The quinazoline/quinazolinone ring is known as a unique scaffold, and its derivatives possess a broad biological activity profile, including antibacterial, antifungal, anticonvulsant, anti-inflammatory, anti-HIV, and analgesic activity, primarily focusing on anticancer activity. In this study, the synthesis of 2-[[4-oxo-3-(substituted phenyl)-3,4-dihydro-(substituted quinazolin-2-yl)]thio]-N′-(aryl/heteroaryl methylene)acetohydrazide (4a–4x) derivatives and their potential anticancer activities were investigated on the lung cancer A549 cell line, the breast cancer MCF-7 cell line, and healthy fibroblast L929 cell line. Compounds 4c, 4i, 4m, and 4u were identified as the most cytotoxic and selective molecules on the A549 cell line (IC50: 44.75–78.13 µM), while 4i, 4l, 4m, and 4u were identified as the most cytotoxic and selective molecules on the MCF-7 cell line (IC50: 14.43–29.39 µM). The mechanisms of action of their anticancer activities were examined and studied. It was determined that these compounds induced strong apoptosis and significantly activated caspase-3 activation in both cell types and that they interrupted the cell cycle in the pre-G (sub G0) phase. Compounds 4m and 4u exhibited EGFR inhibition (IC50: 4.80 µM, IC50: 5.40 µM, respectively) at a level similar to the standard drug gefitinib (IC50: 1.86 ± 0.43 µM). Based on the results of the biological activity assays, molecular docking, and molecular dynamics simulation studies, the 4-quinazolinone–acetyl hydrazone scaffold can be considered a promising structural framework with potential anticancer activity. More specifically, the findings of this study indicate that the acetyl moiety may function as an important pharmacophoric group, while the trisubstituted quinazolinone core may represent a favorable structural feature for caspase-3 activation. However, the same structural framework appears to be less favorable for EGFR inhibition, possibly due to steric constraints within the EGFR binding pockets.

Pyridine and thiazolidine ring systems are unique heterocyclic rings since they are present in the structure of various drug/drug-like molecules and reported in many studies for their distinct biological effects. It is of interest to pharmaceutical chemists because of their chemotherapeutic effect profiles such as antibacterial, antifungal, antiviral, and anticancer; briefly, their cytotoxic effects are very interesting. Because of these cytotoxic activities, in this project, we synthesized chalcone derivatives from the 5th position of the thiazolidin-4-one and its linking pyridine by the hydrazone bridge. The antibacterial activities of the resulted compounds on different gram (+) and (-) bacteria and their antifungal activities tested against several invasive fungi. Due to significant fungistatic activity, the inhibitory activity on lanosterol demethylase (LDM, 5TZ1, CYP51A1) and aromatase (3EQM, CYP19A1) enzymes was evaluated, and in silico approaches were used to clarify and explain the binding modes, and then the structure activity relationship (SAR) was reported. Results of the study indicated that designed molecules were successfully obtained with important antifungal activity, and the mechanism of action was clarified.

ABSTRACT In this study, 2‐(heteroaryl thio)‐ N ‐(4‐methylthiazol‐2‐yl)acetamide ( 3a–3i ) derivatives were synthesized, and the anticancer activity of the compounds were investigated on A549 lung cancer and C6 glioma cell lines. Their anti‐inflammatory activities were tested against COX‐1, COX‐2, and LOX enzymes. Compounds 3a and 3c showed high cytotoxic activity against the A549 cell line, while compounds 3b, 3c, and 3f exhibited selective cytotoxicity against C6. Compared to cisplatin, a strong antiproliferative activity was detected against the C6 cell line. Further studies of anticancer treatments revealed that compound 3c significantly induced apoptosis, caspase‐3 activation, and mitochondrial membrane polarization against the A549 cell line. Compound 3c inhibited COX‐1 by 98.11% and 3h by 90.47%, while showing no significant inhibition of COX‐2 or LOX. Compound 3c , a derivative containing 2‐thiazoline, which showed the most potential in terms of both anticancer and anti‐inflammatory activity among all compounds, was subjected to molecular docking studies on Caspase‐3 and COX‐1 enzymes. Compound 3c was found to interact with Ser205, Arg207, and Gly122 of caspase‐3 enzyme via hydrogen bonds, and similarly, due to its hydrophobic property in both caspase‐3 and COX‐1 enzymes, 3c interacts with the hydrophobic regions of amino acids.

The study aims to synthesize, characterize, and evaluate a series of novel compounds for their potential anticancer activity targeting the A549 lung cancer cell line. The hydrazonothiazole-based pyridine compounds (2a-2o) were characterized through melting point analysis, 1H NMR, 13C NMR, and high-resolution mass spectrometry (HRMS). Their physicochemical properties were evaluated using in silico tools, and all compounds were found to comply with Lipinski's drug-likeness rule, suggesting favorable drug-like characteristics. Biological activity studies revealed that all synthesized compounds exhibited potent cytotoxicity against the A549 cell line, with several compounds showing greater efficacy than the standard drug, cisplatin. Selectivity indices were also calculated, revealing that compounds 2b, 2c, 2f, and 2m exhibited enhanced selectivity for cancer cells relative to healthy cells. Mechanistic studies using flow cytometry demonstrated that these compounds induced apoptosis, with compound 2m demonstrating the highest apoptotic activity. Mitochondrial membrane potential assay and caspase-3 activation confirmed the involvement of mitochondrial pathways in apoptosis induction. Furthermore, MMP-9 enzyme inhibition assays identified compound 2f as the most effective inhibitor, with molecular docking and dynamics simulation studies confirming its strong binding interactions with key residues in the enzyme's active site. Overall, this study suggests that the synthesized compounds, particularly 2b, 2c, 2f, and 2m, hold promise as potential anticancer agents for further development and optimization in the treatment of lung cancer.

Ten N-(2/3/4-substituted phenyl)-2-(imidazo[1,2-a]pyrazin-2-carbonyl)hydrazin-1-carbothioamide derivatives (2a-2j) were synthesized, analyzed utilizing 1H-NMR,13C-NMR, and HRMS. Their antiproliferative activity against the cancerous A549 cell line, and the healthy L929 cell line as well as their potential enzymatic inhibition effect against matrix metalloproteinase-9 (MMP-9) were evaluated. In terms of cytotoxicity, none of the compounds show similar activity against the A549 cell line compared to the reference cisplatin, however, derivatives 2h and 2i that contain 2-chlorophenyl and 3-chlorophenyl moieties, respectively had the highest potency compared to other derivatives, while none of the compounds were cytotoxic against the normal L929 cell line. In terms of MMP-9 inhibition activity, compounds 2f and 2g were the most potent inhibitors compared to other derivatives with % inhibitions of 46.54 and 26.81, respectively. The binding of compound 2f with the ion Zn301 and its bonding amino acids His 230 and His 226 are noticed to be the characteristic interactions that significantly affect the inhibition of MMP-9 enzyme according to the docking studies.

The synthesis of novel 5-nitro-2-{[2-(thiazol-2-yl)hydrazinylidene]methyl}phenol derivatives (2a-2k) and the potential anticancer effects of the compounds against A549 non-small cell lung cancer and L929 connective mouse tissue cells were investigated. Twelve novel hydrazino-thiazole derivatives were synthesized. 1H-NMR, 13C-NMR, IR, UV-Vis and HRMS spectroscopic methods were used to elucidate the structures of the obtained compounds. The compounds 2i, 2g and 2f showed the highest potential on anticancer activity, selectively. Out of all, compound 2i showed the highest cytotoxic activity (IC50 = 14.73 +/- 2.72 mu M) and it induced caspase-3 activation. Molecular docking and molecular dynamics simulations were performed to determine the binding modes of the compounds. Results indicated that compound 2i induced caspase-3 activity and interactions between the caspase-3 enzyme were stable throughout the simulation.

In this work, novel benzothiazole-piperazine acetamide (2a-2l) analogs were synthesized and evaluated their anticancer activity. The (HNMR)-H-1 , (CNMR)-C-13 and LC-MS/MS spectral data and elemental analyses were used to clarify the structure of the final molecules. The title compounds were procured by reacting 2-chloro-N-(6-substituted benzothiazole-2-yl) acetamide with some piperazine derivatives. Cytotoxicity and apoptosis parameters including Annexin V binding capacities, effect on cell cycle, caspase-3 activation and mitochondrial membrane depolarization effect were evaluated to determine anticancer profile of the final molecules on A549 (human lung adenocarcinoma), C6 (glioma cell line) and NIH/3T3 (mouse embryoblast cell line). Mostly, the final molecules showed significant cytotoxic profile with prominent selectivity. 2c (IC50: 7.23 +/- 1.17, SI: 6.93), 2d (IC50: 17.50 +/- 4.95; SI: 11.59), and 2 h (IC50: 10.83 +/- 0.76; SI: 29.23) showed significant and selective cytotoxic activity. Compounds 2b, 2c and 2e provoked apoptosis of A549 cells with potential higher than cisplatin as determined by flow cytometry. The cell cycle analysis of 2b, 2e, 2 g, and 2 h suggested that the A549 cells were affected during G0/G1 phase. Caspase-3 activation was observed on cells by compounds 2a, 2e, 2i and 2l at most. The highest mitochondrial membrane depolarization ratios were seen treated by compounds 2e, 2 h, and 2j. None of the analogs displayed any obvious inhibition activity on MMP-9. The physicochemical properties were predicted for all compounds and also molecular docking and dynamics simulation studies were realized for compound 2e, namely N-(6-methoxybenzothiazol-2-yl)-2-(4-(p-tolyl) piperazin-1-yl) acetamide. The results indicated that merging benzothiazole and piperazine derivatives via acetamide bridge is promising in cancer research because these moieties can interact with the loop and ss-sheet regions of MMP-9. So, 2e was considered as a potential therapeutic agent against lung carcinoma.

Continuous efforts are carried out to find new cancer treatments. Compounds including thiazole or thiomorpholine rings showed favorable biological activities for various diseases including cancer. In this study, a new series of 4-(4-{[2-(4-phenylthiazol-2-yl)hydrazono]methyl}phenyl)thiomorpholine derivatives were synthesized and tested in vitro for their anticancer activity. Twelve compounds including various 4-phenylthiazol and a single 4-(2-naphthyl)thiazole derivatives were synthesized and analyzed by 1H-nuclear magnetic resonance (NMR), 13C-NMR, and high-resolution mass spectrometry (HRMS). The cytotoxic effects of the compounds were tested on the A549 lung cancer cell line and the L929 healthy cell line. Six compounds (3a, 3b, 3c, 3d, 3e, and 3f) showed better inhibitory activity against A549 cells than the reference drug cisplatin. Compound 3f (4-CH3 phenyl derivative) was the most potent with an IC50 of 3.72 µM. The cytotoxic activity against the healthy cell line L929 was evaluated and all of the tested compounds displayed IC50 values of more than 500 µM, indicating a selectivity toward the cancer cell line A549. Activity against matrix metalloproteinase-9 was also tested and the result indicated a %inhibition of 68.02 and 52.77 for compounds 3g and 3j, respectively. In silico evaluation was achieved via Density Functional Theory calculations and molecular dynamic simulations and the results were in line with those of the in vitro tests.

The development of neurological diseases is an important but poorly understood condition around worldwide. Therefore, treatment options remain quite limited. This study looked into how lipopolysaccharide (LPS)-induced neuroinflammation was affected in vivo by the cyclooxygenase (COX) inhibitor 4-methylthiazole derivative compound (MET). A total of 40 male Sprague Dawley rats were separated into five groups. To demonstrate the neuroinflammatory damage induced by LPS and to evaluate the mechanism of action of MET; pro- and anti-inflammatory cytokines, enzymes with inflammatory activity and brain-derived markers were evaluated. The efficacy of the MET compound was also compared with one of the reference drugs, the nonselective COX inhibitor indomethacin (INDO). Biochemical, molecular and histopathological analyses revealed that LPS induced severe neuroinflammation in rat brains. MET compound was observed to suppress neuroinflammation through different pathways. Especially when TNF-α, IL-6 and IL-10 results were compared with INDO, anti-inflammatory activity was found to be high. Our results revealed that MET compound may suppress LPS-induced neuroinflammation via COX enzyme inhibition as well as downregulation of pro-inflammatory cytokines and M1 phenotype microglia.

The medicinal plant Satureja cuneifolia Ten. was widely utilized as spice, tea and traditional medicine. The objective of the current study was to examine the chemical composition and in vitro biological activities (LOX, MMP-1, and MMP-12 enzyme inhibition activity and cytotoxicity on A549 cell line) of Satureja cuneifolia extracts and essential oils. The essential oils of the flowering aerial parts were hydro-distilled at four different distillation times (5, 30, 60, and 180 min) using the Clevenger apparatus. The total essential oil and four fragments were compared in terms of the major component, yield, and distillation time. Volatile compounds of the infusion were extracted by using HS-SPME. Ethanolic extract had the strongest inhibition activity on the LOX enzyme (84.50%), while the essential oils exhibited more cytotoxic activity on the A549 cell line than the extracts. The oils and the infusion were analyzed using GC-MS and the primary chemicals identified by LC-MS/MS.

Lupeol compound is a cyclic triterpene alcohol that is widely found in plants. The compound lupeol has been reported to exhibit antitumor, anti-inflammatory, anxiolytic, neuroprotective and hepatoprotective effects. Recent research shows that lupeol could be a potential medicine for various diseases and also an adjuvant for intractable diseases. Cancer poses a health threat that is increasingly common around the world. Among new cancer cases, lung cancer is one of the most common and deadly cancers worldwide. In this study, the anticancer efficiency of lupeol on human lung adenocarcinoma A549 and glioma C6 cell lines were examined. Various concentrations of lupeol (500, 250, 125, 62.5, 31.25, 15.62, 7.81, 3.90 μM) effectually reduced cell viability in the A549 and C6 cell lines in a dose-dependent manner. These results showed that lupeol had selective anticancer activity against A549 and C6 cell lines.

In an endeavour to identify small molecule COX-1 inhibitors, a colorimetric assay protocol was applied for the in vitro evaluation of COX-1 and 2 inhibitory potential of a series of thiadiazole-benzothiazole hybrids. The most potent and selective COX-1 inhibitor in this series was found as 2-[(5-amino-1,3,4-thiadiazol-2-yl)thio]-N-(6-chlorobenzothiazol-2-yl)acetamide (7) (51.36 ± 3.32% at 100 µM) compared to SC-560 (83.64 ± 3.76% at 1 µM). Compound 7 exerted weaker inhibitory effect on COX-2 (11.05 ± 1.69% at 100 µM). To explore its binding interactions at the active site of human COX-1 (PDB ID: 6Y3C), molecular docking studies were conducted. Compound 7 could establish hydrogen bonds with proper residues thanks to its amide C=O group. In silico studies were employed to shed light on their pharmacokinetic properties. Taken together, compound 7 can be considered as a potential lead compound for the generation of selective COX-1 inhibitors with enhanced efficacy.

Alzheimer’s disease (AD) is basically associated with disturbances of cholinesterase metabolism which result in acetylcholine deficiency. Target of acetylcholinesterase (AChE) inhibitors used in symptomatic therapy of disease is to increase of ACh levels. Consequently, cholinesterase inhibitors were developed to increase acetylcholine is to inhibit AChE and butrylcholinesterase (BuChE). Studies demonstrate the clinical importance of dual inhibitors that inhibit not only the acetylcholinesterase enzyme but also the butyrylcholinesterase enzyme. In recent years, benzimidazoles have attracted particular interest owing to their anticolinesterase activity. In this manner, we have synthesized benzimidazole and morpholine including compounds (2a-i). Final compounds were achieved with the reaction of (benzimidazol-2-yl) methyl morpholine-4-carbodithioate and α-bromoacetophenone derivatives in acetone at room temperature with stirring. Inhibition effects of novel morpholine dithiocarbamates (2a-i) were tested on AChE and BuChE. Compound 2d demonstrated dual inhibitory activity on AChE and BuChE (78±1,56, 70,71±1,53, respectively), with the lowest cytotoxicity to normal cell line.

Considerable efforts have been directed towards the discovery of selective cyclooxygenase isoxyme 1 (COX-1) inhibitors due to the recent work highlighting the involvement of COX-1 in the pathogenesis of pain, neuroinflammation, cancer and cardiovascular disorders. In this context, this paper aims to describe 2-pyrazolines endowed with selective COX-1 inhibitory potency. An efficient microwave-assisted synthetic method was applied for the preparation of a series of pyrazolines, which were tested for their COX-1 and cyclooxygenase isoxyme 2 (COX-2) inhibitory effects using a colorimetric assay. The cytotoxic properties of the most potent derivatives on NIH/3T3 fibroblast cells were determined using MTT method. 1-(3-Fluorophenyl)-5-(3,4-methylendioxyphenyl)- 3-(2-thienyl)-4,5-dihydro-1H-pyrazole (2g) and 1-(3-bromophenyl)- 5-(3,4-methylendioxyphenyl)-3-(2-thienyl)-4,5-dihydro-1H-pyrazole (2h) were determined as selective COX-1 inhibitors. According to the in silico data obtained from Schr?dinger?s QikProp module, both compounds are estimated to possess favourable oral bioavailability and drug-likeness. This work could be a rational guideline for further modifications at different sites on 2-pyrazoline motif to bring out a new class of selective COX-1 inhibitors.

Abstract Objectives In this study, the synthesis of three pyrazoline derivatives and the evaluation of their inhibitory effects on dipeptidyl peptidase (DPP-4) were aimed. Methods Pyrazoline-based compounds (1–3) were obtained via the reaction of 1-(2-furyl)-3-(1,3-benzodioxol-5-yl)-2-propen-1-one with 4-substituted phenylhydrazine hydrochloride. The DPP-4 inhibitory effects of compounds 1–3 were determined with a fluorometric assay using Gly-Pro-aminomethylcoumarin as the fluorogenic substrate. The cytotoxicity of compounds 1–3 on L929 mouse fibroblast (healthy) cell line was evaluated using MTT assay. Results 1-(4-Methylsulfonylphenyl)-3-(2-furyl)-5-(1,3-benzodioxol-5-yl)-2-pyrazoline (2) exhibited the highest DPP-4 inhibitory activity (IC50=5.75 ± 0.35 µM). Moreover, compound 2 exerted no significant cytotoxicity against L929 cells (IC50=34.33 ± 7.09 µM). Conclusions Target compounds exhibited moderate DPP-4 inhibitory activity and compound 2 was identified as the most active compound.

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 mu g/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 mu M. 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.

Targeted therapies have come into prominence in the ongoing battle against non-small cell lung cancer (NSCLC) because of the shortcomings of traditional chemotherapy. In this context, indole-based small molecules, which were synthesized efficiently, were subjected to an in vitro colorimetric assay to evaluate their cyclooxygenase (COX) inhibitory profiles. Compounds 3b and 4a were found to be the most selective COX-1 inhibitors in this series with IC50 values of 8.90 µM and 10.00 µM, respectively. In vitro and in vivo assays were performed to evaluate their anti-NSCLC and anti-inflammatory action, respectively. 2-(1H-Indol-3-yl)-N′-(4-morpholinobenzylidene)acetohydrazide (3b) showed selective cytotoxic activity against A549 human lung adenocarcinoma cells through apoptosis induction and Akt inhibition. The in vivo experimental data revealed that compound 3b decreased the serum myeloperoxidase and nitric oxide levels, pointing out its anti-inflammatory action. Moreover, compound 3b diminished the serum aminotransferase (particularly aspartate aminotransferase) levels. Based on the in vitro and in vivo experimental data, compound 3b stands out as a lead anti-NSCLC agent endowed with in vivo anti-inflammatory action, acting as a dual COX-1 and Akt inhibitor.

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 mu M), and especially 4h (IC50: <0.14 mu M), 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 mu M, 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 mu g/mL; even IC50 values were found to be 1.65 and 2.55 mu M 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.

The essential oil (EO) of Origanum minutiflorum O. Schwarz et P. H. Davis was obtained by the hydrodistillation method. The analysis of the EO was conducted using Gas Chromatography (GC) and Gas Chromatography/Mass Spectrometry (GC/MS). The yield of the EO was determined to be 3.9%. Fifty-six compounds were identified, constituting 97.8% of the EO. The EO was rich in carvacrol at a rate of 83.3%, and the other major compounds were p-cymene (3.0%), beta-caryophyllene (1.3%), trans-sabinene hydrate (1.1%), gamma-terpinene (1.1%), borneol (1.1%), and terpinene-4-ol (1.0%). While the EO (100 mu g/mL) demonstrated the highest inhibition on cyclooxygenase-1 (COX-1) with 55.26%, the inhibitory activities on the other enzymes were as follows: cyclooxygenase-2 (COX-2); 33.10%, and matrix metalloproteinase-9 (MMP-9); 12.87%. The EO had no inhibition on lipoxygenase (LOX). In this research, inhibitory activity of the EO of O. minutiflorum on COXs and MMP-9 enzymes was reported for the first time.

Origanum minutiflorum, an endemic species in Turkiye, is used for both food and medicinal purposes. 70