Exploring Novel Quinoline-1,3,4-Oxadiazole Derivatives for Alzheimer's Disease: Their Design, Synthesis, and In-Vitro and In-Silico Investigations.

INTRODUCTION: Alzheimer's Disease (AD) is a complicated and advanced neurodegenerative condition accompanied by gradual cholinergic neuronal death and higher levels of monoamine oxidase-B (MAO-B) enzyme. In this study, a series of novel hybrid compounds combining 1,3,4-oxadiazole and quinoline moieties were synthesized and evaluated for their potential as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and MAO enzymes. METHODS: The chemical structures of the synthesized compounds were confirmed using various analytical techniques, such as mass spectrometry, infrared spectroscopy (IR), proton nuclear magnetic resonance (1H-NMR), and carbon and nuclear magnetic resonance (13C-NMR). The final products were evaluated for anticholinesterase potential by applying modified Ellman's spectrometric method, whereas a fluorometric method was used to assess MAO inhibition properties. In-silico studies using molecular docking and molecular dynamics simulation (MDS) methods has been also conducted. RESULTS: Among the synthesized compounds, 5a, 5c, and 6a demonstrated substantial activity against AChE, with IC50 values of 0.033 µM, 0.096 µM, and 0.177 µM, respectively. A molecular docking study was performed to elucidate the binding modes and establish the structure-activity relationship (SAR) of the most active compounds (5a, 5c, and 6a). Molecular dynamics simulation (MDS) of the most potent compound, 5a, was also conducted to examine the stability of the interactions with the receptor. Moreover, the physicochemical properties of the active products were also studied. CONCLUSION: Overall, this research contributes to the development of 1,3,4-oxadiazole- quinoline hybrids as potential AChE inhibitors for the treatment of Alzheimer's disease.

Synthesis of new N-(5,6-methylenedioxybenzothiazole-2-yl)-2-[(substituted)thio/piperazine]acetamide/propanamide derivatives and evaluation of their AChE, BChE, and BACE-1 inhibitory activities.

In this study, the synthesis of N-(5,6-methylenedioxybenzothiazole-2-yl)-2-[(substituted)thio/piperazine]acetamide/propanamide derivatives (3a-3k) and to investigate their acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and ß-secretase 1 (BACE-1) inhibition activity were aimed. Mass, 1H NMR, and 13C NMR spectra were utilized to determine the structure of the synthesized compounds. Compounds 3b, 3c, 3f, and 3j showed AChE inhibitory activity which compound 3c (IC50 = 0.030 ± 0.001 µM) showed AChE inhibitory activity as high as the reference drug donepezil (IC50 = 0.0201 ± 0.0010 µM). Conversely, none of the compounds showed BChE activity. Compounds 3c and 3j showed the highest BACE-1 inhibitory activity and IC50 value was found as 0.119 ± 0.004 µM for compound 3j whereas IC50 value was 0.110 ± 0.005 µM for donepezil, which is one of the reference substance. Molecular docking studies have been carried out using the data retrieved from the server of the Protein Data Bank (PDBID: 4EY7 and 2ZJM). Using in silico approach behavior active compounds (3c and 3j) and their binding modes clarified.

Design and synthesis of phenoxy methyl-oxadiazole compounds against Alzheimer's disease.

This study examines the synthesis and evaluation of 11 newly developed compounds as potential anti-Alzheimer's agents that occur via cholinesterase and ß-secretase inhibition. The compounds were tested for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using the modified Ellman method. The results showed that several compounds exhibited significant inhibition of AChE, particularly compounds 6d, 7a, and 7e, which demonstrated high inhibitory activity at lower concentrations, with IC50 values of 0.120, 0.039, and 0.063 µM, respectively. However, the compounds showed limited effectiveness against BChE, with only a few compounds exhibiting moderate inhibition. Compound 7e showed an inhibitory effect against BACE-1 close to that of the standard drug. Structural analysis revealed that the compounds with substituted benzothiazole and thiazole moieties exhibited the most promising inhibitory activity. This study provides valuable insights into the potential of these synthesized derivatives as a treatment against Alzheimer's disease. Moreover, the structure, stability, and properties of the active compounds were further investigated using density functional theory calculations. As a final note, the utilization of molecular docking and molecular dynamics simulation studies allowed us to elucidate the action mechanism of the active compounds and gain insights into the structure-activity relationship against AChE and ß-secretase proteins. These computational techniques provide valuable information on the binding modes, interactions with target enzymes, dynamic behavior, and conformational changes of the compounds, enabling a comprehensive understanding of their biological activity.

Design, Synthesis, and Biological Effect Studies of Novel Benzofuran-Thiazolylhydrazone Derivatives as Monoamine Oxidase Inhibitors.

In recent studies, monoamine oxidase (MAO) inhibitory effects of various thiazolylhydrazone derivatives have been demonstrated. Within the scope of this study, 12 new compounds containing thiazolylhydrazone groups were synthesized. The structures of the obtained compounds were elucidated by 1H NMR, 13C NMR, and high-resolution mass spectrometry (HRMS) methods. The inhibitory effects of the final compounds on MAO enzymes were investigated by means of in vitro methods. In addition to enzyme inhibition studies, enzyme kinetic studies of compounds with high inhibitory activity were examined, and their effects on substrate-enzyme relations were investigated. Additionaly, cytotoxicity tests were carried out to determine the toxicities of the selected compounds, and the compounds were found to be nontoxic. The interactions of the active compound with the active site of the enzyme were characterized by in silico methods.

New N-(1,3,4-thiadiazole-2-yl)acetamide derivatives as human carbonic anhydrase I and II and acetylcholinesterase inhibitors.

Various carbonic anhydrase (CA) enzyme isoforms are known today. In addition to the use of CA inhibitors as diuretics, antiepileptics and antiglaucoma agents, the inhibition of other specific isoforms of CA was reported to have clinical benefits in cancers. In this study, two groups of 1,3,4-thiadiazole derivatives were designed and synthesized to act as human CA I and II (hCA I and hCA II) inhibitors. The activities of these compounds were tested in vitro and evaluated in silico studies. The activity of the synthesized compounds was also tested against acetylcholinesterase (AChE) to evaluate the relation of the newly designed structures to the activity against AChE. The synthesized compounds were analyzed by 1H NMR,13C NMR and high-resolution mass spectroscopy (HRMS). The results displayed a better activity of all the synthesized compounds against hCA I than that of the commonly used standard drug, Acetazolamide (AAZ). The compounds also showed better activity against hCA II, except for compounds 5b and 6b. Only compounds 6a and 6c showed superior activity against AChE compared to the standard agent, tacrine (THA). In silico studies, including absorption, distribution, metabolism and excretion (ADME) and drug-likeness evaluation, molecular docking, molecular dynamic simulations (MDSs) and density functional theory (DFT) calculations, were compatible with the in vitro results and presented details regarding the structure-activity relationship.Communicated by Ramaswamy H. Sarma.

Design and synthesis of novel dithiazole carboxylic acid Derivatives: In vivo and in silico investigation of their Anti-Inflammatory and analgesic effects.

Inflammation is a complex set of interactions that can occur in tissues as the body's defensive response to infections, trauma, allergens, or toxic compounds. Therefore, in almost all diseases, it can be observed because of primary or secondary reasons. Since it is important to control and even eliminate the symptoms of inflammation in the treatment of many diseases, anti-inflammatory and analgesic drugs are always needed in the clinic. Therefore, the discovery of new anti-inflammatory/analgesic drugs with increased effectiveness and safer side effect profiles is among the popular topics of medicinal chemistry. Therefore, in this study, in order to synthesize and diversify new molecules, we focused on the N,N-dithiazole carboxylic acid core and linked it with the chalcone functional group. The final eleven molecules were analyzed via HRMS, 1H NMR, and 13C NMR. The antinociceptive effects of the test compounds were examined by tail-clip, hot-plate, and formalin methods in mice, while their anti-inflammatory activities were investigated by carrageenan-induced inflammation tests in rats. The motor activities of the experimental animals were evaluated using an activity-meter device. Obtained findings revealed that none of the test compounds (10 mg/kg) were effective in the tail-clip and hot-plate tests. However, compounds 4b, 4c, 4f, 4 h, and 4 k in the serial shortened the paw-licking times of mice in the late phase of the formalin test indicating that these compounds had peripherally-mediated antinociceptive effects. The same compounds, moreover, showed potent anti-inflammatory effects by significantly reducing paw edema of rats in the inflammation tests. To provide an approach to pharmacological findings regarding possible mechanisms of action, the binding modes of the most active compounds were investigated by in silico approaches. The results of molecular docking studies indicated that the anti-inflammatory and analgesic activities of the compounds might be related to the inhibition of both COX-1 and COX-2 isoenzymes. Findings obtained from in silico studies showed that 4 k, which was chosen as a model for its analogs in the series, forms strong bindings to the basic residues (Arg120, Tyr355), side pocket loop area and deep hydrophobic regions of the enzyme. Moreover, results of the molecular dynamics simulation studies revealed that ligand-COX enzyme complexes are quite stable. Obtained results of in vivo and in silico studies are in harmony, and all together point out that compounds 4b, 4c, 4f, 4 h, and 4 k have significant anti-inflammatory and analgesic activities with good ADME profiles. The potential of the derivatives, whose pharmacological activities were revealed for the first time in this study, as anti-inflammatory and analgesic drug candidates, needs to be evaluated through comprehensive clinical studies.

Synthesis, molecular docking, and molecular dynamic simulation studies of new 1,3,4-thiadiazole derivatives as potential apoptosis inducers in A549 lung cancer cell line.

1,3,4-Thiadiazoles are structures that are bioisosteres of 1,3,4-oxadiazole and pyrimidine ring, which are found in the structure of many drugs and anticancer active newly studied derivatives. In the past, high effect profiles have been observed in many molecules created, based on the anticancer effects of the 2-amino-1,3,4-thiadiazole (NSC 4728) molecule and acetazolamide molecules. Focusing on these molecules and evaluating them in terms of mechanistic effects, twelve new N-[5-((3,5-dichlorophenoxy) methyl]-1,3,4-thiadiazole derivatives (3a-3i) were synthesized and their biological activities were investigated in lung cancer cells. The anticancer effects of the compounds were evaluated on the A549 and L929 cell lines. Compound 3f, namely 2-[(5-chlorobenzotiyazol-2-yl)thio]-N-[5-[(3,5-dichlorophenoxy)methyl]-1,3,4-thiadiazol-2-yl]acetamide, showed better activity than cisplatin, exhibiting high inhibitory potency (IC50: <0.98 µg/mL) and selectivity against A549 cell line even at the lowest concentration tested. Compounds 3c, 3f, and 3h with the lowest IC50 values of the compounds exhibited an excellent percentage of apoptosis between 72.48 and 91.95% compared to cisplatin. The caspase-3 activation and mitochondrial membrane potential change of the aforementioned three compounds were also studied. Moreover, matrix metalloproteinase-9 (MMP-9) inhibition potential of all final compounds was also investigated and IC50 values for compounds 3b and 3g were identified as 154.23 and 107.28 µM. Molecular docking and molecular dynamic simulation studies for MMP-9 enzyme inhibition were realized on these compounds and the nitrogen atoms of amide and thiadiazole moieties' ascertained that they play a key role in chelating with Zn metal, at the same time, (thio)ether moieties allow conformational change resulting in the ligand can make more stable contacts.Communicated by Ramaswamy H. Sarma.

Synthesis, characterization, molecular docking and molecular dynamics simulations of novel 2,5-disubstituted-1,3,4-thiadiazole derivatives as potential cholinesterase/monoamine oxidase dual inhibitors for Alzheimer's disease.

Designing multi-targeted drugs (MTD) for Alzheimer's disease (AD) is now one of the priorities for medicinal chemists, as the disease has a complicated not fully understood pathological nature and the approved mono-targeted drugs only alleviate the symptoms. In this study, the synthesis, spectral analyses and in vitro inhibition activity against cholinesterase (ChE) and monoamine oxidase (MAO) enzymes of a novel series of N-[5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl]-2-(4-un/substituted) cyclic secondary amino-acetamide/propanamide derivatives were done. Generally, derivatives were more selective against acetylcholinesterase (AChE) and h-MAO-B than butyrylcholinesterase (BChE) and h-MAO-A, respectively. Derivatives 4a, 4b, 3a, 3d and 3b ordered from the most potent to the least displayed significant inhibition against AChE. Also, derivatives 4a, 4b and 3a still maintained their significant inhibition against h-MAO-B in the same potency order, making them dual inhibitors and MTD candidates for AD. Binding interactions with several crucial amino acid residues for activity and selectivity as well as the stability of the most active derivatives-enzyme complex were confirmed utilizing molecular docking and molecular dynamic simulation studies.Communicated by Ramaswamy H. Sarma.

Novel 2,5-disubstituted-1,3,4-thiadiazole derivatives were synthesized.The ChEs/MAOs dual inhibition activity against Alzheimer's disease was tested.Compounds 4a, 4b and 3a were active dual inhibitor against both AChE and h-MAO-B.Compounds 3d and 3b were also active against AChE.No significant inhibition activity against BChE and h-MAO-A.

Design, synthesis and apoptotic effects of novel benzoxazole compounds.

A series of new benzoxazole-hydrazone and benzoxazole-1,3,4-oxadiazole derivatives have been designed, synthesized and evaluated as cytotoxic agents toward human A549 lung cancer cells. Compounds 3d, 3e, 5b, 5c, 5d and 5e were the most potent compounds with IC50 values of <3.9, 10.33, 11.6, 5.00, <3.9 and 4.5 µg/mL, respectively, which are higher than reference drug cisplatin (IC50 = 19.00 µg/mL). The flow cytometry-based apoptosis detection assay was performed to determine their effects on apoptosis in A549 cells. All tested compounds induced apoptosis in A549 cell line.

Novel oxadiazole-thiadiazole derivatives: synthesis, biological evaluation, and in silico studies.

In the search for new anticancer agents, we synthesized a new series of thiazole derivatives carried on thiadiazole-oxadiazole hybrid. Final compounds (5a-5i) were analyzed via 1H NMR, 13C NMR, and HRMS. The pharmacokinetic profile of the targeted compounds was predicted via in silico calculations. Their anticancer properties were determined using MTT method against MCF7 and A549 cell lines. Compounds 5a, 5b and 5c were found more active against MCF7 cells than A549 cells while they were not cytotoxic on L929 healthy cells. Generally, it can be summarized that acetamide moiety has a pivotal role in anticancer activity. For further studies, their aromatase inhibitory activity was evaluated. After determination all these features, the binding modes of the active compounds and the stability and relation of the ligand-enzyme complex were investigated using molecular docking and molecular dynamics simulation studies, respectively. In vitro and in silico studies suggest two important structure-activity relationship (SAR) points that at least one azole ring is essential, and if there is approximately 8.0 ± 0.5 Å distance between the H-bond rich zone of ligand and the heteroaryl ring system of ligand has a major impact on aromatase inhibitory activity. Compounds with small group substitution on thiazole are found potentially may be used for the treatment of anti-breast cancer orally.Communicated by Ramaswamy H. Sarma.

Investigation of Novel Quinoline-Thiazole Derivatives as Antimicrobial Agents: In Vitro and In Silico Approaches.

Infectious diseases are a major concern around the world. Today, it is an urgent need for new chemotherapeutics for infectious diseases. Because of that, our group designed, synthesized, and analyzed 14 new quinoline derivatives endowed with the pharmacophore moiety of fluoroquinolones primarily for their antimicrobial effects. Their cytotoxicity effects were tested against six bacterial and four fungal strains and NIH/3T3 cell line. Additionally, their action mechanisms were evaluated against DNA gyrase and lanosterol 14α-demethylase (LMD). Furthermore, to eliminate the potential side effects, the active compounds were evaluated against the aromatase enzyme. The experimental enzymatic results were evaluated for active compounds' binding modes using molecular docking and molecular dynamics simulation studies. The results were utilized to clarify the structure-activity relationship (SAR). Finally, compound 4m was the most potent compound for its antifungal activity with low cytotoxicity against healthy cells and fewer possible side effects, while compounds 4j and 4l can be used alone for special patients who are suffering from fungal infections in addition to the primer disease.

Synthesis of Some New 1,3,4-Oxadiazole Derivatives and Evaluation of Their Anticancer Activity.

In this work, some new 2-[(5-((2-acetamidophenoxy)methyl)-1,3,4-oxadiazol-2-yl)thio]acetamide derivatives (4a-4l) were synthesized and studied for their anticancer activity. Twelve new compounds were tested on the A549 human lung cancer cell line, C6 rat glioma cell line, and L929 murine fibroblast cell line. Compounds 4f, 4i, 4k, and 4l (IC50: 1.59-7.48 µM), and especially 4h (IC50: <0.14 µM), exhibited excellent cytotoxic profile on A549 with selectivity. Compounds 4g and 4h showed remarkable antiproliferative activity on the C6 cell line with IC50 values of 8.16 and 13.04 µM, respectively. The compounds with the lowest IC50 value on the A549 cell line (4f, 4h, 4i, 4k, and 4l) were further studied to determine the mechanism of action. These compounds were found to induce apoptosis with a higher ratio (16.10-21.54%) than that of the standard drug cisplatin (10.07%). Compound 4f displayed mitochondrial membrane depolarization and caspase-3 activation at most, whereas compounds 4h (89.66%) and 4i (78.78%) had outstanding retention rates in the G0/G1phase of the cell cycle (cisplatin 74.75%). Compounds 4f, 4g, 4h, and 4l exhibited matrix metalloproteinase-9 (MMP-9) inhibition higher than 75% at 100 µg/mL; even IC50 values were found to be 1.65 and 2.55 µM for 4h and 4l. In addition, in silico physicochemical properties of the compounds and molecular docking interaction of compound 4h on the MMP-9 enzyme were evaluated; the desired and expected results were obtained.

Synthesis, anticholinesterase activity, molecular docking, and molecular dynamic simulation studies of 1,3,4-oxadiazole derivatives.

Two new series of 1,3,4-oxadiazoles bearing pyridine and thiazole heterocycles (4a-h and 5a-h) were synthesized (2,5-disubstituted-1,3,4-oxadiazoles). The structures of these newly synthesized compounds were confirmed by 1 H nuclear magnetic resonance (NMR), 13 C NMR, high-resolution mass spectrometric and Fourier transform infrared spectroscopic methods. All these compounds were evaluated for their enzyme inhibitory activities against two cholinesterase enzymes, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). From the studies, we identified compounds 4a, 4h, 5a, 5d, and 5e as selective AChE inhibitors, with IC50 values ranging from 0.023 to 0.037 µM. Furthermore, docking studies of these compounds were performed at the active sites of their target enzymes. The molecular docking study showed that 5e possessed an ideal docking pose with interactions inside AChE.

Synthesis, density functional theory calculation, molecular docking studies, and evaluation of novel 5-nitrothiophene derivatives for anticancer activity.

Within the scope of this study, new 2-{2-[(5-nitrothiophen-2-yl)methylene]hydrazinyl}thiazole derivatives (2a-j) were synthesized and investigated for their potential anticancer and enzyme inhibition activities. Spectroscopic techniques were used to determine the structures of substances. The anticancer activities of compounds were detected in A549 human lung carcinoma and L929 murine fibroblast cell lines, determining cytotoxicity, apoptosis, mitochondrial membrane integrity, and caspase-3 activation. Compounds 2b bearing 4-nitrophenyl, 2c bearing phenyl, and 2d bearing 4-cyanophenyl moieties were specified with high anticancer activity, acting through an apoptotic pathway with an apoptosis ratio of 9.61%-15.59%. Mitochondrial membrane depolarization was determined to be 25.53% and 22.33% for compounds 2b and 2c, respectively. Furthermore, compound 2c exhibited excellent caspase-3 activation. A molecular docking study was realized with compound 2c on the caspase-3 enzyme. Furthermore, the electronic characteristics of the active compounds were investigated using density functional theory (DFT) at the B3LYP/6-31G (d, p) level. The frontier molecular orbital energy and atomic net charges were examined.

Synthesis, antimicrobial activity and modeling studies of thiazoles bearing pyridyl and triazolyl scaffolds.

In this study, novel 4-(5-((2/3/4-substituted benzyl)thio)-4-(4-substituted phenyl)-4H-1,2,4-triazol-3-yl)-2-(pyridin-3/4-yl)thiazoles were synthesized following a multi-step synthetic procedure. All the compounds were screened with a panel of gram positive/negative bacteria, yeasts, and molds for antimicrobial activity using the disc diffusion method. Then, the minimum inhibitor concentration (MIC) and the minimum bactericidal concentration (MBC) values of active compounds were determined against Micrococcus luteus, Bacillus cereus, Listeria monocytogenes, and Staphylococcus aureus using the broth microdilution technique. These compounds were also screened for their inhibitory activities against S. aureus DNA gyrase by supercoiling assay. Furthermore, the crystal structure of S. aureus DNA gyrase B ATPase was subjected to a docking experiment to identify the possible interactions between the most active ligand and the active site. Lastly, the in silico technique was performed to analyze and predict the drug-likeness, molecular and ADME properties of the synthesized molecules.

Synthesis of novel thiazolyl hydrazone derivatives as potent dual monoamine oxidase-aromatase inhibitors.

The inhibitory effects of 2-thiazolyl hydrazones on monoamine oxidase enzymes are known for a long time. In this study, a new series of 2-thiazolyl hydrazone derivatives were synthesized starting from 6-methoxy-2-naphthaldehyde. All of the synthesized compounds were investigated in terms of their monoamine oxidase (MAO) inhibitory effects and significant results were found. The results showed that compound 2j potently inhibited MAO-A and MAO-B, while compound 2t strongly and selectively inhibited MAO-B compared to standard drugs. Compounds 2k and 2q exhibited selective and satisfying inhibition on MAO-B. In the aromatase inhibition studies of the compounds, it was determined that compounds 2q and 2u had high inhibitory properties. Molecular docking studies on MAO-A, MAO-B, and aromatase enzymes were carried out for the aforementioned compounds. Additionally, molecular dynamics simulation was studied for compound 2q on MAO-B and aromatase complexes. Finally, the Field-based QSAR study was developed and the structure-activity relationship (SAR) was explained. For the first time, dual inhibitors on MAO and aromatase enzyme were investigated together. The aim of this approach is for finding the potential agents that do not cause the cognitive disorders and may even treat neurodegenerative symptoms, thus, the aim was reached successfully.

Novel benzofurane-pyrazole derivatives with anti-inflammatory, cyclooxygenase inhibitory and cytotoxicity evaluation.

Novel benzofurane-pyrazolone hybrids have been synthesized for evaluating their anti-inflammatory and cytotoxic properties. 4-(2-chloroacetyl)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one were reacted with α-hydroxy aldehyde or α-hydroxy ketone derivatives to obtain nine novel pyrazolone derivatives. Structures were successfully elucidated by 1H NMR, 13C NMR, IR and HRMS. Enzyme inhibitory activity was measured on cyclooxygenases (COXs) as considered to address anti-inflammatory activity. Compound 2 showed the highest activity on both COX-1 and COX-2 subtypes with 12.0 µM and 8.0 µM IC50, respectively. This activity was found close to indomethacin COX-2 inhibition measured as 7.4 µM IC50. Rest of the compounds (1, 3-9) showed 10.4-28.1 µM IC50 on COX-2 and 17.0-35.6 µM IC50 on COX-1 (Compound 1 has no activity on COX-1). Tested compounds (1-9) showed activity on NO production. Only compound was the 4, which showed a low inhibition on IL-6 levels. Cell viability was up to 60% at 100 µM for all compounds (1-9) on RAW 264.7 and NIH3T3 cell lines, thus compounds were reported to be noncytotoxic.

New chromanone derivatives containing thiazoles: Synthesis and antitumor activity evaluation on A549 lung cancer cell line.

Novel 2-[2-(chroman-4-ylidene)hydrazinyl]-4/5-substituted thiazole derivatives (2a-i) were synthesized and investigated for their anticancer activity. Cytotoxic activity on A549 and NIH/3T3 cell lines was determined, most of the compounds exhibited high cytotoxic profile with selectivity. Selected compounds 2b, 2c, 2e, 2g, 2h, and 2i were tested to determine induction of apoptosis, mitochondrial membrane depolarization, and cell cycle arrest. The results showed that the compounds induced apoptosis intrinsically that they triggered loss of mitochondrial potential through increasing the accumulation of cells in G2/M. Besides, intrinsic apoptotic pathway was supported by down-regulation of anti-apoptotic protein Bcl-2 and up-regulation of proapoptotic protein Bax. Molecular docking study for compounds 2b, 2c, and 2g was promoted experimental outcomes.

Apoptotic Effect of Novel Benzimidazole Derivatives Bearing Pyridyl/Pyrimidinyl Piperazine Moiety.

BACKGROUND: Benzimidazole derivatives bearing pyridyl/pyrimidinyl piperazine moiety has attracted attention in medicinal chemistry and modern drug discovery since it exhibited a variety of biological activities, including anticancer activity. OBJECTIVE: In this study, we designed and synthesized novel 1-[2-oxo-2-(4-substituted phenyl)ethyl]benzimidazol-2- yl)methyl 4-(2-pyridyl/pyrimidin-2-yl)piperazine-1-carbodithioate derivatives (2a-m). We also investigated their anticancer activities against A549 lung adenocarcinoma and C6 rat glioma cell lines. We further studied the selectivity of the compounds against the NIH/3T3 mouse embryonic fibroblast cell line. Cholinesterase inhibition effects of these compounds were also investigated to measure the relationship between anticancer activity and cholinesterases. METHODS: The cytotoxic activities of these acquired thirteen final compounds were screened using MTT assay on A549, C6, and NIH/3T3 cell lines. Cell proliferation ELISA, BRDU (colorimetric) assay was used to measure the proliferation in replicative cells in which DNA synthesis occurs. Flow cytometric analysis was used to measure apoptotic cell percentages, caspase 3 activity, and mitochondrial membrane depolarised cell percentages. RESULTS: Compounds 2e, 2f, and 2k were shown to be the most active antitumor agents with selective cytotoxicities (the results for A549 were 76.58±6.43, 55.13±5.75, and 32.94±3.02 µM, respectively; and for C6 they were 86.48±3.60, 97.12±30.21, and 59.29±3.95 µM, respectively), high DNA synthesis inhibition rates and high apoptotic cell percentages on both cell lines. CONCLUSION: The results showed that compounds 2e, 2f, and 2k have potential anticancer activity against A549 and C6 cell lines.

Synthesis, antimicrobial and antioxidant activities of pyridyl substituted thiazolyl triazole derivatives

In this present study, 63 different 5-[4-methyl-2-(pyridin-3/4-yl)thiazole-5-yl]-4-substituted-3-substituted benzylthio-4H-1,2,4-triazole derivatives were synthesized, and evaluated for their in vitro antimicrobial activity against various human pathogenic microorganisms and antioxidant activity. The derivatives were synthesized in a multi-step synthesis procedure including triazole and thiazole ring closure reactions, respectively. The synthesized derivatives (A1-24; B1-39) were screened for their antibacterial, antifungal, and antioxidant activities compared to standard agents. The derivatives possessing 3-pyridyl moiety particularly exhibited relatively high antibacterial activity (MIC= < 3.09-500 µg/mL) against Gram-positive bacteria, and compounds possessing 4-pyridyl moiety showed remarkable antioxidant activity