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Resistance to existing drugs develops because of insensible use of antibacterial and antifungal drugs. Therefore, there is a need for the development of new drug candidate compounds. The thiazole ring has many biological activities. It is possible to include antibacterial and antifungal activities among these activities. In addition to these, the thiazole ring has been preferred because it is the bioisostere of the imidazole ring in the structure of many antifungal drugs. For this purpose, within the scope of this study, 7 new thiazole compounds were synthesized, and their structure determinations were carried out using HRMS, 1H-NMR, 13C-NMR spectroscopic methods. Their antibacterial and antifungal activities were investigated by in vitro methods. As a result of activity tests, compound 3e showed activity against C.krusei strain with MIC50=31.25 ug/mL. The potential effectiveness of the compound 3e on the 14alpha-demethylase enzyme (PDB ID:3LD6) was tested by in silico studies.

In this study, some new compounds, which are 2aminothiadiazole derivatives linked by a phenyl bridge to the 2position of the benzimidazole ring, were designed and synthesized as antimicrobial agents. The structures of the compounds were elucidated by 1 H and 13 C NMR spectroscopy, high-resolution mass spectrometry, and elemental analysis. The antifungal activities of the synthesized compounds were tested on Candida albicans, Candida krusei, Candida glabrata, and Candida parapsilosis. Compound 5f is more active against C. albicans and C. glabrata than standard fluconazole and varicanazole. Compounds were also evaluated for their counteracting activity against Gram-positive Escherichia coli, Serratia marcescens, Klebsiella pneumoniae, and Pseudomonas aeruginosa and Gram-negative Enterococcus faecalis, Bacillus subtilis, and Staphylococcus aureus. Compounds 5c and 5h had minimum inhibitory concentrations against E. faecalis close to that of the standard azithromycin. Molecular docking studies were performed against Candida species’ 14-α demethylase enzyme. 5f was the most active compound against Candida species, which gave the highest docking interaction energy. The stabilities of compounds 5c and 5f with CYP51 were tested using 100 ns molecular dynamics simulations. According to the theoretical ADME calculations, the profiles of the compounds are suitable in terms of limiting rules. HOMO−LUMO analysis showed that 5h is chemically more reactive (represented with the lower ΔE = 3.432 eV) than the other molecules, which is compatible with the highest antibacterial activity result.

In this study, novel pyridine-containing thiazolyl hydrazone derivatives were synthesized. Structure determinations of the compounds were performed using 1H NMR, 13C NMR and HRMS techniques. The biological activities of the compounds were evaluated against MAO enzymes by in vitro fluorometric method. As a result of activity studies, compound 3a showed selective inhibitory activity against MAO-B enzyme with IC50 = 0.088 + 0.003 µM. The selectivity index of this compound is greater than 1136. Molecular docking studies were carried out using 2V5Z crystal. It has been observed that docking studies and activity studies are in harmony.

Amaç: Depresyon önemli bir psikiyatrik hastalıktır ve dünyada görülme sıklığı yüksektir. Dünya Sağlık Örgütü tarafından, 2012 yılında yaklaşık 350 milyon kişinin depresyon ile mücadele ettiğini belirtilmiştir. Özellikle monoamin oksidaz-A inhibitörleri depresyon tedavisinde kullanılmaktadır. Monoamin oksidaz inhibitörlerinin bu alanda kullanımı, yeni bileşiklerin geliştirilmesini de değerli kılmaktadır. Materyal ve Metot: 5 yeni molekülden oluşan pirol türevi (2a-2e) bileşikler sentezlenmiştir. Elde edilen bileşiklerin yapıları spektroskopik yöntemler kullanılarak aydınlatılmıştır. Bileşiklerin in vitro monoamin oksidaz enzim inhibitor etkinlikleri incelenmiştir. Bulgular: Sentezlenen bileşikler içerisinde 2b ve 2c kodlu bileşikler monoamin oksidaz-A enzimine karşı önemli düzeyde inhibitor etkinlik göstermiştir. Sonuç: Sentezlenen bileşiklerin selektif monoamin oksidaz-A inhibitör potansiyelleri incelendiğinde umut verici sonuçlara ulaşıldığı görülmektedir. Elde edilen bileşikler üzerinde yapılan modifikasyonlar ile daha etkili yeni bileşiklere ulaşılması planlanmaktadır.

Monoamine oxidase (MAO) enzymes have an important place in neurodegenerative diseases. While MAO-A inhibitors are used in depression; MAO-B enzyme has an important place in Parkinson's disease. Within the scope of this study, 7 new piperazine-dithiocarbamate derivative compounds were synthesized. Structure determinations of the compounds were performed using 1H-NMR, 13C-NMR and HRMS spectroscopic methods. The MAO inhibitory activities of the compounds were determined by in vitro fluorometric methods. According to the obtained results, compound 2d with IC50=0.108±0.004 µM; compound 2e exhibited inhibitory activity with an IC50=0.074±0.003 µM.

The use of dual acetylcholinesterase (AChE)-monoamine oxidase B (MAO-B) inhibitors is a new approach in the treatment of Alzheimer disease (AD). In this work, 14 new benzothiazoles (4a-4n) were designed and synthesized. In biological activity studies, the AChE, butyrylcholinesterase (BChE), MAO-A and MAO-B inhibitory potentials of all compounds were evaluated using the

The activity of the synthesized compounds against breast cancer was investigated. Molecular docking studies were performed against aromatase, MAO-B, and Caspase-3 enzymes.

MAO-A inhibitors are used in the treatment of depression. There are many studies showing that the thiazolyl-hydrazone structure is a pharmacophore structure for the MAO enzyme. In previous studies by our team, activity studies were carried out with thiazolyl-hydrazone derivatives containing pyrrolidine, morpholine, and piperazine. All of them were displayed MAO-A selective inhibition profile. Additionally, derivatives containing piperazine ring were most active. For this purpose, thiazolyl-hydrazone derivatives containing piperazine were synthesized, but this time an active group, formyl group, was added to the piperazine ring as a substituent. Based on this view, new thiazolyl-hydrazone compounds were synthesized, characterized, and screened for their hMAO-A and hMAO-B inhibitory activity by an in vitro fluorometric method. The structure of the compound was tried to be fully elucidated using 2D NMR technique. The compound including 2,4-dimethyl substituent (3i) were found to be the most effective agents in the series against MAO-A enzyme with the IC50 value of 0.080 ± 0.003 µM. The docking study of compound 3i revealed that there is a strong interaction between the active sites of hMAO-A and analyzed compound.

Alzheimer's disease (AD) is a neurological, progressive illness that typically affects the elderly and is clinically distinguished by memory and cognitive decline. Due to a number of factors, including the absence of a radical treatment, an increase in the patient population over time, the high cost of care and treatment, and a significant decline in patients' quality of life, the importance of this disease has increased. These factors have all prompted increased interest among researchers in this field. The chemical structure of the donepezil molecule, the most popular and effective treatment response for AD, served as the basis for the design and synthesis of 42 novel indan-1-one derivatives in this study. Using IR

Background: The carbonic anhydrases (CAs) which are found in most living organisms is a member of the zinc-containing metalloenzyme family. The abnormal levels and activities are frequently associated with various diseases therefore CAs have become an attractive target for the design of inhibitors or activators that can be used in the treatment of those diseases. Methods: Herein, we have designed and synthesized new benzimidazole-hydrazone derivatives to investigate the effects of these synthesized compounds on CA isoenzymes. Chemical structures of synthesized compounds were confirmed by 1H NMR, 13C NMR, and HRMS. The synthetic derivatives were screened for their inhibitory potential against carbonic anhydrase I and II by in vitro assay. Results: These compounds have IC50 values of 5.156-1.684 μM (hCA I) and 4.334-2.188 μM (hCA II). Inhibition types and Ki values of the compounds were determined. The Ki values of the compounds were 5.44 ± 0.14 μM-0.299 ± 0.01 μM (hCA I) and 3.699 ± 0.041 μM-1.507 ± 0.01 μM (hCA II). The synthetic compounds displayed inhibitory action comparable to that of the clinically utilized reference substance, acetazolamide. According to this, compound 3p was the most effective molecule with an IC50 value of 1.684 μM. Accordingly, the type of inhibition was noncompetitive and the Ki value was 0.299 ± 0.01 μM. Conclusion: According to the in vitro test results, detailed protein-ligand interactions of the compound 3p, which is more active against hCA I than standard azithromycin (AZM), were analyzed. In addition, the cytotoxic effects of the compounds on the L929 healthy cell line were evaluated.

Dithiocarbamate derivatives possess diverse biological activities. This work further expands their activity profile by identifying seven benzylamine-containing dithiocarbamate derivatives with piperazine and piperidine substitutions at the main moiety, and five piperazine-containing dithiocarbamates with various substitutions at the piperazine moiety as new inhibitors of α-glucosidase. Compounds bearing the benzylamine moiety exhibited more potent inhibition of the enzyme than the piperazine derivatives. Majority of the compounds non-competitively inhibited α-glucosidase that led to the identification of a new allosteric site on the enzyme with the help of molecular dynamics and docking studies. These studies suggest that the compounds regulate inhibition of the enzyme by binding to an allosteric site that is located in the vicinity of the active site. This is the first report on the allosteric inhibition of α-glucosidase by dithiocarbamate derivatives that provides insights into the mechanism of inhibition of the enzyme at molecular level. Moreover, it also explores new avenues for drug development of α-glucosidase inhibitors as antidiabetic drugs.

In this study, a series of imidazole derivatives was designed, synthesized, and evaluated forin vitrobiological activity on the human breast cancer cell line MCF7 by MTT assay. To determine the selectivity of the compounds, their cytotoxic effects on the L929 (healthy mouse fibroblast) cell line were also investigated. Compounds1a, 1b, and1dwere found to be more effective than the reference drug cisplatin against the MCF7 cell line. It is seen that the cytotoxic effects of the compounds on the L929 cell line are quite low, and the compounds are found to be highly selective. The inhibition potentials of the compounds1a, 1b, 1d, and1kwhich were effective on the MCF7 cell line, and on the aromatase enzyme were evaluated and it was found that the compounds had similar effects to the reference drug letrozole. Further, the interactions between the best active compounds and the human aromatase cytochrome P450 (CYP) enzyme were analyzed through a molecular docking study. The findings suggest that these compounds could be a promising candidate for the creation of a new family of non-steroidal aromatase inhibitors. Finally, computational ADME-Tox studies of compounds1a, 1b, 1d, and1kwere performed and found to have the appropriate profile.

In this study, some new propargyl derivatives were synthesized considering potential monoamine oxidase-B (MAO-B) inhibition potency of propargyl moiety. In synthesis studies, 2-chlorobenzimidazole was reacted with propargyl bromide in the presence of NaH and compound 1 was obtained. Compound 1 was treated with various benzylamine derivatives and final products (2a-2c) were gained. Structures of obtained compounds were established by spectroscopic methods. Effects of the synthesized compounds against MAO enzymes were observed by using in-vitro fluorimetric method. Activity studies revealed that synthesis compounds inhibited MAO enzymes to different extends. .

The development of new enzyme inhibitors in degenerative brain diseases has gained more attention. Enzyme inhibitors play an effective role in controlling central nervous system diseases. For this purpose, a novel series of hydrazone derivatives containing imidazolidine ring aimed against Alzheimer\"s disease (AD), have been designed and synthesized. The acetylcholinesterase (AChE) enzyme inhibitory activity of these compounds was investigated. The structures of the compounds were determined by IR, H-1 and C-13-NMR and mass spectroscopic methods. Inhibition studies on the cholinesterase (ChE) enzymes and beta-amyloid plaque inhibition test of the compounds were performed. Based on the experimental results, compound 3j bearing dimethoxy substituent on the aromatic ring like donepezil exhibited the most AChE inhibitory activity with the IC50 values of 0.023 +/- 0.001 mu M. Owing to obtained biological activity and molecular docking study results, it is thought that the most active compound 3j may play a role in both symptomatic and palliative treatment of AD.

Alzheimer's disease (AD) is a slowly progressive neurodegenerative disease that causes dementia in people aged 65 and over. In the present study, a series of thiadiazole hybrid compounds with benzothiazine derivatives as acetylcholinesterase inhibitors were developed and evaluated for their biological activity. The AChE and BChE inhibition potentials of all compounds were evaluated by using the in vitro Ellman method. The biological evaluation showed that compounds

Chalcones targeting neurodegenerative diseases have been known as attractive structures in drug design and discovery. In this study, phenothiazine-based chalcones as ChEs and MAOs inhibitors were designed and synthesizedviabase-catalyzed Claisen-Schmidt condensation, and chemical structures of the compounds were elucidated by NMRs and HRMS. Compounds3and9showed promising inhibition potency against AChE enzyme with IC(50)values of 0.221 mu M and 0.053 mu M while compound9displayed remarkable inhibition potency toward MAO-B enzyme with IC(50)value of 0.048 mu M. Compound9, as a dual-target inhibitor, selectively inhibited AChE and MAO-B enzymes. This promising behavior is an advantage for the compound since MAO-B and AChE inhibition have a role in Alzheimer's disease. Fused tricyclic ring systems such as phenothiazine incorporated with chalcone moiety being multitargeting ligands may help scientists for the rational design of novel lead compounds targeting neurodegenerative illnesses.

Inhibition of aromatase enzymes is very important in the prevention of estrogen-related diseases and the regulation of estrogen levels. Aromatase enzyme is involved in the final stage of the biosynthesis of estrogen, in the conversion of androgens to estrogen. The development of new compounds for the inhibition of aromatase enzymes is an important area for medicinal chemists in this respect. In the present study, new benzimidazole derivatives have been designed and synthesized which have reported anticancer activity in the literature. Their anticancer activity was evaluated against human A549 and MCF-7 cell lines by MTT assay. In the series, concerning MCF-7 cell line, the most potent compounds were the 4-benzylpiperidine derivatives 2c, 2g, and 2k with IC50 values of 0.032 ± 0.001, 0.024 ± 0.001, and 0.035 ± 0.001 µM, respectively, compared to the reference drug cisplatin (IC50 = 0.021 ± 0.001 µM). Then, these compounds were subject to further in silico aromatase enzyme inhibition assays to determine the possible binding modes and interactions underlying their activity. Thanks to molecular docking studies, the effectiveness of these compounds against aromatase enzyme could be simulated. Consequently, it has been found that these compounds can be settled very properly to the active site of the aromatase enzyme.

Monoamine oxidases (MAOs) are important drug targets for the management of neurological disorders. Herein, a series of new 1,3,4-thiadiazole derivatives bearing various alkyl/arylamine moieties as MAO inhibitors were designed and synthesized. All of the compounds were more selective against hMAO-A than hMAO-B. The half maximal inhibitory concentration (IC(50)) values of most of the compounds were lower than that of the common drug moclobemide (IC(50) = 4.664 μM) and compound 6b was proven to be the most active compound (IC(50) = 0.060 μM). Moreover, it was seen that compound 6b showed a similar inhibition profile to that of clorgyline (IC(50) = 0.048 μM). The inhibition profile was found to be reversible and competitive for compound 6b with MAO-A selectivity. Molecular modelling studies aided in the understanding of the interaction modes between compound 6b and MAO-A. Furthermore, this compound was predicted to have a good pharmacokinetic profile and high BBB penetration. Therefore, such compounds are of interest towards developing new MAO inhibitors.

Many studies have been conducted on the selective inhibition of human monoamine oxidase B (hMAO-B) enzyme using benzylamine-sulphonamide derivatives. Using various chemical modifications on BB-4h, which was reported previously by our team and showed a significant level of MAO-B inhibition, novel benzylamine-sulphonamide derivatives were designed, synthesised, and their MAO inhibition potentials were evaluated. Among the tested derivatives, compounds 4i and 4t achieved IC50 values of 0.041 ± 0.001 µM and 0.065 ± 0.002 µM, respectively. The mechanism of hMAO-B inhibition by compounds 4i and 4t was studied using Lineweaver–Burk plot. The nature of inhibition was also determined to be non-competitive. Cytotoxicity tests were conducted and compounds 4i and 4t were found to be non-toxic. Molecular docking studies were also carried out for compound 4i, which was found as the most potent agent, within hMAO-B catalytic site.

A series of novel tetrazole-S-alkyl-piperazine derivatives were synthesized and evaluated for their antifungal activity against C. albicans (ATCC 24433), C. krusei (ATCC 6258) and C. parapsilosis (ATCC 22019) and antibacterial activity against E. coli (ATCC 25922), S. marcescens (ATCC 8100), K. pneumoniae (ATCC 13883), P. aeruginosa (ATCC 27853), E. faecalis (ATCC 2942), B. subtilis (ATCC), S. aureus (ATCC 29213), S. epidermidis (ATCC 12228). Among the synthesized compounds, 1-(4-cycylohexylpiperazin-1-yl)-2-((1-methyl-1H-tetrazol-5-yl)thio)ethan-1-one (2b) (MIC = 7.81 µg/mL) and 1-(4-(4-chlorobenzyl)piperazin-1-yl)-2-((1-methyl-1H-tetrazol-5-yl)thio)ethan-1-one (2f) (MIC = 3.90 µg/mL) displayed significant antifungal activity and compared to reference drugs voriconazole and fluconazole. Besides, compound 2b has showed also higher antibacterial activity against E. faecalis (ATCC 2942) as a reference drug azithromycin, with a MIC value of 3.90 µg/mL, and compound 2d was found to be effective against S. epidermidis (ATCC 12228) as the same reference drug, with a MIC value of 7.81 µg/mL. All the derivatives were efficiently synthesized by a two-step process. The structure of the newly synthesized compounds was elucidated by their 1H NMR, 13C NMR, LC-MS/MS, and elemental analysis. In this study, the detailed synthesis, spectroscopic and biological evaluation data are reported. Molecular docking studies of all compounds were performed with the sterol 14-alpha demethylase enzyme of C. albicans, the target enzyme of azole antifungal drugs.

Breast cancer is the most frequent female cancer and second cause of cancer-related deaths among women around the world. Two thirds of breast cancer patients have hormone-dependent tumors, which is very likely be treated with hormonal therapy. Aromatase is involved in the biosynthesis of estrogen thus a critical target for breast cancer. In this study, in order to identify new aromatase enzyme inhibitors, a series of benzimidazole-1,3,4-oxadiazole derivatives were synthesized and characterized by 1H NMR, 13C NMR, and MS spectra analyses. In the in vitro anticancer assay, all the compounds tested anticancer activities using MTT-based assay against five cancer cell lines (MCF-7, A549, HeLa, C6, and HepG2). Among them, compound 5a exhibited the most potent activity with IC50 values of 5.165 ± 0.211 μM and 5.995 ± 0.264 μM against MCF-7 and HepG2 cell lines. Compound 5a was included in the BrdU test to determine the DNA synthesis inhibition effects for both cell types. Furthermore, compound 5c was also found to be more effective than doxorubicin on the HeLa cell line. The selectivity of anticancer activity was evaluated in NIH3T3 cell line. In vitro, enzymatic inhibition assays of aromatase enzyme were performed for compound 5a acting on the MCF-7 cell line. For compound 5a, in silico molecular docking and dynamics simulations against aromatase enzyme was performed to determine possible protein-ligand interactions and stability. DFT study was performed to evaluate the quantum mechanical and electronic properties of compound 5a. Finally, the theoretical ADME properties of the potential aromatase inhibitor compound 5a were analyzed by calculations. Communicated by Ramaswamy H. Sarma

In this study, two novel series of thiazolylhydrazone derivatives containing 4-ethylpiperazine (

To develop new acetylcholinesterase (AChE)-monoamine oxidase-B (MAO-B) dual inhibitors against Alzheimer's disease, the benzimidazole ring, which has a propargyl side chain with previously proven selective MAO-B inhibitory activity, was used as the main structure. Moreover, like donepezil, it was thought that the enzyme AChE would provide π-π interactions with the peripheral anionic side in this structure. Piperazine derivatives were chosen for the cationic active site. The synthesis of the compounds was carried out in five steps. The structures of the compounds were determined using

Isomerism plays a key role in determining potency, selectivity and type of inhibition exhibited by enzyme inhibitors. We present 20 new benzylidene-hydrazinyl-thiazole inhibitors of α-glucosidase featuring positional isomerism of the methyl group at 3 and 4 positions of their piperidine ring. This structural property helped understand their potency and selectivity to the enzyme yielding new clues to α-glucosidase inhibition. The isomerism was pivotal to improving or deteriorating enzyme binding and potency of inhibition shown by the target compounds. Data from enzyme kinetics experiments were in agreement with docking and molecular dynamics simulations revealing a direct influence of isomerism on enzyme-inhibitor molecular interactions. Generally, the 4-methyl derivatives showed more selectivity toward the enzyme since they established more and stronger molecular contacts with the enzyme than their 3-methyl counterparts. However, the isomerism did not significantly affect the type of inhibition since majority of the compounds exhibited noncompetitive enzyme inhibition except for one. Our work provides essential and interesting clues to understanding α-glucosidase inhibition by thiazole isomers that would help explore new avenues to designing and developing better α-glucosidase inhibitors as antidiabetic drugs.

According to the cholinergic hypothesis, an increase in the acetylcholine level in Alzheimer's disease patients relatively slows down the symptoms of the disease. The most commonly used drug, donepezil, is a cholinesterase inhibitor. In this study, 12 new chalcones (2a-l) were designed and synthesized. In biological activity studies, the acetylcholinesterase (AChE) and butyrylcholinesterase inhibitory potentials of all compounds were evaluated using the in vitro Ellman method. The biological evaluation showed that compounds 2d, 2f, 2j, and 2l displayed significant activity against AChE. The compounds 2d, 2f, 2j, and 2l displayed IC

In this study, due to the potential anticancer effects of the benzimidazole ring system, a series of benzimidazole-1,3,4-oxadiazole derivatives were synthesized and characterized by 1H NMR, 13C NMR, and MS spectra analyses. In the in vitro anticancer assay, all the compounds tested anticancer activities using MTT-based assay against five cancer cell lines (MCF-7, A549, HeLa, C6, and HepG2). Among them, compound 5a exhibited the most potent activity with IC50 values of 5,165±0,211 μM and 5,995±0,264 μM against MCF-7 and HepG2 cell lines. Compound 5a was included in the BrdU test to determine the DNA synthesis inhibition effects for both cell types. Furthermore, compound 5c was also found to be more effective than doxorubicin on the HeLa cell line. The selectivity of anticancer activity was evaluated in NIH3T3 (mouse embryo fibroblast cell line) cell line. In vitro, enzymatic inhibition assays of aromatase enzyme were performed for compound 5a acting on the MCF-7 cell line. For compound 5a, in silico molecular docking against aromatase enzyme was performed to determine possible protein-ligand interactions and binding modes.

The mechanism of action of nonsteroidal anti-inflammatory drugs (NSAIDs) is inhibition of specific prostaglandin (PG) synthesis by inhibition of cyclooxygenase (COX) enzymes. The two COX isoenzymes show 60% similarity. It is known that the nonspecific side effects of conventional NSAIDs are physiologically caused by inhibition of the COX-1 enzyme. Therefore, the use of COX-2 selective inhibitors is seen to be a more beneficial approach in reducing these negative effects. However, some of the existing COX-2 selective inhibitors show cardiovascular side effects. Therefore, studies on the development of new selective COX-2 inhibitors remain necessary. It is important to develop new COX-2 inhibitors in the field of medicinal chemistry. Accordingly, novel N -acyl hydrazone derivatives were synthesized as new COX-2 inhibitors in this study. The hydrazone structure, also known for its COX activity, is important in terms of many biological activities and was preferred as the main structure in the design of these compounds. A methyl sulfonyl pharmacophore was added to the structure in order to increase the affinity for the polar side pocket present in the COX-2 enzyme. It is known that methyl sulfonyl groups are suitable for polar side pockets. The synthesis of the compounds ( 3a-3j ) was characterized by spectroscopic methods. Evaluation of in vitro COX-1/COX-2 enzyme inhibition was performed by fluorometric method. According to the enzyme inhibition results, the obtained compounds displayed the predicted selectivity for COX-2 enzyme inhibition. Compound 3j showed important COX-2 inhibition with a value of IC 50 =0.143 uM. Interaction modes between the COX-2 enzyme and compound 3j were investigated by docking studies.

MAO-A inhibitors are used in the treatment of depression. There are many studies showing that the thiazolyl-hydrazone structure is a pharmacophore structure for the MAO enzyme. In previous studies by our team, activity studies were carried out with thiazolyl-hydrazone derivatives containing pyrrolidine, morpholine, and piperazine. All of them were displayed MAO-A selective inhibition profile. Additionally, derivatives containing piperazine ring were most active. For this purpose, thiazolyl-hydrazone derivatives containing piperazine were synthesized, but this time an active group, formyl group, was added to the piperazine ring as a substituent. Based on this view, new thiazolyl-hydrazone compounds were synthesized, characterized, and screened for their

A new series of 6-chloro-N\"-(substituted benzylidene)nicotinohydrazide were synthesized via condensation reactions between the corresponding hydrazides and aldehydes . All compounds were tested for their AChE and BuChE inhibitory activity. Compounds P5, P7, P9, P10 and P12 exhibited significant AChE inhibition potencies. Among them, compound P5 having para nitro substituent was found to be the most effective derivative against AChE with an IC50 value of 0.027 +/- 0.001 mu M. After that, the BACE-1 and beta-amyloid plaque inhibitory potencies of selected compounds P5, P7, P9, P10 and P12 were evaluated. Among them, compound P5 displayed the highest inhibition rate against the BACE-1 enzyme and beta-amyloid plaque. Molecular docking studies were carried out using both AChE and BACE-1 crystals to determine the compound\"s interactions with the enzyme\"s active sites. Furthermore, we evaluated the ADMET properties of compounds and their blood-brain barrier (BBB) permeation was also found to be high. (C) 2022 Elsevier B.V. All rights reserved.

Aromatase inhibitors used against hormone-dependent breast cancer, especially in post-menopausal women, are very susceptible to the development of resistance due to their limited number and long-term use. In this study, it is aimed to obtain new aromatase inhibitors including thiazole and dihydrofuran ring systems. Synthesis of compounds (2a-2l) were performed according to literature methods. Their structures were elucidated by 1H NMR, 13C NMR and APCI-MS spectroscopic methods. MTT test was carried out to assess the cell proliferation effects of the different compounds on two different pulmonary cell lines (A549, CCD-19Lu) and mammary cell line (MCF7). According to MTT assay, it was observed that the calculated IC50 values of some compounds for the CCD-19Lu cell line were found higher than for the A549 and MCF7 cell lines. Considering the viability results, it was found that the selected compounds (2a, 2c, 2e, 2g, 2h, 2l) showed favourable safety profile and have anticancer activities. Apoptotic activities of the selected compounds were investigated by flow cytometry analysis. And were found that have apoptotic effects on cancerous cell lines. In the light of this information, the aromatase inhibition potentials of 2g and 2l compounds, which are the most active derivatives, were examined in vitro and it was determined that they showed a similar inhibition profile with letrazole. Interaction modes between aromatase enzyme and compounds 2g and 2l were investigated by docking studies. In conclusion, findings of these study indicate that compounds 2g and 2l possess significant anticancer activity.

WOS: 000489544600002, DNA topoisomerase I regulates DNA topological structure in many cellular metabolic processes and is a validated target for the development of antitumor agents. in this work, a series of novel 2-[(5-(4-(5(6)-substituted-1H-benzimidazol-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)thio]-1-(4-substitutedphenyl)ethan-1-ones (4a-4s) derivatives have been synthesized and evaluated for DNA Topo I inhibition and cytotoxicity. the structures of the compounds (4a-4s) were confirmed by IR, H-1-NMR, C-13-NMR, 2D NMR, and mass spectroscopy. Anticancer activity of these compounds was assessed against two different human cancer cell lines A549 (human lung adenocarcinoma) and HepG2 (human liver cancer cell line), as well as normal mouse embryonic fibroblast cells (NIH3T3). IC50 values of compounds 4a, 4c, and 4f were highest than those exhibited for the reference drug cisplatin. Then, the inhibitory effect of 4a, 4c, and 4f compounds on topoisomerase I enzyme with the relaxation assay was investigated on supercoiled DNA using agarose gel electrophoresis. the Annexin V-FITC assay demonstrated that these compounds induce cell death by apoptosis., Anadolu University Scientific Research Projects CommissionAnadolu University [1602S065], This study was financially supported by Anadolu University Scientific Research Projects Commission, Project no. 1602S065.

Carbonic anhydrase (CA) enzymes are involved in many physiological events. These enzymes, which contain Zn

Breast cancer is the most common cancer type amoung post-menopausal women. Aromatase inhibitors were used in the treatment of patients. However, drug resistance may develop in long-term drug use, especially in 3rd and 4th stage (advanced) cancer cases. Therefore, there is a constant need for new agents. In this study, new triazolothiadiazine derivatives were synthesized and their anticancer activities were investigated. Compounds 2k, 2s, and 2w showed inhibitor activity against MCF-7 cell line with IC

Thirty novel 2,5-disubstituted-1,3,4-oxadiazole derivatives bearing urea moiety were designed and synthesized. IR, 1H-NMR, 13C-NMR and mass spectroscopic methods and elemental analysis were used to confirm the structures of the compounds. Their monoamine oxidase inhibitory activity was determined against the MAO-A and MAO-B isoforms. None of the compounds showed the potent MAO-A inhibitory activity, while the MAO-B inhibition was significantly found in the range of 62 to 98%. Among them, the compounds H8, H9 and H12 bearing chloro substituent at the fourth position of phenylurea were found to show potent monoamine oxidase B inhibitory activity with IC50 values 0.039–0.066 µM. To define and evaluate the interaction mechanism between compound H8 and monoamine oxidase B, molecular docking studies have been made.

Alzheimer’s disease (AD) is a slowly progressive neurodegenerative disease that causes dementia in people aged 65 and over. In the present study, a series of thiadiazole hybrid compounds with benzothiazine derivatives as acetylcholinesterase inhibitors were developed and evaluated for their biological activity. The AChE and BChE inhibition potentials of all compounds were evaluated by using the in vitro Ellman method. The biological evaluation showed that compounds 3i and 3j displayed significant inhibitory activity against AChE. Compounds 3i and 3j showed IC50 values of 0.027 µM and 0.025 µM against AChE, respectively. The reference drug donepezil (IC50 = 0.021 µM) also showed significant inhibition against AChE. Further docking simulation also revealed that these compounds (3i and 3j) interacted with the active site of the enzyme similarly to donepezil. The antioxidant study revealed that compounds 3i and 3j exhibited greater antioxidant effects. An in vitro blood–brain barrier permeability study showed that compounds 3i and 3j are promising compounds against AD. The cytotoxicity study of compounds 3i and 3j showed non-cytotoxic with an IC50 value of 98.29 ± 3.98 µM and 159.68 ± 5.53 µM against NIH/3T3 cells, respectively.

Nonsteroidal anti-inflammatory drugs (NSAIDs) cause peptic lesions in the gastrointestinal mucosa by inhibiting the cyclooxygenase-1 (COX-1) enzyme. Selective COX-2 inhibition causes decreased side effects over current NSAIDs. Therefore, the studies about selective inhibition of COX-2 enzyme are very important for new drug development. The design, synthesis and biological activity evaluation of novel derivatives bearing thiazolylhydrazine-methyl sulfonyl moiety as selective COX-2 inhibitors were aimed in this paper. The structures of synthesized compounds were assigned using different spectroscopic techniques such as 1H NMR, 13C NMR and HRMS. In addition, the estimation of ADME parameters for all compounds was carried out using in silico process. The evaluation of in vitro COX-1/COX-2 enzyme inhibition was applied according to the fluorometric method. According to the enzyme inhibition results, synthesized compounds showed the selectivity against COX-2 enzyme inhibition as expected. Compounds 3a, 3e, 3f, 3g, 3i and 3j demonstrated significant COX-2 inhibition potencies. Among them, compound 3a was found to be the most effective derivative with an IC50 value of 0.140 ± 0.006 μM. Moreover, it was seen that compound 3a displayed a more potent inhibition profile at least 12-fold than nimesulide (IC50 = 1.684 ± 0.079 μM), while it showed inhibitory activity at a similar rate of celecoxib (IC50 = 0.132 ± 0.005 μM). Molecular modelling studies aided in the understanding of the interaction modes between this compound and COX-2 enzyme. It was found that compound 3a had a significant binding property. In addition, the selectivity of obtained derivatives on COX-2 enzyme could be explained and discussed by molecular docking studies.

Many studies have been conducted on the selective inhibition of human monoamine oxidase B (hMAO-B) enzyme using benzylamine-sulphonamide derivatives. Using various chemical modifications on BB-4h, which was reported previously by our team and showed a significant level of MAO-B inhibition, novel benzylamine-sulphonamide derivatives were designed, synthesised, and their MAO inhibition potentials were evaluated. Among the tested derivatives, compounds 4i and 4t achieved IC50 values of 0.041 ± 0.001 µM and 0.065 ± 0.002 µM, respectively. The mechanism of hMAO-B inhibition by compounds 4i and 4t was studied using Lineweaver–Burk plot. The nature of inhibition was also determined to be non-competitive. Cytotoxicity tests were conducted and compounds 4i and 4t were found to be non-toxic. Molecular docking studies were also carried out for compound 4i, which was found as the most potent agent, within hMAO-B catalytic site.

Novel stability-indicating HPLC methods have been presented for the analysis of Tasimelteon (TSM) besides its main degradation products in bulk and pseudo tablet formulations in this study. For the LC-DAD method; quantitation of TSM and its separation with other degradation products were achieved on an Ascentis ExpressTM pentafluorophenylpropyl (F5)-bonded fused-core silica particle column (2.7 μm particle size 100 × 4.6 mm, Supelco) using the mobile phase consisted of acetonitrile: acetate buffer (0.025 M, pH 4.5): water (40:10:50, v/v/v); the elution was performed at 0.8 mL min-1 flow rate, detecting the compounds at 281 nm. In addition to regular in- house validation studies, the developed method was tested on another UPLC instrument to assess its ruggedness for possible method transfer demands. For the LC-MS/MS method, analyte quantitation was achieved on a second-generation monolithic silica column (Chromolith™ High-Resolution RP-18e, 100 × 4.6 mm from Merck KGaA, Germany); the mobile phase was a mixture with 0.1 % (v/v) formic acid in water and 0.1 % (v/v) formic acid in acetonitrile (60: 40 (v/v), pH = 2.5). The instrumental and analytical performances of all three instrumental systems were compared with each other in terms of the working range, LOD, and LOQ. In addition to the above, a new degradation product was identified using LCMS-IT-TOF system. It can be concluded that among the similar ones in the literature, this study is the most comprehensive method optimization and validation study to date about TSM, in which a novel degradation product was also reported.

WOS: 000512945000001, In this study, a novel series of benzothiazole-thiazolylhydrazine (3a-3i) was synthesized and their structures were characterized by H-1-NMR, C-13-NMR spectrometry, and mass spectroscopy. These compounds were evaluated as inhibitors of type A and type B monoamine oxidase (MAO) enzymes. the most active compound 3b (2-((2-(2-(4-(4-Nitrophenyl)thiazol-2-yl)hydrazineylidene)-2-phenylethyl)thio)benzothiazole) showed strong inhibitory activity at hMAO-A (IC50 of 0.095 +/- 0.004 mu M). Furthermore, compound 3i (2-((2-(2-(4-(2,4-dichlorophenyl)thiazol-2-yl)hydrazineylidene)-2-phenylethyl)thio)benzothiazole) showed significant inhibition profile on hMAO-A with the IC50 values 0.141 +/- 0.006 mu M., Anadolu University BAPAnadolu University [1805S190], This study was carried out with the support of Anadolu University BAP Project No: 1805S190.