Fragment-based design and synthesis of coumarin-based thiazoles as dual c-MET/STAT-3 inhibitors for potential antitumor agents.

c-MET and STAT-3 are significant targets for cancer treatments. Here, we describe a class of very effective dual STAT-3 and c-MET inhibitors with coumarin-based thiazoles (3a-o) as its scaffold. Spectroscopic evidence (NMR, HRMS, and HPLC) validated the structural discoveries of the new compounds. The cytotoxic activity of these compounds was also tested against a panel of cancer cells in accordance with US-NCI guidelines. Compound 3g proved to be active at 10 µM, thus it was automatically scheduled to be tested at five doses. Towards SNB-75 (CNS cancer cell line), compound 3g showed notable in vitro anti-cancer activity with GI50 = 1.43 µM. For the molecular targets, compound 3g displayed potent activity towards STAT-3 and c-MET having IC50 of 4.7 µM and 12.67, respectively, compared to Cabozantinib (IC50 = 15 nM of c-MET) and STAT-3-IN-3 (IC50 = 2.1 µM of STAT-3). Moreover, compound 3g significantly induced apoptosis in SNB-75 cells, causing a 3.04-fold increase in apoptotic cell death (treated cells exhibited 11.53 % overall apoptosis, against 3.04 % in reference cells) and a 3.58-fold increase in necrosis. Moreover, it arrests cells at the G2 phase. Dual inhibition of c-MET and STAT-3 protein kinase was further validated using RT-PCR. The target compound's binding mechanism was determined by the application of molecular docking.

DFT, Molecular Docking, ADME, and Cardiotoxicity studies of Persuasive Thiazoles as Potential Inhibitors of the Main Protease of SARS-CoV-2.

This study explores the capability of thiazoles as potent inhibitors of SARS-CoV-2 Mpro. Seventeen thiazoles (1-17) were screened for their linking affinity with the active site of SARS-CoV-2 Mpro and compared with the FDA-recommended antiviral drugs, Remdesivir and Baricitinib. Density Functional Theory (DFT) calculations provided electronic and energetic properties of these ligands, shedding light on their stability and reactivity. Molecular docking analysis revealed that thiazole derivatives exhibited favorable linking affinities with various functional sites of SARS-CoV-2 proteins, including spike receptor-linking zone, nucleocapsid protein N-terminal RNA linking zone, and Mpro. Notably, compounds 3, 10, and 12 displayed the best interaction with 6LZG as compared to FDA-approved antiviral drugs Remdesivir and Baricitinib, while compounds 1, 10, and 8 exhibited strong linking with 6M3M and also better than Remdesivir and Baricitinib. Additionally, compounds 3, 1, and 6 showed promising interactions with 6LU7 but only compound 3 performed better than Baricitinib. An ADME (Absorption, Distribution, Metabolism, and Excretion) study provided insights into the pharmacokinetics and drug-likeness of these compounds, with all ligands demonstrating good physicochemical characteristics, lipophilicity, water solubility, pharmacokinetics, drug-likeness, and medicinal chemistry attributes. The results suggest that these selected thiazole derivatives hold promise as potential candidates for further drug development.

Quinoline-based thiazolyl-hydrazones target cancer cells through autophagy inhibition.

Heterocyclic pharmacophores such as thiazole and quinoline rings have a significant role in medicinal chemistry. They are considered privileged structures since they constitute several Food and Drug Administration (FDA)-approved drugs for cancer treatment. Herein, we report the synthesis, in silico evaluation of the ADMET profiles, and in vitro investigation of the anticancer activity of a series of novel thiazolyl-hydrazones based on the 8-quinoline (1a-c), 2-quinoline (2a-c), and 8-hydroxy-2-quinolyl moiety (3a-c). The panel of several human cancer cell lines and the nontumorigenic human embryonic kidney cell line HEK-293 were used to evaluate the compound-mediated in vitro anticancer activities, leading to [2-(2-(quinolyl-8-ol-2-ylmethylene)hydrazinyl)]-4-(4-methoxyphenyl)-1,3-thiazole (3c) as the most promising compound. The study revealed that 3c blocks the cell-cycle progression of a human colon cancer cell line (HCT-116) in the S phase and induces DNA double-strand breaks. Also, our findings demonstrate that 3c accumulates in lysosomes, ultimately leading to the cell death of the hepatocellular carcinoma cell line (Hep-G2) and HCT-116 cells, by the mechanism of autophagy inhibition.

Sulfonyl thioureas with a benzo[d]thiazole ring as dual acetylcholinesterase/butyrylcholinesterase and human monoamine oxidase A and B inhibitors: An in vitro and in silico study.

A series of sulfonyl thioureas 6a-q containing a benzo[d]thiazole ring with an ester functional group was synthesized from corresponding substituted 2-aminobenzo[d]thiazoles 3a-q and p-toluenesulfonyl isothiocyanate. They had remarkable inhibitory activity against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), monoamine oxidase (MAO)-A, and MAO-B. Among thioureas, several compounds had notable activity in the order of 6k > 6 h > 6c (AChE), 6j > 6g > 6k (BChE), 6k > 6g > 6f (MAO-A), and 6i > 6k > 6h (MAO-B). Compound 6k was an inhibitor of interest due to its potent or good activity against all studied enzymes, with IC50 values of 0.027 ± 0.008 µM (AChE), 0.043 ± 0.004 µM (BChE), 0.353 ± 0.01 µM (MAO-A), and 0.716 ± 0.02 µM (MAO-B). This inhibitory capacity was comparable to that of the reference drugs for each enzyme. Kinetic studies of two compounds with potential activity, 6k (against AChE) and 6j (against BChE), had shown that both 6k and 6j followed competitive-type enzyme inhibition, with Ki constants of 24.49 and 12.16 nM, respectively. Induced fit docking studies for enzymes 4EY7, 7BO4, 2BXR, and 2BYB showed active interactions between sulfonyl thioureas of benzo[d]thiazoles and the residues in the active pocket with ligands 6k, 6i, and 6j, respectively. The stability of the ligand-protein complexes while each ligand entered the active site of each enzyme (4EY7, 7BO4, 2BXR, or 2BYB) was confirmed by molecular dynamics simulations.

Evaluation of thiopyrano[2,3-d]thiazole derivatives as potential anticonvulsant agents.

Anticonvulsant drug discovery has achieved significant progress; however, pharmacotherapy of epilepsy continues to be a challenge for modern medicine and pharmacy. To expand the chemical space of heterocycles as potential antiepileptic agents, herein we report on the synthesis and evaluation of anticonvulsant properties of a series of thiopyrano[2,3-d]thiazoles. The studied heterocycles are characterized by satisfactory drug-likeness and pharmacokinetics properties, calculated in silico using SwissADME. The anticonvulsant activity of thiopyrano[2,3-d]thiazole derivatives was evaluated in vivo using the subcutaneous pentylenetetrazole test. Three hits, that is, compounds 12, 14, and 16, that caused a pronounced anticonvulsant effect were identified. Derivatives 12, 14, and 16 positively affected the latent period of onset of clonic seizures, number of seizures, mortality rate, and duration of the seizure period of animals under experimental conditions. The anticonvulsant properties of compound 14 were equivalent to the effect of the reference drug, sodium valproate. All hit compounds are characterized by satisfying toxicity properties in the human lymphocytes and HEK293 cell line. The most active hit 14 possesses a potential affinity with the GABAA receptor in the molecular docking study and forms a stable complex in the molecular dynamics experiments equal to diazepam. Preliminary SAR results were obtained and discussed based on screening data.

Synthesis of 1,3,5-Triazepines and Benzo[f][1,3,5]triazepines and Their Biological Activity: Recent Advances and New Approaches.

This review article discusses the recent progress in synthesizing seven-membered ring 1,3,5-triazepine and benzo[f][1,3,5]triazepine derivatives. These derivatives can be either unsaturated, saturated, fused, or separated. This review covers strategies and procedures developed over the past two decades, including cyclo-condensation, cyclization, methylation, chlorination, alkylation, addition, cross-coupling, ring expansions, and ring-closing metathesis. This review discusses the synthesis of 1,3,5-triazepine derivatives using nucleophilic or electrophilic substitution reactions with various reagents such as o-phenylenediamine, 2-aminobenzamide, isothiocyanates, pyrazoles, thiazoles, oxadiazoles, oxadiazepines, and hydrazonoyl chloride. This article systematically presents new approaches and techniques for preparing these compounds. It also highlights the biological importance of benzo[f][1,3,5]triazepine derivatives, which have been used as drugs for treating nervous system diseases. This review aims to provide researchers with the necessary information to create and develop new derivatives of these compounds as quickly as possible.

Synthesis, Molecular Docking, and Dynamic Simulation Targeting Main Protease (Mpro) of New, Thiazole Clubbed Pyridine Scaffolds as Potential COVID-19 Inhibitors.

Many biological activities of pyridine and thiazole derivatives have been reported, including antiviral activity and, more recently, as COVID-19 inhibitors. Thus, in this paper, we designed, synthesized, and characterized a novel series of N-aminothiazole-hydrazineethyl-pyridines, beginning with a N'-(1-(pyridine-3-yl)ethylidene)hydrazinecarbothiohydrazide derivative and various hydrazonoyl chlorides and phenacyl bromides. Their Schiff bases were prepared from the condensation of N-aminothiazole derivatives with 4-methoxybenzaldehyde. FTIR, MS, NMR, and elemental studies were used to identify new products. The binding energy for non-bonding interactions between the ligand (studied compounds) and receptor was determined using molecular docking against the SARS-CoV-2 main protease (PDB code: 6LU7). Finally, the best docked pose with highest binding energy (8a = -8.6 kcal/mol) was selected for further molecular dynamics (MD) simulation studies to verify the outcomes and comprehend the thermodynamic properties of the binding. Through additional in vitro and in vivo research on the newly synthesized chemicals, it is envisaged that the achieved results will represent a significant advancement in the fight against COVID-19.

Design, synthesis, and in silico study of hybrid oxoazetidine conjugated thiazoles as anti-EGFR with cytotoxicity activity.

We report a series of hybrid oxoazetidine conjugated thiazoles as epidermal growth factor receptor (EGFR) inhibitors, which were synthesized and tested using a variety of in silico and in vitro studies. The compounds were found to be active against breast and hepatic cancer cell lines, with Compounds 7a, 7b, and 7e being the most potent ones. The derivatives were also evaluated for molecular docking and complementarity studies to explicate fundamental substituent groups essential for their bioactivity. Moreover, the structural activity relationship of the analogues was performed for future compound optimization. These studies advocated that the analogues have a high affinity towards EGFR with favorable anticancer potential. The study advised that the derivatives have potency against breast and hepatic cancer and can assist as an initial scaffold for further development of anti-EGFR compounds.

An expeditious on-water regioselective synthesis of novel arylidene-hydrazinyl-thiazoles as DNA targeting agents.

A series of twenty novel (E)-arylidene-hydrazinyl-thiazole derivatives has been synthesized employing α-bromo-ß-diketones, thiosemicarbazide, and aromatic/heteroaromatic aldehydes with a simple and facile one-pot multicomponent reaction passageway. This organic transformation proceeds efficiently in aqueous media and demonstrated a large functional group tolerance. The structures and stereochemistry of the regioisomeric product were rigorously characterized using heteronuclear 2D NMR experiments. The binding potential of the synthesized analogs with B-DNA dodecamer d(CGCGAATTCGCG)2 was primarily screened using molecular modeling tools and further, mechanistic investigations (either groove or intercalation) were performed using various spectroscopic techniques such as UV-Visible, Fluorescence, and Circular dichroism. The absorption spectra showed a hyperchromic shift in the absorption maxima of ctDNA with successive addition of thiazole derivatives, implying groove binding mode of interactions, further supported by displacement assay and circular dichroism analysis. Furthermore, steady-state fluorescence analysis revealed the static mode of quenching and moderate bindings between the ligand and DNA biomolecule. The competitive studies showed that the derivatives having a pyridinyl (heteroaromatic) group in their structure, bind with the nucleic acid of calf-thymus (ctDNA) more effectively in the minor groove region as compared with the aromatic substitutions.

I2-catalyzed one-pot oxidative condensation of thiourea, methyl ketones, and aryl thiols into 5-sulfenylated 2-amino-1,3-thiazoles by DMSO.

A one-pot, efficient oxidative-condensation process for constructing both 4-alkyl and 4-aryl-5-(arylthio) thiazol-2-amines using DMSO/I2 is introduced. In this procedure, methyl ketones, thiourea, DMSO, and thiols are reacted together in the presence of molecular I2 at 80 °C simply to produce 4-alkyl or aryl-5-(arylthio)thiazol-2-amines due to formation of a C-S bond between thiourea and methyl carbon linked to carbonyl group and the another C-S bond formation between thiol and thiazol ring. Under reaction conditions, both aryl and alkyl methyl ketones including acetophenone and substituted acetophenones also, 2-alkanones such as acetone, 2-butanone, 2-pentanone, and 2-heptanone yield those products successfully.

Design, synthesis and neuraminidase inhibitory activity of 4-methyl-5-(3-phenylacryloyl) thiazoles.

A series of 4-methyl-5-(3-phenylacryloyl)thiazoles based on chalcones were designed, synthesized and evaluated for their influenza neuraminidase (NA) inhibitory activity in vitro. A preliminary structure-activity relationship (SAR) analysis showed that thiazoles bearing amide had greater potency. It also showed that mono-hydroxyl group at 4-position on phenyl ring was more effective than other electron-releasing groups or electron-withdraw groups. Compounds A2 and A26 were more potent against NA with IC50 values of 8.2 ± 0.5 µg/mL and 6.2 ± 1.4 µg/mL, respectively. Molecular docking study demonstrated that thiazoles skeleton was benefit for the NA inhibitory activity.

Synthesis, characterization, antioxidant and antiparasitic activities new naphthyl-thiazole derivatives.

In this work, 13 thiosemicarbazones (1a - m) and 16 thiazoles (2a - p) were obtained, which were properly characterized by spectroscopic and spectrometric techniques. The pharmacokinetic properties obtained in silico revealed that the derivatives are in accordance with the parameters established by lipinski and veber, showing that such compounds have good bioavailability or permeability when administered orally. In assays of antioxidant activity, thiosemicarbazones showed moderate to high antioxidant potential when compared to thiazoles. In addition, they were able to interact with albumin and DNA. Screening assays to assess the toxicity of compounds to mammalian cells revealed that thiosemicarbazones were less toxic when compared to thiazoles. In relation to in vitro antiparasitic activity, thiosemicarbazones and thiazoles showed cytotoxic potential against the parasites Leishmania amazonensis and Trypanosoma cruzi. Among the compounds, 1b, 1j and 2l stood out, showing inhibition potential for the amastigote forms of the two parasites. As for the in vitro antimalarial activity, thiosemicarbazones did not inhibit Plasmodium falciparum growth. In contrast, thiazoles promoted growth inhibition. This study shows in a preliminary way that the synthesized compounds have antiparasitic potential in vitro.

Design and Synthesis of Pyridine and Thiazole Derivatives as Eco-friendly Insecticidal to Control Olive Pests.

Treatment of p-tosyloxybenzaldehyde (1) with ethyl cyanoacetate afforded ethyl 2-cyano-3-(4-{[(4-methylphenyl)sulfonyl]oxy}phenyl)acrylate (2) which reacted with some active methylene derivatives under microwave irradiation in presence of ammonium acetate yielded pyridine derivatives 3-7. On the other hand, when treatment of compound 1 with thiosemicarbazide gave 4-tosyloxybenzylidenethiosemicarbazone (8), which allowed to react with some active methylene compounds, such as: ethyl bromoacetate, chloroacetonitrile or phenacyl bromide derivatives gave thiazole derivatives 9-13. The structure of all products were confirmed by elemental and spectroscopic analyses such as IR, 1 H-NMR, 13 CNMR and mass spectra. The advanced of this method are short reaction time (3-7 min), excellent yield, pure products, and low-cost processing. In the final category, the toxicological characteristics of all compounds were tested towards Saissetia oleae (Olivier, 1791) (Hemiptera: Coccidae). With respect to the LC50 values. It has been found that compound 3 possesses the highest insecticidal bioefficacy compared with other products, with values of 0.502 and 1.009 ppm, for nymphs and adults female, respectively. This study paves the way towards discovering new materials for potential use as insecticidal active agents.

Synthesis of Thiazole-Chalcone Hybrid Molecules: Antioxidant, Alpha(α)-Amylase Inhibition and Docking Studies.

The molecular hybrid approach is very significant to combat various drug-resistant disorders. A simple, convenient, and cost-effective synthesis of thiazole-based chalcones is accomplished, using a molecular hybrid approach, in two steps. The compound 1-(2-phenylthiazol-4-yl)ethanone (3) was used as the main intermediate for the synthesis of 3-(arylidene)-1-(2-phenylthiazol-4-yl)prop-2-en-1-ones (4a-f). Thin layer chromatography was used to testify the formation and purity of all synthesized compounds. Further structural confirmation of all compounds was achieved via different spectroscopic techniques (UV, FT-IR, 1 H- and 13 C-NMR) and elemental analysis. All synthesized compounds were tested for their α-amylase inhibition and antioxidant potential. The cytotoxic property of compounds was also tested with in vitro haemolytic assay. All tested compounds showed moderate to excellent α-amylase inhibition and antioxidant activity. All tested compounds are found safe to use due to their less toxicity when compared to the standard Triton X. The molecular docking simulation study of all synthesized compounds was also conducted to examine the best binding interactions with human pancreatic α-amylase (pdb: 4 W93) using AutodockVina. The molecular docking results authenticated the in vitro amylase inhibition results, i.e., 3-(3-Methoxyphenyl)-1-(2-phenylthiazol-4-yl)prop-2-en-1-one (4e) exhibited lowest IC50 value 54.09±0.11  µM with a binding energy of -7.898 kcal/mol.

Design, synthesis, and antitumor screening of new thiazole, thiazolopyrimidine, and thiazolotriazine derivatives as potent inhibitors of VEGFR-2.

New thiazole, thiazolopyrimidine, and thiazolotriazine derivatives 3-12 and 14a-f were synthesized. The newly synthesized analogs were tested for in vitro antitumor activity against HepG2, HCT-116, MCF-7, HeP-2, and Hela cancer cells. Results indicated that compound 5 displayed the highest potency toward the tested cancer cells. Compound 11b possessed enhanced effectiveness over MCF-7, HepG2, HCT-116, and Hela cancer cells. In addition, compounds 4 and 6 showed promising activity toward HCT-116, MCF-7, and Hela cancer cells and eminent activity against HepG2 and HeP-2 cells. Moreover, compounds 3-6 and 11b were tested for their capability to inhibit vascular endothelial growth factor receptor-2 (VEGFR-2) activity. The obtained results showed that compound 5 displayed significant inhibitory activity against VEGFR-2 (half-maximal inhibitory concentration [IC50 ] = 0.044 µM) comparable to sunitinib (IC50 = 0.100 µM). Also, the synthesized compounds 3-6 and 11b were subjected to in vitro cytotoxicity tests over WI38 and WISH normal cells. It was found that the five tested compounds displayed significantly lower cytotoxicity than doxorubicin toward normal cell lines. Cell cycle analysis proved that compound 5 induces cell cycle arrest in the S phase for HCT-116 and Hela cancer cell lines and in the G2/M phase for the MCF-7 cancer cell line. Moreover, compound 5 induced cancer cell death through apoptosis accompanied by a high ratio of BAX/BCL-2 in the screened cancer cells. Furthermore, docking results revealed that compound 5 showed the essential interaction bonds with VEGFR-2, which agreed with in vitro enzyme assay results. In silico studies showed that most of the analyzed compounds complied with the requirements of good oral bioavailability with minimal toxicity threats in humans.

Synthesis and Molecular Docking of Some Novel 3-Thiazolyl-Coumarins as Inhibitors of VEGFR-2 Kinase.

One crucial strategy for the treatment of breast cancer involves focusing on the Vascular Endothelial Growth Factor Receptor (VEGFR-2) signaling system. Consequently, the development of new (VEGFR-2) inhibitors is of the utmost importance. In this study, novel 3-thiazolhydrazinylcoumarins were designed and synthesized via the reaction of phenylazoacetylcoumarin with various hydrazonoyl halides and α-bromoketones. By using elemental and spectral analysis data (IR, 1H-NMR, 13C-NMR, and Mass), the ascribed structures for all newly synthesized compounds were clarified, and the mechanisms underlying their formation were delineated. The molecular docking studies of the resulting 6-(phenyldiazenyl)-2H-chromen-2-one (3, 6a-e, 10a-c and 12a-c) derivatives were assessed against VEGFR-2 and demonstrated comparable activities to that of Sorafenib (approved medicine) with compounds 6d and 6b showing the highest binding scores (-9.900 and -9.819 kcal/mol, respectively). The cytotoxicity of the most active thiazole derivatives 6d, 6b, 6c, 10c and 10a were investigated for their human breast cancer (MCF-7) cell line and normal cell line LLC-Mk2 using MTT assay and Sorafenib as the reference drug. The results revealed that compounds 6d and 6b exhibited greater anticancer activities (IC50 = 10.5 ± 0.71 and 11.2 ± 0.80 µM, respectively) than the Sorafenib reference drug (IC50 = 5.10 ± 0.49 µM). Therefore, the present study demonstrated that thiazolyl coumarins are potential (VEGFR-2) inhibitors and pave the way for the synthesis of additional libraries based on the reported scaffold, which could eventually lead to the development of efficient treatment for breast cancer.

Synthesis, In Vitro Evaluation and Molecular Docking Studies of Novel Thiophenyl Thiazolyl-Pyridine Hybrids as Potential Anticancer Agents.

Many literature reports revealed the anticancer activity of pyridine and thiazole derivatives, especially in lung cancer. Therefore, a new series of thiazolyl pyridines linked with thiophene moiety via hydrazone group was prepared by one-pot multi-component reaction of (E)-1-(4-methyl-2-(2-(1-(thiophen-2-yl)ethylidene)hydrazinyl)thiazol-5-yl)ethanone with benzaldehyde derivatives and malononitrile in a good yield. Then, compound 5 and the thiazolyl pyridines were investigated for their in vitro anticancer activity against lung cancer (A549) cell line using MTT assay compared to doxorubicin as a reference drug. The structure of all the newly synthesized compounds was established based on spectroscopic data and elemental analyses. For better insight to investigate their mechanism of action on A549 cell line, docking studies were performed, targeting epidermal growth factor receptor (EGFR) tyrosine kinase. The results obtained revealed that the tested compounds displayed excellent anticancer activities against lung cancer cell line except 8c and 8f compared to reference drug. Based on the data obtained, it can be inferred that the novel compounds, as well as their key intermediate, compound 5, demonstrated potent anticancer activity against lung carcinoma by inhibiting EGFR.

Novel sulfonyl thiazolyl-hydrazone derivatives as EGFR inhibitors: Design, synthesis, biological evaluation and molecular docking studies.

New hydrazonoyl-sulfonylthiazoles were designed and synthesized as EGFR inhibitors. The new sulfonylthiazole derivatives were assessed in vitro to measure their effect on EGFR. They revealed marked inhibitory activity against EGFR kinase having IC50 range from 0.037 to 0.317 µM compared to reference drug dasatinib (IC50 = 0.077 µM). Six derivatives of the newly synthesized compounds showed potent inhibitory activity relative to dasatinib. Furthermore, the new hits were examined concerning their cytotoxic effect on human breast cancer cell line (MCF7), hepatic cancer cell line (HepG2) using MTT assay. N-(2-Benzenesulfonyl-1-phenyl-ethylidene)-N'-(4-methyl-thiazol-2-yl)-hydrazine (IC50 = 1.24 µM) revealed higher potency than dasatinib (IC50 = 11.6 µM) against MCF7cell line. Besides, N-(2-benzenesulfonyl-1-phenyl-ethylidene)-N'-(4-methyl-5-p-tolylazo-thiazol-2-yl)-hydrazine exhibited excellent cytotoxicity against HepG2cell line (IC50 = 3.61 µM), exceeding that of dasatinib (IC50 = 14.10 µM). In addition to low cytotoxic effect on normal (WI-38) cells, describing the high safety profiles of these compounds. Moreover, molecular docking was done in order to determine the possible binding modes of such compounds inside the binding site of EGFR.

Azomethine-clubbed thiazoles as human tissue non-specific alkaline phosphatase (h-TNAP) and intestinal alkaline phosphatase (h-IAP) Inhibitors: kinetics and molecular docking studies.

Thiazole derivatives are known inhibitors of alkaline phosphatase, but various side effects have reduced their curative efficacy. Conversely, compounds bearing azomethine linkage display a broad spectrum of biological applications. Therefore, combining the two scaffolds in a single structural unit should result in joint beneficial effects of both. A new series of azomethine-clubbed thiazoles (3a-i) was synthesized and appraised for their inhibitory potential against human tissue non-specific alkaline phosphatase (h-TNAP) and human intestinal alkaline phosphatase (h-IAP). Compounds 3c and 3f were found to be most potent compounds toward h-TNAP with IC50 values of 0.15 ± 0.01 and 0.50 ± 0.01 µM, respectively, whereas 3a and 3f exhibited maximum potency for h-IAP with IC50 value of 2.59 ± 0.04 and 2.56 ± 0.02 µM, respectively. Molecular docking studies were also performed to find the type of binding interaction between potential inhibitor and active sites of enzymes. The enzymes inhibition kinetics studies were carried out to define the mechanism of enzyme inhibition. The current study leads to discovery of some potent inhibitors of alkaline phosphatase that is promising toward identification of compounds with druggable properties.

Synthesis of Arylidenehydrazinyl-4-methoxyphenylthiazole Derivatives: Docking Studies, Probing Type II Diabetes Complication Management Agents.

Thiazole has been a key scaffold in antidiabetic drugs. In quest of new and more effective drugs a simple, efficient, high yielding (67-79 %) and convenient synthesis of arylidenehydrazinyl-4-methoxyphenyl)thiazoles is accomplished over two steps. The synthesis involved the condensation of aryl substituted thiosemicarbazones and 2-bromo-4-methoxyacetophenone in absolute ethanol. The structures of the resulting thiazoles are in accord with their UV/VIS, FT-IR, 1 H-, 13 C-NMR and HRMS data. All compounds were evaluated for alpha(α)-amylase inhibition potential, antiglycation, antioxidant abilities and biocompatibility. The compounds library identified 2-(2-(3,4-dichlorobenzylidene)hydrazinyl)-4-(4-methoxyphenyl)thiazole as a lead molecule against α-amylase inhibition with an IC50 of 5.75±0.02 µM. α-Amylase inhibition is also supported by molecular docking studies against α-amylase. All the obtained thiazoles also showed promising antiglycation activity with 4-(4-methoxyphenyl)-2-{2-[2-(trifluoromethyl)benzylidene]hydrazinyl}thiazole exhibiting the best inhibition (IC50 = 0.383±0.001 mg/mL) compared to control. The tested compounds are also biocompatible at the concentration used i. e., 10 µM.