and Methods: The ethanol extract of fresh aerial parts of N. arbor-tristis was used in the present studies which was subjected to a bio-assay guided fractionation followed by chromatographic separations. The structures of pure compounds were elucidated using various spectroscopic techniques. The inhibition of urease enzyme was evaluated by weatherburn indophenol method. Molecular docking studies were determined by using Molecular Operating Environment (MOE) version 2020.0901 version. The intracellular ROS production from phagocytes was determined by chemiluminescence assay and NO generation was detected by Griess method. The proinflammatory cytokine TNF-α was quantified by ELISA. Cytotoxic activity was assessed by MTT assay., Results: One previously undescribed iridoid glycoside arborside F (1) and four known iridoid glycosides arborside A (2), arborside C (3), loganin (4) and 7-O-trans-cinnamoyl-6β-hydroxyloganin (5) were isolated and characterized in the present studies and their urease inhibitory activity was determined. Among these, 2 and 5 showed strong urease inhibition (IC 50  = 12.1 ± 1.74 and 14.1 ± 0.59 μM respectively) (standard acetohydroxamic acid IC 50  = 20.3 ± 0.42 μM), whereas rest of compounds showed moderate to low inhibition. Kinetic studies revealed that compounds 2 and 5 possess competitive type of inhibition. Molecular docking showed polar and non-polar interactions of compounds 2 and 5 with urease enzyme residues. Compounds 2 and 3 showed inhibition of ROS from whole blood (IC 50  = 1.6 ± 0.3 and 2.5 ± 0.09 μg/mL respectively) and PMNs (IC 50  = 1.5 ± 0.03 and 1.4 ± 0.0 μg/mL respectively). Compound 2 significantly inhibited nitric oxide and proinflammatory cytokine TNF-α (IC 50  = 18.2 ± 3.0 and 73.8 ± 6.6 μg/mL respectively). Compounds 1, 4 and 5 were inactive on ROS. All isolated compounds were non-toxic on normal mouse fibroblasts (NIH-3T3) cells., Conclusions: The ethno pharmacological repute of N. arbor-tristis in treating gastric and anti-inflammatory ailments is supported by present studies which resulted in isolation of a potent urease inhibitory and anti-inflammatory agent arborside A (2) a potential anti-ulcer and anti-inflammatory drug lead., 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 © 2023 Elsevier B.V. All rights reserved.)

Many heterocycles have been developed as drugs due to their capacity to interact productively with biological systems. The present study aimed to synthesize cocrystals of the heterocyclic antitubercular agent pyrazinamide (PYZ, 1, BCS III) and the commercially available anticonvulsant drug carbamazepine (CBZ, 2, BCS class II) to study the effect of cocrystallization on the stability and biological activities of these drugs. Two new cocrystals, namely, pyrazinamide-homophthalic acid (1/1) (PYZ:HMA, 3) and carbamazepine-5-chlorosalicylic acid (1/1) (CBZ:5-SA, 4), were synthesized. The single-crystal X-ray diffraction-based structure of carbamazepine-trans-cinnamic acid (1/1) (CBZ:TCA, 5) was also studied for the first time, along with the known cocrystal carbamazepine-nicotinamide (1/1) (CBZ:NA, 6). From a combination drug perspective, these are interesting pharmaceutical cocrystals to overcome the known side effects of PYZ (1) therapy, and the poor biopharmaceutical properties of CBZ (2). The purity and homogeneity of all the synthesized cocrystals were confirmed by single-crystal X-ray diffraction, powder X-ray diffraction and FT-IR analysis, followed by thermal stability studies based on differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Detailed intermolecular interactions and the role of hydrogen bonding towards crystal stability were evaluated quantitatively via Hirshfeld surface analysis. The solubility of CBZ at pH 6.8 and 7.4 in 0.1 N HCl and H 2 O were compared with the values of cocrystal CBZ:5-SA (4). The solubility of CBZ:5-SA was found to be significantly improved at pH 6.8 and 7.4 in H 2 O. All the synthesized cocrystals 3-6 exhibited a potent urease inhibition (IC 50 values range from 17.32 ± 0.89 to 12.3 ± 0.8 µM), several times more potent than standard acetohydroxamic acid (IC 50  = 20.34 ± 0.43 µM). PYZ:HMA (3) also exhibited potent larvicidal activity against Aedes aegypti. Among the synthesized cocrystals, PYZ:HMA (3) and CBZ:TCA (5) were found to possess antileishmanial activity against the miltefosine-induced resistant strain of Leishmania major, with IC 50 values of 111.98 ± 0.99 and 111.90 ± 1.44 µM, respectively, in comparison with miltefosine (IC 50  = 169.55 ± 0.20 µM).

A library of thiosemicarbazide derivatives of isoniazid 3-27, was synthesized and evaluated for their anti-inflammatory and urease inhibition activities, by using in vitro bioassays. Among these compounds 9, 10, 12, 21, and 26 were identified as new derivatives. Prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs) and infections caused by Helicobacter pylori (ureolytic bacteria), are the two most significant causes of gastric and peptic ulcers. We focused on the identification of the dual inhibitors of inflammation and urease enzyme. Compound 23 was identified as the best dual inhibitor of inflammation (ROS; IC 50  = 12.3 µg/mL), and urease enzyme inhibition activity (IC 50  = 22.4 µM). Many of these compounds showed comparable activities to the standard anti-inflammatory drug (ibuprofen, IC 50  = 11.2 µg/mL) and urease inhibitor (thiourea/acetohydraoxamic acid, IC 50  = 21.1/20.3 µM). Compound 12 was found to be the most potent urease inhibitor (IC 50  = 12.3 µM) and good inhibitor of inflammation (IC 50  = 27.7 µg/mL). Compounds 19, 11, 13, 9, 17, 10, and 16, were also found to be potent inhibitors of urease. Cytotoxicity was also evaluated and all the compounds were found to be non-cytotoxic, except compound 18 and the parent drug isoniazid (IC 50  = 29.5 and 28.5 µM, respectively).

Urease is an enzyme of amidohydrolase family and is responsible for the different pathological conditions in the human body including peptic ulcers, catheter encrustation, kidney stone formation, hepatic coma, encephalopathy, and many others. Therefore, the search for potent urease inhibitors has attracted major scientific attention in recent years. Urea and thiourea derivatives of tryptamine (1-25) were synthesized via reaction of tryptamine with different substituted phenyl isocyanates/isothiocyanates. The synthetic compounds were evaluated for their urease enzyme inhibitory activity and they exhibited good inhibitory potential against urease enzyme in the range of (IC 50  = 11.4 ± 0.4-24.2 ± 1.5 μM) as compared to the standard thiourea (IC 50  = 21.2 ± 1.3 μM). Out of twenty-five compounds, fourteen were found to be more active than the standard. Limited structure-activity relationship suggested that the compounds with CH 3 , and OCH 3 substituents at aryl part were the most potent derivatives. Compound 14 (IC 50  = 11.4 ± 0.4 μM) with a methyl substituent at ortho position was found to be the most active member of the series. Whereas, among halogen substituted derivatives, para substituted chloro compound 16 (IC 50  = 13.7 ± 0.9 μM) showed good urease inhibitory activity. These synthetic derivatives were found to be non-cytotoxic in cellular assay. Kinetic studies revealed that the compounds 11, 12, 14, 17, 21, 22, and 24 showed a non-competitive type of inhibition. In silico study identified the possible bindings interactions of potential inhibitors with the active site of enzyme. These newly identified inhibitors of urease enzyme can serve as leads for further research and development., (Copyright © 2018. Published by Elsevier Inc.)

The current study was designed to evaluate the urease inhibitory profile of extract and fractions of Pistacia atlantica ssp. cabulica Stocks followed by bioactivity-guided isolated compounds. The crude extract was found significantly active with urease inhibitor (95.40% at 0.2 mg/mL) with IC50 values of 32.0 ± 0.28 μg/mL. Upon fractionation, ethyl acetate fraction displayed 100% urease inhibition with IC50 values of 19.9 ± 0.51 μg/mL at 0.2 mg/mL. However, n-hexane and chloroform fractions exhibited insignificant urease inhibition. Similarly, the isolated compound, transilitin (1) and dihydro luteolin (2) demonstrated marked urease attenuation with 95 and 98% respectively, at 0.15 mg/mL. Both the isolated compounds showed marked potency with IC50 values of 8.54 ± 0.54 and 9.58 ± 2.22 μg/mL, respectively. In short, both the extract and fractions and isolated compounds showed marked urease inhibition and thus a useful natural source of urease inhibition.

In this paper, we have examined eight new first‐row transition metal complexes (1–8). Mutli‐donor ligands based on barbituric and thiobarbituric acids were used in complexation reactions. The synthesized complexes were analyzed using FT‐IR and UV–vis spectroscopy, elemental (CHN) analysis, and single‐crystal X‐ray diffraction analysis. These complexes exhibited significant urease enzyme inhibition with IC50 values in the range of 13.73 ± 1.08–43.21 ± 1.50 μM. We observed excellent binding orientation of these complexes in the active site of Urease. The molecular docking results correlate well with in vitro observations. [ABSTRACT FROM AUTHOR]

The current research reports the synthesis of a library of thiosemicarbazones (3-16) through a two-step chemical transformation. All the synthesized derivatives were purified and fully characterized through mass spectrometry, NMR spectroscopy (1H-, and 13C-NMR), and IR spectroscopy. All the members of the synthesized library were found to be new except compound 8. The synthesized library was screened for its inhibition potential against the urease enzyme. Almost all the compounds exhibited potent activity with the IC50 = 5.3 ± 0.8 − 15.5 ± 0.6 µM in comparison to the thiourea and acetohydroxamic acid used as standard (IC50 = 21.1 ± 0.2, 20.5 ± 0.4 µM). While significant activity was exhibited by compounds 14 and 15 with the IC50 = 23.6 ± 0.6 and 27.3 ± 1.2 µM. Furthermore, kinetic studies were carried out to determine the inhibition mode and molecular docking was employed to recognize the ligand-enzyme interactions. Thereby, the docking results are well in the direction of the in vitro results. Compounds ((E)-N-(2,5-dichlorophenyl)-2-(4-fluorobenzylidene)hydrazine-1-carbothioamide (3) and (E)-2-(2-chlorobenzylidene)-N-(2-fluorophenyl) hydrazinecarbothioamide (5) were identified as the most potent inhibitors of urease by both the in vitro and in silico studies. [ABSTRACT FROM AUTHOR]

Introduction: The genus Euphorbia is known to contain diterpenoids, and several isolated compounds which exhibited biological activities including significant multidrug resistance reversal effects. This work is focused on the isolation, in vitro and in silico studies of two natural bio-active flavonoids (1 & 2) isolated from Euphorbia pulcherrima bark for the very first time. Methods: The phytochemical investigation resulted in the identification of two flavonoids: 3,5,7-trihydroxy-2-(4-hydroxy-3-methoxyphenyl)-6-methoxy-4H-chromen-4-one (1) and 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-6-methoxy-4H-chromen-4-one (2), which were isolated for the first time from Euphorbia pulcherrima. Results: The chemical structures of the two isolated compounds were confirmed by 1H NMR, 13C NMR, and ESI-HRMS spectral data. The Bioactivity activity of these compounds was evaluated; results revealed that compounds 1 & 2 exhibit promising urease inhibitory potential with IC50 values of 15.3 ± 2.13 μM and 19.0 ± 2.43 μM, respectively, whereas the positive control thiourea had an IC50 of 21.0 ± 0.23 μM. Similarly, these compounds were also evaluated against the tyrosinase enzyme; results showed that compound 1 displays significant inhibitory activity with an IC50 value of 48.7 ± 2.19 μM, whereas compound 2 exhibited a moderate effect with an IC50 value of 74.8 ± 1.79 μM, when compared with the standard (alpha-kojic acid, IC50 = 47.6 ± 0.67 μM). Additionally, compounds 1 and 2 also exhibited anti-glycation and phosphodiesterase inhibitory activities. Conclusion: Studies dealing with the drug like properties such as in silico screening (docking study) was also carried out to discover the structural features of both compounds 1 and 2. Results indicated that the docking scores of compounds 1 and 2 are in agreement with their IC50 values. Isolation and characterization of two bioactive flavonoids (1 and 2) from Euphorbia pulcherrima. In silico and in vitro enzyme inhibition studies were conducted to identify the therapeutic potential of flavonoids 1 and 2. Drug-like properties were calculated to discover important pharmacophoric features. [ABSTRACT FROM AUTHOR]

The recent study was designed to explore Dodonaea viscosa, Juniperus excelsa, Helianthemum lippii, and Euryops pinifolius using methanolic (MeOH) extract. Their subfractions were examined against urease, carbonic anhydrase II (CA-II), α-glucosidase enzymes, and free radicals scavenging significance based on local practices via standard methods. Significance potential against the urease enzyme was presented by ethyl acetate fraction (EtOAc) of D. viscosa with (I C 50 = 125 ± 1.75 μg/mL), whereas the H. lippii (I C 50 = 1 46 ± 1.39 μg/mL) in the EtOAc was found efficient to scavenge the free radicals. Besides, that appreciable capacity was observed by the J. excelsa, D. viscosa, J. excelsa, and E. pinifolius as compared to the standard acarbose (I C 50 = 377.24 ± 1.14 μg/mL). Maximum significance was noticed in methanolic (MeOH) extract of J. excelsa and presented carbonic anhydrase CA-II (I C 50 = 5.1 ± 0.20 μg/mL) inhibition as compared to the standard (acetazolamide). We are reporting, for the first time, the CA-II inhibition of all the selected medicinal plants and α-glucosidase, urease, and antioxidant activities of the E. pinifolius. Thus, further screening is needed to isolate the promising bioactive ingredients which act as an alternative remedy to scavenge the free radicals, antiulcer, and act as a potential source to develop new antidiabetic drugs for controlling postprandial blood sugar as well as carbonic anhydrase inhibitors. [ABSTRACT FROM AUTHOR]

Phytochemical studies of methanol soluble fractions of Abrus precatorius Linn (Fabaceae) led to the isolation of four abruquinones (abruquinones M, A, E, and B). Structures of the compounds were elucidated using spectroscopic analyses - 1D, 2D NMR, HRESI-MS. Evaluation of the therapeutic effects of A. precatorius fractions showed significant (p < 0.05) antibacterial and antiurease activities. Further therapeutic evaluation of the compounds showed that abruquinones M, A, E, and B demonstrated antibacterial activities by inhibiting significantly (p < 0.05) the growth of multidrug resistant S. aureus (MIC values ranged from 20 - 30 μg/mL) (µM) via induction of morphological damages with concomitant membrane segmentation. Abruquinones A and B showed significant (p < 0.05) urease inhibiting activity (IC50 values 35.2 and 37.7 µM, respectively), docked tightly to the side chains of urease enzyme active site via π-cation interactions, as well as showed cytotoxicity against AU565 and MDA-MB231 breast cancer cells (IC50 values 23.13 and 9.05 μM, respectively). These findings suggest abruquinones (isoflavanquinones) from A. precatorius roots as viable candidates for further mechanistic studies on possible antibacterial, antiurease, and anticancer drug development. [ABSTRACT FROM AUTHOR]

The current study aims at exploring enzyme inhibition of four species of medicinal herbs, namely Senna bicapsularis, Thevetia peruviana, Nerium oleander and Vinca major. Plant selection was done on the basis of their therapeutic uses by local practitioners. The crude methanolic extracts of these plants were tested for their α-glycosidase and urease enzyme inhibition potential. The observed urease inhibitory potential for the crude extract of S. bicapsularis, T. peruviana and N. oleander were 8.3 ± 0.33 μg, 6.98 ± 0.98 μg and 9.56 ± 1.43 μg, respectively while the V. major did not show any inhibition. In addition, the IC50 value for Thiourea was 22.3 ± 1.14 μg. The crude extracts of S. bicapsularis, T. peruviana, N. oleander, V. major were shown to inhibit α-glycosidase activity with an IC50 value of 630.3 ± 0.03 μg, 700.7 ± 2.43 μg, 430.4 ± 3.97 μg, and the standard (acarbose) 880 ± 1.03 μM, respectively. Based on the TLC profile, the extract of S. bicapsularis was subjected to column chromatography and the major component named rhein (1) was identified. Compound 1 exhibited excellent urease and α-glycosidase inhibitory activity with an IC50 value of 7.4 ± 0.32 and 622.3 ± 1.03 μM, respectively. [ABSTRACT FROM AUTHOR]

Utilizing multi-target drugs shows great promise as an effective strategy against polygenic diseases characterized by intricate patho-mechanisms, such as ulcers, skin dermatitis, and cancers. The current research centers around the creation of hybrid compounds, connecting dibenzazepine and isoxazole, with the aim of exploring their potential as inhibitors for urease and tyrosinase enzymes. Analogs 6a, 6b, 6d, 6 h-6j, and 6 l demonstrated strong inhibitory potential against tyrosinase enzyme with IC 50 values of 4.32 ± 0.31–12.36 ± 0.48. Whereas analogs 6a, 6c, 6e, 6f, 6h-6m, and 6r exhibited potent inhibitory activities against urease enzyme with IC 50 values of 3.67 ± 0.91–15.60 ± 0.18 μM. Furthermore, compounds 6i, 6n, and 6r showed weak toxic effect in BJ-cell line, whereas the remaining compounds were found non-toxic to normal cell line. The mechanistic studies of potent inhibitors of both the enzymes showed competitive mode of inhibition. Molecular docking was employed to establish the relationship between structure and activity and to elucidate the interaction mechanism. This analysis revealed that the active analogs exhibited crucial interactions with the active site residues of urease and tyrosinase, thus corroborating our experimental results. Hence, the generated derivatives of dibenzazepine-linked isoxazoles present intriguing starting points for further investigations into their potential as inhibitors of urease and tyrosinase, with the potential for future modification and enhancement. [ABSTRACT FROM AUTHOR]

In the current investigation, the chemical composition of the essential oils (EOs) from the stem and leaves of Acridocarpus orientalis A. Juss. were evaluated by gas chromatography (GC) and gas-chromatography-mass spectrometry (GC-MS). The main volatile constituents identified in the essential oil of stem were rich in methyl 8-pimaren-18-oate (43.8 %), octacosane (5.8 %), heptacosane (4.6 %) and hexacosane (4.1 %), methyl dehydroabietate (3.9 %) and methyl pimar-8(14)-en-18-oate (3.6 %), while tetracosane (16.6 %), heptacosane (16.4 %), docosane (13.9 %), hentriacontane (13.5 %), heneicosane (10.9 %) and α-pinene (7.7 %) were abundant in the EO of leaves. Both essential oils, screened against urease, α-glucosidase and carbonic anhydrase II (CA-II) enzyme inhibitory activities, were found active against CA-II and inactive against urease and α-glucosidase enzymes. The leaves of AO were found more active only against CA-II enzyme having IC50 values of 45.6 ± 1.0 μg/mL than stem (156.3 ± 1.5 μg/mL). The results determined that the EO of leaves could be a promising target for anti-cancer treatment. This is the first report, up to the best of the author's knowledge, on the chemical composition and CA-II activity of this essential oil. [ABSTRACT FROM AUTHOR]

Endophytic fungi are a substantial source of bioactive secondary metabolites. Present studies on Aspergillus nidulans-an endophytic fungus from Nyctanthes arbor-tristis Linn. afforded one new 1, 5-dihydroxy-3-methylxanthone-6-carboxylic acid methyl ester (1) and one known 5, 10-dihydro-phenazine-1-carboxylic acid (2) compound. The structures were elucidated by spectral techniques (Mass, 1D and 2D NMR), and their urease, carbonic anhydrase and prolyl endopeptidase inhibitory activities were evaluated. Compound 1 showed notable prolyl endopeptidase inhibition (IC50 = 3.13 ± 0.09 µM) and compound 2 showed significant carbonic anhydrase (IC50 =14.3 ± 1.05 µM) and urease (IC50 = 24.3 ± 1.15 µM) inhibition. [ABSTRACT FROM AUTHOR]

• A novel series of N4 -substitution of cinnamaldehyde with thiosemicarbazones 3a-q were synthesized. • Structures were characterized by FTIR, 1HNMR, 13CNMR and ESI-MS. • All compounds displayed significant urease inhibition with IC 50 values of 11.4 ± 0.23–80.6 µM. • Kinetic studies showed that compound 3o is a competitive inhibitor with ki value 8.65 ± 0.37 µM. • Molecular docking studies were carried out to establish their structure-activity relationship and binding interaction. Hyperactivity of urease enzyme induces pathogenesis of peptic ulcers and gastritis. The excess of urease can be reduced by introducing various inhibitors. The risk of high urease content also partakes in agriculture field where it declines the environmental health. This alarming situation leads to the mandatory quest of such novel scaffolds that must work wonders in the field of medicinal chemistry. Consequently, we herein report a novel series of N4 -substitution of cinnamaldehyde with thiosemicarbazones 3a-q as potential candidates for urease inhibition. These new N4 -substituted thiosemicarbazones 3a-q of indistinct chemical scaffolds were characterized by advanced spectroscopic techniques, such as ESI-MS, 13CNMR, 1HNMR, and FTIR. All newly synthesized compounds showed significant urease inhibitions with IC 50 values in range of 11.4 ± 0.23 to 80.6 ± 0.52 μM. Furthermore, kinetic studies of compound 3o displayed competitive type of inhibition with ki value 8.65 ± 0.37 µM. For analysis of structure‒activity relationship and interactions pattern of all compounds, molecular docking was used, which revealed excellent binding interactions of compounds with the active site residues, such as nickel atom coordination, π–cation, π–π interactions, and hydrogen bonding. Additionally, the predicted pharmacokinetics and drug-likeness of compounds suggest that these compounds have good pharmacokinetic and physicochemical properties, and these compounds follow rules of drug-likeness. [ABSTRACT FROM AUTHOR]

• Synthesis of amantadine derivatives was carried out using ultra sonication method. • Synthesized analogs were evaluated for their urease, and α-glucosidase enzyme inhibition activities. • Molecular docking was performed in order to predict the binding interactions with respective enzymes. • Potent inhibitors of urease and α-glucosidase enzyme were obtained. • Kinetic studies were carried out to determine the mode of inhibition. Ultrasonic synthesis of 26 amantadine derivatives, (3-28) including seven new compounds, are reported with significantly reduced synthesis time and increased percentage yield relative to literature data. Evaluation of the urease, and α-glucosidase enzyme inhibitory activities of all amantadine derivatives are being reported here for the first time. Three compounds were found to be potent urease inhibitors (IC 50 = 9.32 ± 1.01 µM, to IC 50 = 11.32 ± 1.05 µM) as compared to the standard drug acetohydroxamic acid (IC 50 = 20.3 ± 0.4 µM). Five compounds were found to be potent inhibitors of α-glucosidase (IC 50 = 40.63 ± 1.70, to 50.07 ± 1.73) as compared to standard drug acarbose (IC 50 = 875.75 ± 2.08 µM). Kinetic studies were performed to investigate competitive and non-competitive inhibition of α-glucosidase enzymes and mixed type inhibition of urease enzyme. All compounds along with parent drug was checked for their cytotoxicity against human fibroblast (B.J.) cell line. Four compounds were found to be toxic, while the rest were nontoxic. Furthermore, in silico studies were performed to predict the binding interactions of the compounds at the active site of the enzymes. The two most active adamantane analogs against urease are those with m- and o-fluoro substitution due to specific interactions with CME592, HOH1918 and GLN635 (3.04, 2.74, and 3.21 Å). Ortho analogs interact with GLN635 (3.04, 3.10 Å). The two analogs having diflouro and tri flouro methyl group, showed a slight lower activity as compared to the first two compounds. This analysis clearly indicates the importance of position of fluoro group in urease inhibition activity. Similarly, in α-glucosidase inhibitors, three compounds with p-OCH 3, ethyl groups, and di-fluoro were found to be the most active inhibitors in excellent agreement with experimental data. This study identifies new analogs with potent α-glucosidase and urease inhibitory activities. and, thus, may be of therapeutic importance. [Display omitted] [ABSTRACT FROM AUTHOR]