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Tyrosinase plays a pivotal role in the hyperpigmentation and enzymatic browning of fruit and vegetable. Therefore, tyrosinase inhibitors can be of interest in industries as depigmentation compounds as well as anti-browning agents. In the present study, a series of chlorophenylquinazolin-4(3H)-one derivative were rationally designed and synthesized. The formation of target compounds was confirmed by spectral characterization techniques such as IR

A new series of metronidazole-1,2,3-triazole derivatives 6a–o was synthesized and evaluated as Helicobacter pylori urease inhibitors. All the synthesized compounds were more potent than standard inhibitor thiourea against urease. Among the synthesized compounds, compound 6f (IC50 = 1.975 ± 0.25 µM) with inhibitory activity around 11-fols more than thiourea (IC50 = 22.00 ± 0.14 µM) was the most potent compound. Kinetic study of this compound revealed that compound 6f inhibited urease in an uncompetitive mode. Based on molecular modeling study, compound 6f pointed toward the bi-nickel center and stabilized by H-bond and T-shape π–π hydrophobic interactions with the critical residues His492 and Asp633. Moreover, it anchored to the helix-turn-helix motif in the active site cavity through interaction with His593 and Arg609. Consequently, it proposed that compound 6f through stabilization of active site flap inhibited urease activity.

Background: α-Glucosidase is a hydrolyzing enzyme that plays a crucial role in the degradation of carbohydrates and starch to glucose. Hence, α-glucosidase is an important target in carbohydrate mediated diseases such as diabetes mellitus. Objective: In this study, novel coumarin containing dithiocarbamate derivatives 4a-n were synthesized and evaluated against α-glucosidase in vitro and in silico. Methods: These compounds were obtained from the reaction between 4-(bromomethyl)-7- methoxy-2H-chromen-2-one 1, carbon disulfide 2, and primary or secondary amines 3a-n in the presence of potassium hydroxide and ethanol at room temperature. In vitro α-glucosidase inhibition and kinetic study of these compounds were performed. Furthermore, a docking study of the most potent compounds was also performed by Auto Dock Tools (version 1.5.6). Results: Obtained results showed that all the synthesized compounds exhibited prominent inhibitory activities (IC50 = 85.0 ± 4.0-566.6 ± 8.6 μM) in comparison to acarbose as a standard inhibitor (IC50 = 750.0 ± 9.0 μM). Among them, the secondary amine derivative 4d with pendant indole group was the most potent inhibitor. Enzyme kinetic study of the compound 4d revealed that this compound competes with a substrate to connect to the active site of α-glucosidase and therefore is a competitive inhibitor. Moreover, a molecular docking study predicted that this compound interacted with the α-glucosidase active site pocket. Conclusion: Our results suggest that the coumarin-dithiocarbamate scaffold can be a promising lead structure for designing potent α-glucosidase inhibitors for the treatment of type 2 diabetes.

In this paper, novel 2-((5-amino-1,3,4-thiadiazol-2-yl)thio)-N-arylacetamide derivatives (7a–l) are designed, synthesized, and evaluated in vitro for their urease inhibitor activities. The compounds are synthesized efficiently in three steps in high isolated yields from amines, 2-chloroacetyl chloride, hydrazinecarbothioamide, and carbon disulfide. The molecular docking simulation were performed using AutoDock4 by docking all synthesized compound and standard inhibitors into the crystal structure of Jack bean urease. Comparison between the urease inhibitory activity of compounds 7a–l with the IC50 of (2.85–5.83 µM) and thiourea and hydroxyurea as standards inhibitors with the IC50 of (22.00 and 100.00 µM, respectively) proved the high activity of the synthesized compounds against the mentioned enzyme. Docking results were in good agreement with experimental results and indicate that synthesized compounds could interact well with the active site of the urease enzyme and among all; compound 7j shows more favorable interactions with the active site which confirm its great inhibitory activity with IC50 of 2.85 µM. Therefore, compound 7j might be a promising candidate for further evaluation.

In this study, a new series of quinazolinone-1,2,3-triazole-acetamide hybrids 8a–m, using by molecular hybridization of the potent α-glucosidase inhibitor pharmacophores, was designed and evaluated against carbohydrate-hydrolyzing enzymes α-glucosidase and α-amylase. All the synthesized compounds with IC50 values in the range of 45.3 ± 1.4 µM to 195.5 ± 4.7 µM were significantly more potent than standard inhibitor against α-glucosidase, while these compounds were not active against α-amylase in comparison to standard inhibitor. Representatively, compound 8a with IC50 = 45.3 ± 1.4 µM was around 17 times more potent than standard inhibitor acarbose (IC50 = 750.0 ± 12.5 µM). The inhibition kinetic analysis of the compound 8a indicated that this compound was a competitive α-glucosidase inhibitor. Molecular modeling analysis confirmed that the most potent inhibitors 8a and 8b well accommodated in the modeled α-glucosidase active site and it was also revealed that these compounds formed stable inhibitor–receptor complexes with the α-glucosidase in comparison to acarbose. In silico pharmacokinetic and toxicity of the most potent compounds were evaluated and obtained results were compared with acarbose. Furthermore, the most potent compounds were also evaluated against human normal cells and no cytotoxicity was observed.

To identify potent urease inhibitors, in the current study, a series of thioxothiazolidinyl-acetamides were designed and synthesized. The prepared compounds were characterized by spectroscopic techniques, including FTIR, 1HNMR, 13CNMR, and elemental analysis. In the enzymatic assessments, it was demonstrated that all derivatives had significant urease inhibition with IC50 values in the range of 1.473–9.274 µM in comparison with the positive control hydroxyurea (IC50 = 100.21 ± 2.5 µM) and thiourea (IC50 = 23.62 ± 0.84 µM). Compound 6i (N-benzyl-3-butyl-4-oxo-2-thioxothiazolidine-5-carboxamide) was the most active agent with an IC50 value of 1.473 µM. Additionally, kinetic investigation and in silico assessments of 6i was carried out to understand the type of inhibition and behavior of the most potent derivative within the binding site of the enzyme. Noteworthy, the anti-urease assay against P. vulgaris revealed 6e and 6i as the most active agents with IC50 values of 15.27 ± 2.40 and 17.78 ± 3.75 µg/mL, respectively. Antimicrobial evaluations of all compounds reveal that compounds 6n and 6o were the most potent antimicrobial agents against the standard and resistant S. aureus. 6n and 6o also showed 37 and 27% inhibition in the development of biofilm by S. aureus at 512 µg/ml. Furthermore, the MTT test showed no toxicity up to 100 µM. Taken together, the study suggests that the synthesized thioxothiazolidinyl-acetamides bases derivatives may serve as potential hits as urease inhibitors.

In the design of novel drugs, the formation of hybrid molecules via the combination of several pharmacophores can give rise to compounds with interesting biochemical profiles. A series of novel quinazolin-sulfonamid derivatives (

In this study, a novel series of 2,4-dioxochroman-1,2,3-triazole hybrids 8a-l was synthesized by click reaction. These compounds were screened against α-glucosidase through in vitro and in silico evaluations. All the synthesized hybrids exhibited excellent α-glucosidase inhibition in comparison to standard drug acarbose. Representatively, 3-((((1-(3,4-dichlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)amino)methylene)chroman-2,4- dione 8h with IC50 = 20.1 ± 1.5 μM against α-glucosidase, was 37-times more potent than acarbose. Enzyme kinetic study revealed that compound 8h was a competitive inhibitor against α-glucosidase. In silico docking study on chloro derivatives 8h, 8g, and 8i were also performed in the active site of α -glucosidase. Evaluations on obtained interaction modes and binding energies of these compounds confirmed the results obtained through in vitro α-glucosidase inhibition.

A novel series of (thio)barbituric-phenoxy-N-phenylacetamide derivatives 7a-l was synthesized and evaluated against Helicobacter pylori urease. The latter assay revealed that all the synthesized compounds 7a-l (IC50 = 0.69 ± 0.33–2.47 ± 0.23 μM) were significantly more potent than two used standard inhibitors, thiourea (IC50 = 23 ± 0.73 μM) and hydroxyurea (IC50 = 100 ± 1.7 μM). Docking study of the synthesized compounds demonstrated that these compounds as well fitted in the urease active site. Moreover, molecular dynamic study of the most potent compound 7d showed that this compound created important interactions with the active site flap residues, Cys592 and His593. Furthermore, in silico pharmacokinetic study predicted that all the synthesized compounds are drug-like.

Thiophene-based analogs have been fascinated by a growing number of scientists as a potential class of biologically active compounds. Furthermore, they play a vital role for medicinal chemists to improve advanced compounds with a variety of biological effects. The current review envisioned to highlight some recent and particularly remarkable examples of the synthesis of thiophene derivatives by heterocyclization of various substrates from 2012 on.

α-Glucosidase plays a major role in degradation of carbohydrates to glucose. Therefore, inhibition of this enzyme can be useful in the treatment of carbohydrate-related diseases such as diabetes, cancer, and viral infections. In this study, a new series of acridine-9-carboxamide linked to 1,2,3-triazole-N-phenylacetamide derivatives 5a–m were designed, synthesized, and evaluated as potent α-glucosidase inhibitors. All the synthesized compounds showed excellent to good inhibitory activity against α-glucosidase with IC50 values of 80.3 ± 0.9–564.3 ± 7.2 µM in comparison with standard drug acarbose (IC50 value = 750.0 ± 10.5 μM). Among the synthesized compounds, the most active compound was 3-bromo derivative 5h with inhibitory activity around 9.3 times more than acarbose. this compound was selected for farther biological evaluations. Kinetic study of compound 5h revealed that it is a competitive inhibitor against α-glucosidase. Docking study of compound 5h and its regioisomer 5i with 4-bromo substituent were also carried out in the active site of α-glucosidase to gain an insight into the interaction modes of the synthesized compounds and rationalized structure–activity relationship between these two compounds. Compound 5h was also evaluated against α-amylase and no activity was observed in comparison with acarbose. Furthermore, in vitro cytotoxic assay of compound 5h against human normal and cancer cell lines HDF and MCF-7, respectively, revealed that this compound is a noncytotoxic agent. In silico pharmacokinetic and toxicity assays of compound 5h was performed and obtained results were compared with acarbose.

We have designed and synthesized phthalimide-Schiff base-coumarin hybrids 8a–b, 9a–d, 10a–b, and 11a–d and evaluated them for α-glucosidase inhibitory potential against yeast form of this enzyme. For the synthesis of title compounds 4-hydroxybenzaldehyde, 4-hydroxy-3-methoxybenzaldehyde, 2-hydroxybenzaldehyde, 2-hydroxybenzaldehyde derivatives, coumarin-3-carbohydrazide, and coumarin-7-yloxy-acetohydrazide were used. In vitro α-glucosidase inhibition revealed that all the synthesized compounds exhibited outstanding α-glucosidase inhibition with IC50 values ranging between 85.2 ± 1.7 and 577.7 ± 7.5 µM when compared with the standard inhibitor acarbose having IC50 value 750.0 ± 12.0 µM. The most potent compounds were 4-hydroxybenzaldehyde derivative 8a with coumarin-3-carbohydrazide moiety, 2-hydroxy-5-nitrobenzaldehyde derivative 11d with coumarin-7-yloxy-acetohydrazide moiety, and 2-hydroxy-5-nitrobenzaldehyde derivative 9d with coumarin-3-carbohydrazide moiety. Molecular docking studies were carried out to understand the interaction modes and binding energies of the most active compounds and standard drug acarbose. This studies predicted that compounds 8a, 11d, and 9d (respectively with binding energies = − 10.77, − 8.65, and − 8.66 kcal/mol) bind to active site α-glucosidase more easily than acarbose (binding energy = − 4.04 kcal/mol).

In this work, a novel series of phthalimide-4,5-dihydrothiazole-amide derivatives 5a–f have been synthesized and evaluated for their anti-epileptic activities against pentylenetetrazole (PTZ)-induc...

Background: These days epilepsy is a common neurological disorder, which can affect on quality of life by unpredictable seizure. Thalidomide is one of the drugs to control the epilepsy but side effects such as teratogenicity, made it difficult to use. Methods: Six new analogues of N-aryl-4-(1,3-dioxoisoindolin-2-yl)benzamides were synthesized and tested for anti-seizure activity. To evaluate the anti-seizure activity of these new derivatives, 40 mice in 8 groups were received 10 mg/Kg of each new derivatives 30 min before the injection of pentylenetetrazole (PTZ, 70 mg/kg) to induced seizures. Latency time to first symptom of seizure was measured and compared to vehicle and standard groups. Docking methodology was applied to study on mode of interaction between GABAA receptor and synthetized compounds. Results: Structures of the all synthesized compounds were confirmed by NMR and mass spectroscopy. The latency time and mortality rate were individually measured for an hour after injection of pentylenetetrazole. Docking study revealed that synthesized compounds and thalidomide interact in similar conformation with GABAA receptor. Conclusion: The experimental and docking results were found in good correlation and demonstrated that the most active compound (5a), with 3,4-dimethylphenyl residue increased the duration of seizure inhibition threshold in comparison with thalidomide.

A series of novel 4-phenylpiperazine-carbodithioate-N-phenylacetamide hybrids (6a-n) was designed, synthesized, and evaluated for their in vitro inhibitory activity against the metabolic enzymes, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glucosidase. The obtained results showed that most of the synthesized compounds exhibited high to good anti-AChE and anti-BChE activity in the range of nanomolar concentrations in comparison to tacrine as a positive control. Molecular modeling of the most potent compounds 6e and 6i demonstrated that these compounds interacted with important residues of the AChE and BChE active sites. Moreover, all the newly synthesized compounds 6a-n had significant K

Animal studies are recognized as a significant step forward in the bridging between drug discovery and clinical applications. Animal models, due to their relative genetic, molecular, physiological, and even anatomical similarities to humans, can provide a suitable platform for unraveling the mechanisms underlying human diseases and discovering new therapeutic approaches as well. Recently, zebrafish has attracted attention as a valuable experimental and pharmacological model in drug discovery and development studies due to its prominent characteristics such as the high degree of genetic similarity with humans, genetic manipulability, and prominent clinical features. Since advancing a theory to a valid and reliable observation requires the manipulation of animals, it is, therefore, essential to use efficient modeling methods appropriate to the different aspects of experimental conditions. In this context, applying several various approaches such as using chemicals, pathogens, and genetic manipulation approaches allows zebrafish development into a preferable model that mimics some human disease pathophysiology. Thus, such modeling approaches not only can provide a framework for a comprehensive understanding of the human disease mechanisms that have a counterpart in zebrafish but also can pave the way for discovering new drugs that are accompanied by higher amelioration effects on different human diseases.

Organoids are three-dimensional cultures of stem cells in an environment similar to the body's extracellular matrix. This is also a novel development in the realm of regenerative medicine. Stem cells can begin to develop into 3D structures by modifying signaling pathways. To form organoids, stem cells are transplanted into the extracellular matrix. Organoids have provided the required technologies to reproduce human tissues. As a result, it might be used in place of animal models in scientific study. The key goals of these investigations are research into viral and genetic illnesses, malignancies, and extracellular vesicles, pharmaceutical discovery, and organ transplantation. Organoids can help pave the road for precision medicine through genetic editing, pharmaceutical development, and cell therapy.PubMed, Google Scholar, and Scopus were used to search for all relevant papers written in English (1907-2021). The study abstracts were scrutinized. Studies on the use of stem-cell-derived organoids in regenerative medicine, organoids as 3D culture models for EVs analysis, and organoids for precision medicine were included. Articles with other irrelevant aims, meetings, letters, commentaries, congress and conference abstracts, and articles with no available full texts were excluded.According to the included studies, organoids have various origins, types, and applications in regenerative and precision medicine, as well as an important role in studying extracellular vesicles.Organoids are considered a bridge that connects preclinical studies to clinical ones. However, the lack of a standardized protocol and other barriers addressed in this review, hinder the vast use of this technology.Organoids are 3D stem cell propagations in biological or synthetic scaffolds that mimic ECM to allow intercellular or matrix-cellular crosstalk. Because these structures are similar to organs in the body, they can be used as research models. Organoids are medicine's future hope for organ transplantation, tumor biobank formation, and the development of precision medicine. Organoid models can be used to study cell-to-cell interactions as well as effective factors like inflammation and aging. Bioengineering technologies are also used to define the size, shape, and composition of organoids before transforming them into precise structures. Finally, the importance of organoid applications in regenerative medicine has opened a new window for a better understanding of biological research, as discussed in this study.

The field of regenerative medicine (RM) as an innovative technology has the ability to affect the healthcare system. It develops a variety of techniques through stem cell biology, genetics, bioengineering, biomaterial science, and tissue engineering to replace or restore the role of lost, disabled, or aging cells in the human body. However, the field's proficiency has still been underwhelming at the clinical trial level. This could be due to the innovation of such technologies, as well as their incredible nature. Therefore, managing the infrastructure framework for the safe and efficient application of the aforementioned field of science would help in the process of progress. In this context, the current review focuses on how to establish infrastructures for more effective RM.

A series of 5-nitrofuran-2-yl-thiadiazole linked to different cyclohexyl-2-(phenylamino)acetamides were rationally designed and synthesized. All synthetic compounds were evaluated for their urease inhibitory activity and exhibited good inhibitory potential against urease with IC

In the development of novel anti-α-glucosidase agents, we synthesized novel thieno[2,3-b]quinoline-hydrazones 9a-n by facile and efficient conventional chemical reactions. These compounds were characterized by IR

A new series of thiosemicarbazide-1,2,3-triazole hybrids 10a-o has been synthesized, characterized by 1H NMR, 13C NMR, and screened for their in vitro α-glucosidase inhibitory activity. All of the synthesized compounds displayed excellent α-glucosidase inhibitory activity with IC50 values in the range of 75.0 ± 0.5 to 253.0 ± 0.5 μM, as compared to the standard drug acarbose (IC50 = 750.0 ± 1.5 μM). Among the synthesized compounds, compound 10h (IC50 = 75.0 ± 0.5) with 4-methoxy group at phenyl part of thiosemicarbazide moiety and 2,6-dichloro substituents at benzyl moiety was found to be the most potent compound. Kinetic analysis revealed that compound 10h is a competitive inhibitor for α-glucosidase. Docking study of compound 10h in the active site of α-glucosidase showed that this compound interacted with residues His239, His279, Glu304, Gly306, and Arg312.

This review article is focused on the synthesis of compounds with quinazolinones and benzo di/triazepine scaffolds. These invaluable derivatives are of great interest in medicinal and pharmaceutical studies because of their important biological properties. Quinazolinones have diverse applications due to their antibacterial, analgesic, antiinflammatory, antifungal, antimalarial, antihypertensive, CNS depressant, anticonvulsant, antihistaminic, antiparkinsonism, antiviraland and anticancer activities. On the other hand, pharmacological properties of benzodiazepines include antianxiety, anticancer, anticonvulsant, antagonists of cholecystokinin receptors (CCK), antileishmanial, sleep-inducing muscle relaxant and several other useful and interesting properties. As an example, three main categories of drugs, namely anxiolytics, sedative hypnotics (sleep inducers) and anticonvulsants are constructed by 1,4-benzodiazepines. Finally, benzotriazepines are believed to possess various pharmacological properties such as antipsychotic and antitumor activities. Hence, this review is divided into three major sections, considering quinazolinones, benzodiazepines and benzotriazepines. In the first section, we take a brief look at various approaches towards synthesis of substituted quinazolin-4(3H)-ones and 2,3-dihydroquinazolin-4(1H)-ones. Also in this section, we try to give an overview of the synthetic routes and strategies recently reported for the generation of various classes of substituted 4(3H)-quinazolinones and 2,3-dihydroquinazolin-4(1H)-ones. Accordingly, quinazolin-4(3H)-ones, were subdivided into three major classes: 2-substituted, 3-substituted and 2,3-disubstituted-quinazolinones. 2,3- dihydroquinazolin-4(1H)-ones also were subdivided into six sub-categories: 2-monosubstituted, 2,2- disubstituted, 2,3-disubstituted, 1,2,3-trisubstituted, 2,2,3-trisubstituted 2,3-dihydroquinazolin-4(1H)-ones and boron-containing quinazoline-4(1H)-ones. In the other two sections, we cover the literature related to synthesis of benzo di/triazepine. The most recent developments are highlighted with a special emphasis on new synthetic routes based on isatoic anhydride as starting material.

A new series of quinazolinone-2-thio-metronidazole derivatives 9a-o was designed, synthesized and assayed for their activities against metabolic enzymes human carbonic anhydrase I and II (hCAs I and II), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glucosidase. The results indicated that all the synthesized compounds exhibited excellent inhibitory activities against mentioned enzymes as compared with standard inhibitors. Representatively, the most potent compound against CA enzymes, 4-fluorophenyl derivative 9i, was 4 and 7-times more potent than standard inhibitor acetazolamide against hCA I and II, respectively; 4-fluorobenzyl derivative 9m as the most potent compound against cholinesterase enzymes, was around 11 and 21-times more potent than standard inhibitor tacrine against AChE and BChE, respectively; the most active α-glucosidase inhibitor 9h with 4-methoxyphenyl moiety was 5-times more active that acarbose as standard inhibitor. Furthermore, in order to study interaction modes of the most potent compounds in the active site of their related enzymes, molecular modeling was performed. Druglikeness, ADME, and toxicity profile of the compounds 9i, 9m, and 9h were also predicted.

A series of new benzofuran-1,3,4-oxadiazole containing 1,2,3-triazole-acetamides 12a-n as potential anti-α-glucosidase agents were designed and synthesized. α-Glucosidase inhibition assay demonstrated that all the synthesized compounds 12a-n (half-maximal inhibitory concentration [IC50 ] values in the range of 40.7 ± 0.3-173.6 ± 1.9 μM) were more potent than standard inhibitor acarbose (IC50 = 750.0 ± 12.5 µM). Among them, the most potent compound was compound 12c, with inhibitory activity around 19-fold higher than acarbose. Since the most potent compound inhibited α-glucosidase in a competitive mode, a docking study of this compound was also performed into the active site of α-glucosidase. In vitro and in silico toxicity assays of the title compounds were also performed.

Age-related macular degeneration as one of the most common causes of worldwide vision loss needs a proper approach for treatment. Therein, cell therapy and regenerative medicine can hold a great promise to be an effective approach. Accordingly, some preclinical and clinical studies were conducted to search around the therapeutic influence of stem cells in Age-related macular degeneration models and subjects. Hereupon, the purpose of the current review is to discuss the mechanisms of age-related macular degeneration, appropriate animal models along with suitable dosage and route of stem cell administration for its treatment.

In this study, inhibitory activity of 30 traditional medicinal plant extracts were examined and evaluated against MMP-9 activity by an orthogonal screening method based on an enzyme inhibition assay along with a surface plasmon resonance (SPR)-based binding assay. Five extracts exhibited reasonable inhibitory activity using inhibition assay. The most potent inhibition was found in Onopordum acanthium L. extract. Therefore, its active compound (onopordia) was isolated and identified as a new MMP-9 inhibitor. In order to evaluate binding profile of O. acanthium extract and onopordia, MMP-9 was immobilized on SPR carboxymethyldextran chip. Equilibrium constant (KD), maximum binding capacity (Rmax) and ΔGbinding values for the interaction of onopordia and MMP-9 were found to be 3 nM, 1190 μRIU and −51.37 kJ/mol. Docking analysis supported the strong binding of onopordia to the MMP-9 active site. This new SPR based biosensor could represent a simple, sensitive, real time and label-free method for screening medicinal plant extracts for identifying potential MMP-9 inhibitors in short time.

A novel series of phthalimide-dithiocarbamate hybrids was synthesized and evaluated for in vitro inhibitory potentials against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The anti-cholinesterase results indicated that among the synthesized compounds, the compounds 7g and 7h showed the most potent anti-AChE and anti-BuChE activities, respectively. Molecular docking and dynamic studies of the compounds 7g and 7h, respectively, in the active site of AChE and BuChE revealed that these compounds as well interacted with studied cholinesterases. These compounds also possessed drug-like properties and were able to cross the BBB.