Design, synthesis and biological evaluation of a new series of imidazothiazole-hydrazone hybrids as dual EGFR and Akt inhibitors for NSCLC therapy.

In search of small molecules for targeted therapy of non-small cell lung carcinoma (NSCLC), an efficient four-step synthetic route was followed for the synthesis of new imidazothiazole-hydrazone hybrids, which were assessed for their cytotoxic effects on human lung adenocarcinoma (A549) and human lung fibroblast (CCD-19Lu) cells. Among them, compounds 4, 6, 13, 16, 17 and 21 exhibited selective cytotoxic activity against A549 cell line. In vitro mechanistic studies were performed to assess their effects on apoptosis, caspase-3, cell cycle, EGFR and Akt in A549 cells. Compounds 6, 16, 17 and 21 promoted apoptotic cell death more than erlotinib. According to the in vitro data, it is quite clear that compound 6 promotes apoptosis through caspase-3 activation and arrests the cell cycle at the G0/G1 phase in A549 cells. Compounds 16 and 17 arrested the cell cycle at the S phase, whereas compounds 4, 13 and 21 caused the cell cycle arrest at the G2/M phase. The most effective EGFR inhibitor in this series was found as compound 13, followed by compounds 17 and 16. Furthermore, Akt inhibitory effects of compounds 16 and 17 in A549 cells were close to that of GSK690693. In particular, it can be concluded that the cytotoxic and apoptotic effects of compounds 16 and 17 are associated with their inhibitory effects on both EGFR and Akt. Molecular docking studies suggest that compounds 16 and 17 interact with crucial amino acid residues in the binding sites of human EGFR (PDB ID: 1M17) and Akt2 (PDB ID: 3D0E). Based on the in silico data, both compounds are predicted to possess favorable oral bioavailability and drug-likeness. Further studies are required to benefit from these compounds as anticancer agents for targeted therapy of NSCLC.

Design, Synthesis, and Evaluation of New Pyrazolines As Small Molecule Inhibitors of Acetylcholinesterase.

In pursuit of identifying small molecule inhibitors of acetylcholinesterase (AChE), the synthesis of new 2-pyrazolines was performed efficiently. A modified spectrophotometric method was used to examine their inhibitory effects on AChE as well as butyrylcholinesterase. Four compounds (2a, 2g, 2j, and 2l) were identified as selective AChE inhibitors. Molecular docking studies were conducted to explore their potential interactions with the active site of AChE (PDB code: 4EY7). 1-(3-Nitrophenyl)-3-(thiophen-3-yl)-5-[4-(4-morpholinyl)phenyl]-2-pyrazoline (2l) exerted significant AChE inhibitory action with an IC50 value of 0.040 µM close to donepezil (IC50 = 0.021 µM). In addition to π-π interactions with Tyr341, Tyr124, and Trp86 residues, compound 2l was also capable of forming two hydrogen bonds and a salt bridge at the active site of AChE thanks to its nitro group at the meta position of the phenyl moiety linked to the N 1 position of the pyrazoline scaffold. The higher inhibitory effect of compound 2l on AChE when compared to other compounds in this series might be explained by these additional interactions. Based on the in vitro parallel artificial membrane permeability assay, compound 2l was found to have high blood-brain barrier permeability. In vitro and in silico studies suggest that compound 2l is a potent inhibitor of AChE, which is an important target for neurodegenerative disorders, particularly Alzheimer's disease.

Design, Synthesis, and In Vivo Evaluation of a New Series of Indole-Chalcone Hybrids as Analgesic and Anti-Inflammatory Agents.

Indole-chalcone hybrids have burst into prominence as potent weapons in the battle against pain and inflammation due to their unique features, allowing these ligands to form pivotal interactions with biological targets. In this context, the base-catalyzed Claisen-Schmidt condensation of 3',4'-(methylenedioxy)acetophenone with heteroaromatic aldehydes carrying an indole scaffold yielded new chalcones (1-7). The central and peripheral antinociceptive activities of all chalcones (compounds 1-7) at the dose of 10 mg/kg (i.p.) were evaluated by hot plate (supraspinal response), tail immersion (spinal response), and acetic acid-induced writhing tests in mice. The anti-inflammatory activities of compounds 1-7 were also investigated by means of a carrageenan-induced mouse paw edema model. The results revealed that compounds 1-7 extended the latency of response to thermal stimulus significantly in a hot-plate test similar to dipyrone (300 mg/kg; i.p.), the positive control drug. However, only compounds 2-7 were found to be significantly effective in the tail-immersion test. Compounds 1-7 also significantly showed analgesic effect by reducing the number of writhes and anti-inflammatory activity by inhibiting edema formation at different time intervals and levels. 1-(1,3-Benzodioxol-5-yl)-3-(1-methyl-1H-indol-2-yl)prop-2-en-1-one (4) drew attention by providing the highest efficacy results in both acute analgesia and inflammation models. Based on the in silico data acquired from the QikProp module, compound 4 was predicted to possess favorable oral bioavailability and drug-like properties. Taken together, it can be concluded that chalcones (1-7), especially compound 4, are outstanding candidates for further research to investigate their potential use in the management of pain and inflammation.

Design, Synthesis, and Evaluation of a New Series of 2-Pyrazolines as Potential Antileukemic Agents.

In an attempt to identify small molecules for the treatment of leukemia, 12 new pyrazolines (2a-l) were synthesized efficiently. WST-1 assay was performed to examine their cytotoxic features on HL-60 human acute promyelocytic leukemia (APL), K562 human chronic myeloid leukemia (CML), and THP-1 human acute monocytic leukemia cells. Four compounds (2e, 2f, 2g, and 2h) were determined as promising antileukemic agents on HL-60 and K562 cells. IC50 values of compounds 2f, 2h, 2e, 2g, and bortezomib for the HL-60 cell line were found as 33.52, 42.89, 48.02, 62.34, and 31.75 µM, while IC50 values of compounds 2h, 2g, 2f, 2e, and bortezomib for K562 cells were determined as 33.61, 50.23, 57.28, 76.90, and 42.69 µM, respectively. Further studies were carried out to shed light on the mechanism of antileukemic action. According to the data obtained by in vitro experiments, 1-(4-fluorophenyl)-3-(thiophen-3-yl)-5-(4-(4-methylpiperazin-1-yl)phenyl)-2-pyrazoline (2f) and 1-(3-bromophenyl)-3-(thiophen-3-yl)-5-(4-(4-methylpiperazin-1-yl)phenyl)-2-pyrazoline (2h) have proved to be potential antileukemic agents with remarkable cytotoxicity against HL-60 and K562 cells by activation of caspase 3, thereby inducing apoptosis.

Design, Synthesis, and Evaluation of a New Series of Hydrazones as Small-Molecule Akt Inhibitors for NSCLC Therapy.

In an endeavor to identify small molecules for the management of non-small-cell lung carcinoma, 10 new hydrazone derivatives (3a-j) were synthesized. MTT test was conducted to examine their cytotoxic activities against human lung adenocarcinoma (A549) and mouse embryonic fibroblast (L929) cells. Compounds 3a, 3e, 3g, and 3i were determined as selective antitumor agents on A549 cell line. Further studies were conducted to figure out their mode of action. Compounds 3a and 3g markedly induced apoptosis in A549 cells. However, both compounds did not show any significant inhibitory effect on Akt. On the other hand, in vitro experiments suggest that compounds 3e and 3i are potential anti-NSCLC agents acting through Akt inhibition. Furthermore, molecular docking studies revealed a unique binding mode for compound 3i (the strongest Akt inhibitor in this series), which interacts with both hinge region and acidic pocket of Akt2. However, it is understood that compounds 3a and 3g exert their cytotoxic and apoptotic effects on A549 cells via different pathway(s).

Discovery of Small Molecule COX-1 and Akt Inhibitors as Anti-NSCLC Agents Endowed with Anti-Inflammatory Action.

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.

Design, synthesis and biological evaluation of a new series of arylidene indanones as small molecules for targeted therapy of non-small cell lung carcinoma and prostate cancer.

In an attempt to identify small molecules for targeted therapy of non-small cell lung carcinoma (NSCLC) and prostate cancer (PCa), new arylidene indanones (1-10) were synthesized via the Claisen-Schmidt condensation of 5,6-methylenedioxy-1-indanone with p-substituted benzaldehyde. Compounds 1-10 were assessed for their cytotoxic effects on human lung adenocarcinoma (A549) and human pancreatic ductal carcinoma (PANC-1) cells as well as human normal lung fibroblast (CCD-19Lu) and human normal pancreatic ductal epithelial (hTERT-HPNE) cells. Among them, compounds 2, 4 and 10 were more effective on A549 and PANC-1 cells than cisplatin. Compounds 1 and 9 also showed more potent cytotoxic activity towards PANC-1 cells than cisplatin. In vitro assays were performed to assess their effects on DNA synthesis, apoptosis, caspase-3, mitochondrial membrane potential, intracellular calcium levels, morphological changes in cancer cells. Furthermore, all compounds were investigated for their inhibitory effects on cathepsin L (CatL) and cathepsin D (CatD). Compounds 2 and 4 exerted potent anti-NSCLC action through caspase-independent apoptosis induced by an increase in intracellular calcium level and correspondingly the disruption of the ΔΨm. These compounds also caused apoptotic morphological alterations in A549 cells. Compound 4 also inhibited both cathepsins but its inhibitory potency on CatL was more significant. Based on in vitro mechanistic assays, compound 4 was identified as a promising anticancer agent for targeted therapy of NSCLC. On the other hand, the marked anti- PCa activity of compound 1 mediated by apoptotic cell death is also noteworthy, but further enzymatic assays are required to elucidate its main mechanism of action.

A New Series of Indeno[1,2-c]pyrazoles as EGFR TK Inhibitors for NSCLC Therapy.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death throughout the world. Due to the shortcomings of traditional chemotherapy, targeted therapies have come into prominence for the management of NSCLC. In particular, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy has emerged as a first-line therapy for NSCLC patients with EGFR-activating mutations. In this context, new indenopyrazoles, which were prepared by an efficient microwave-assisted method, were subjected to in silico and in vitro assays to evaluate their potency as EGFR TK-targeted anti-NSCLC agents. Compound 4 was the most promising antitumor agent towards A549 human lung adenocarcinoma cells, with an IC50 value of 6.13 µM compared to erlotinib (IC50 = 19.67 µM). Based on its low cytotoxicity to peripheral blood mononuclear cells (PBMCs), it can be concluded that compound 4 exerts selective antitumor action. This compound also inhibited EGFR TK with an IC50 value of 17.58 µM compared to erlotinib (IC50 = 0.04 µM) and induced apoptosis (56.30%). Taking into account in silico and in vitro data, compound 4 stands out as a potential EGFR TKI for the treatment of NSCLC.

EGFR-Targeted Pentacyclic Triterpene Analogues for Glioma Therapy.

Glioma, particularly its most malignant form, glioblastoma multiforme (GBM), is the most common and aggressive malignant central nervous system tumor. The drawbacks of the current chemotherapy for GBM have aroused curiosity in the search for targeted therapies. Aberrantly overexpressed epidermal growth factor receptor (EGFR) in GBM results in poor prognosis, low survival rates, poor responses to therapy and recurrence, and therefore EGFR-targeted therapy stands out as a promising approach for the treatment of gliomas. In this context, a series of pentacyclic triterpene analogues were subjected to in vitro and in silico assays, which were conducted to assess their potency as EGFR-targeted anti-glioma agents. In particular, compound 10 was the most potent anti-glioma agent with an IC50 value of 5.82 µM towards U251 human glioblastoma cells. Taking into account its low cytotoxicity to peripheral blood mononuclear cells (PBMCs), compound 10 exerts selective antitumor action towards Jurkat human leukemic T-cells. This compound also induced apoptosis and inhibited EGFR with an IC50 value of 9.43 µM compared to erlotinib (IC50 = 0.06 µM). Based on in vitro and in silico data, compound 10 stands out as a potential orally bioavailable EGFR-targeted anti-glioma agent endowed with the ability to cross the blood-brain barrier (BBB).

Identification of a new class of potent aldose reductase inhibitors: Design, microwave-assisted synthesis, in vitro and in silico evaluation of 2-pyrazolines.

Aldose reductase (AR) acts as a multi-disease target for the design and development of therapeutic agents for the management of diabetic complications as well as non-diabetic diseases. In the search for potent AR inhibitors, the microwave-assisted synthesis of twenty new compounds with a 1,3-diaryl-5-(4-fluorophenyl)-2-pyrazoline moiety as a common fragment in their structure (1-20) was carried out efficiently. Compounds 1-20 were subjected to in vitro studies, which were conducted to assess their AR inhibitory effects and cytotoxicity towards L929 mouse fibroblast (normal) cells. Among these compounds, 1-(3-bromophenyl)-3-(4-piperidinophenyl)-5-(4-fluorophenyl)-2-pyrazoline (20) was identified as the most promising AR inhibitor with an IC50 value of 0.160 ± 0.005 µM exerting competitive inhibition with a Ki value of 0.019 ± 0.001 µM as compared to epalrestat (IC50 = 0.279 ± 0.001 µM; Ki = 0.801 ± 0.023 µM) and quercetin (IC50 = 4.120 ± 0.123 µM; Ki = 6.082 ± 0.272 µM). Compound 20 displayed cytotoxicity towards L929 cells with an IC50 value of 18.75 ± 1.06 µM highlighting its safety as an AR inhibitor. Molecular docking studies suggested that π-π stacking interactions occurred between the m-bromophenyl moiety of compound 20 and Trp21. Based on in silico pharmacokinetic studies, compound 20 was found to possess favorable oral bioavailability and drug-like properties. It can be concluded that compound 20 is a potential orally bioavailable AR inhibitor for the management of diabetic complications as well as non-diabetic diseases.

A new series of benzoxazole-based SIRT1 modulators for targeted therapy of non-small-cell lung cancer.

In an attempt to identify potential anticancer agents for non-small-cell lung cancer (NSCLC) targeting sirtuin 1 (SIRT1), the synthesis of a new series of benzoxazoles (3a - i) was carried out through a facile and versatile synthetic route. The compounds were evaluated for their cytotoxic effects on A549 human lung adenocarcinoma and NIH/3T3 mouse embryonic fibroblast cells using the MTT assay. 2-[(5-Nitro-1H-benzimidazol-2-yl)thio]-N-(2-methylbenzoxazol-5-yl)acetamide (3e) and 2-[(5-chloro-1H-benzimidazol-2-yl)thio]-N-(2-methylbenzoxazol-5-yl)acetamide (3g) were the most potent and selective anticancer agents in this series against the A549 cell line, with IC50 values of 46.66 ± 11.54 and 55.00 ± 5.00 µM, respectively. The flow cytometry-based apoptosis detection assay was performed to determine their effects on apoptosis in A549 cells. Both compounds induced apoptosis in a dose-dependent manner. The effects of compounds 3e and 3g on SIRT1 activity were determined. On the basis of in vitro studies, it was observed that compound 3g caused a significant decrease in SIRT1 levels in a dose-dependent manner, whereas compound 3e increased the SIRT1 levels. According to molecular docking studies, the substantial alteration in the type of action could be attributed to the difference between the interactions of compounds 3e and 3g with the same residues in the active site of SIRT1 (PDB code: 4IG9). On the basis of in silico ADME (absorption, distribution, metabolism, and excretion) studies, these compounds are predicted to possess favorable ADME profiles. According to the in vitro and in silico studies, compounds 3e and 3g, small-molecule SIRT1 modulators, were identified as potential orally bioavailable anticancer agents for the targeted therapy of NSCLC.

A New Series of Triazolothiadiazines as Potential Anticancer Agents for Targeted Therapy of Non-Small Cell Lung and Colorectal Cancers: Design, Synthesis, In silico and In vitro Studies Providing Mechanistic Insight into Their Anticancer Potencies.

BACKGROUND: Targeted therapies acting on specific molecular targets in cancer cells with better curative efficacy and lower toxicity have come into prominence for the management of nonsmall cell lung cancer (NSCLC) and colorectal cancer (CRC). COX-2 stands out as a plausible target for anticancer agents due to its pivotal role in tumor initiation, progression and invasion. OBJECTIVES: Due to the importance of triazolothiadiazine scaffold in targeted anticancer drug discovery, the aim of this work is the design of new triazolothiadiazines as potential anticancer agents for the targeted therapy of NSCLC and CRC. METHODS: New triazolo[3,4-b]-1,3,4-thiadiazines (2a-g) were synthesized via the ring closure reactions of 2-bromo-1-arylethanones with 4-amino-5-((5-methoxy-2-methyl-1H-indol-3-yl)methyl)-2,4- dihydro-3H-1,2,4-triazole-3-thione (1), which was obtained via the solvent-free reaction of 5- methoxy-2-methyl-3-indoleacetic acid with thiocarbohydrazide. MTT assay was performed to determine their cytotoxic effects on A549 human lung adenocarcinoma, Caco-2 human colorectal adenocarcinoma and CCD-19Lu human lung fibroblast cells. The most potent compounds were evaluated for their effects on apoptosis, caspase-3, mitochondrial membrane potential, cell cycle, ultrastructural morphological changes and COX-2 in A549 and Caco-2 cells. In silico docking and Absorption, Distribution, Metabolism and Excretion (ADME) studies were also performed using Schrödinger's Maestro molecular modeling package. RESULTS: 6-(4-Chlorophenyl)-3-[(5-methoxy-2-methyl-1H-indol-3-yl)methyl]-7H-[1,2,4]triazolo[3,4- b][1,3,4]thiadiazine (2e) was the most potent and selective anticancer agent in this series against A549 and Caco-2 cell lines. Compound 2e induced early apoptosis, caused mitochondrial membrane depolarization and arrested cell cycle at G0/G1 phase in A549 cells. On the other hand, compound 2e triggered intrinsic apoptotic pathway involving caspase-3 activation in Caco-2 cells. Compound 2e caused apoptotic morphological changes in both cancer cell lines. The cytotoxic and apoptotic effects of this compound on CRC were found to be related to its selective COX-2 inhibitory activity. According to molecular docking studies, compound 2e showed good affinity to the active site of COX-2 (PDB code: 4COX). Based on in silico ADME studies, the compound is predicted to possess a favorable ADME profile. CONCLUSION: According to in vitro and in silico studies, compound 2e was identified as a potential orally bioavailable anticancer agent for COX-2-targeted therapy of CRC.

In Vitro and In Silico Evaluation of Anticancer Activity of New Indole-Based 1,3,4-Oxadiazoles as EGFR and COX-2 Inhibitors.

Epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) are crucial targetable enzymes in cancer management. Therefore, herein, new 2-[(5-((1H-indol-3-yl)methyl)-1,3,4-oxadiazol-2-yl)thio]-N-(thiazol/benzothiazol-2-yl)acetamides (2a-i) were designed and synthesized as EGFR and COX-2 inhibitors. The cytotoxic effects of compounds 2a-i on HCT116 human colorectal carcinoma, A549 human lung adenocarcinoma, and A375 human melanoma cell lines were determined using MTT assay. 2-[(5-((1H-Indol-3-yl)methyl)-1,3,4-oxadiazol-2-yl)thio]-N-(6-ethoxybenzothiazol-2-yl)acetamide (2e) exhibited the most significant anticancer activity against HCT116, A549, and A375 cell lines with IC50 values of 6.43 ± 0.72 µM, 9.62 ± 1.14 µM, and 8.07 ± 1.36 µM, respectively, when compared with erlotinib (IC50 = 17.86 ± 3.22 µM, 19.41 ± 2.38 µM, and 23.81 ± 4.17 µM, respectively). Further mechanistic assays demonstrated that compound 2e enhanced apoptosis (28.35%) in HCT116 cells more significantly than erlotinib (7.42%) and caused notable EGFR inhibition with an IC50 value of 2.80 ± 0.52 µM when compared with erlotinib (IC50 = 0.04 ± 0.01 µM). However, compound 2e did not cause any significant COX-2 inhibition, indicating that this compound showed COX-independent anticancer activity. The molecular docking study of compound 2e emphasized that the benzothiazole ring of this compound occupied the allosteric pocket in the EGFR active site. In conclusion, compound 2e is a promising EGFR inhibitor that warrants further clinical investigations.

Pyrazole Incorporated New Thiosemicarbazones: Design, Synthesis and Investigation of DPP-4 Inhibitory Effects.

Dipeptidyl peptidase-4 (DPP-4) inhibition has been recognized as a promising approach to develop safe and potent antidiabetic agents for the management of type 2 diabetes. In this context, new thiosemicarbazones (2a-o) were prepared efficiently by the reaction of aromatic aldehydes with 4-[4-(1H-pyrazol-1-yl)phenyl]thiosemicarbazide (1), which was obtained via the reaction of 4-(1H-pyrazol-1-yl)phenyl isothiocyanate with hydrazine hydrate. Compounds 2a-o were evaluated for their DPP-4 inhibitory effects based on a convenient fluorescence-based assay. 4-[4-(1H-pyrazol-1-yl)phenyl]-1-(4-bromobenzylidene)thiosemicarbazide (2f) was identified as the most effective DPP-4 inhibitor in this series with an IC50 value of 1.266 ± 0.264 nM when compared with sitagliptin (IC50 = 4.380 ± 0.319 nM). MTT test was carried out to assess the cytotoxic effects of compounds 2a-o on NIH/3T3 mouse embryonic fibroblast (normal) cell line. According to cytotoxicity assay, compound 2f showed cytotoxicity towards NIH/3T3 cell line with an IC50 value higher than 500 µM pointing out its favourable safety profile. Molecular docking studies indicated that compound 2f presented π-π interactions with Arg358 and Tyr666 via pyrazole scaffold and 4-bromophenyl substituent, respectively. Overall, in vitro and in silico studies put emphasis on that compound 2f attracts a great notice as a drug-like DPP-4 inhibitor for further antidiabetic research.

Thiazolyl-pyrazoline derivatives: In vitro and in silico evaluation as potential acetylcholinesterase and carbonic anhydrase inhibitors.

Alzheimer's disease (AD) is a complex, predominant, and progressive form of dementia. The treatment of AD alters depending on the cognitive and behavioral symptoms. The utility of cholinergic replacement by acetylcholinesterase (AChE) inhibitors in AD treatment has been well-documented so far. Recent studies have also demonstrated that human carbonic anhydrases (hCAs) serve as important targets for AD treatment. In an attempt to identify potent AChE and hCA inhibitors, new thiazolyl-pyrazolines (3a-k) were designed based on the molecular hybridization of thiazole and pyrazoline scaffolds. A facile and versatile synthetic route consisting of three steps, namely Claisen-Schmidt reaction, the formation of the 2-pyrazoline ring system, and Hantzsch thiazole synthesis was used to prepare compounds 3a-k. The synthesized derivatives were experimentally validated for efficacy by in vitro and direct enzymatic assays. Furthermore, the compounds were subjected to in silico screening using Schrödinger Suite software to identify the binding affinities of potential compounds based on Glide XP scoring, MM-GBSA calculating, and validation. The results of in vitro and in silico studies revealed that compounds 3a, 3f, and 3d were the most promising derivatives in this series due to their significant effects on AChE, hCA I, and hCA II, respectively.

Design, synthesis, in vitro and in silico investigation of aldose reductase inhibitory effects of new thiazole-based compounds.

Aldose reductase (AR) catalyzes the NADPH-dependent reduction of glucose to sorbitol in the polyol pathway, which plays an important role in the development of diabetic complications including cataract, retinopathy, nephropathy, and neuropathy. AR has been considered as an important target to heal these long-term diabetic complications and for this reason the development of new AR inhibitors is an important approach in modern medicinal chemistry. In the current study, new 4-aryl-2-[2-((3,4-dihydro-2H-1,5-benzodioxepine-7-yl)methylene)hydrazinyl]thiazole derivatives (1-12) were synthesized and screened for their inhibitory effects on AR which was purified by diverse chromatographic methods with a yield of 1.40% and a specific activity of 2.00 EU/mg. All compounds were determined as promising AR inhibitors with the Ki values in the range of 0.018 ± 0.005 µM-3.746 ± 1.321 µM compared to the quercetin (Ki = 7.025 ± 1.780 µM). In particular, 4-(4-cyanophenyl)-2-[2-((3,4-dihydro-2H-1,5-benzodioxepin-7-yl)methylene)hydrazinyl]thiazole (3) was detected as the most potential AR inhibitor in this series with the Ki value of 0.018 ± 0.005 µM and the compound showed competitive AR inhibition. The cytotoxic effects of compounds 1-12 were investigated on L929 mouse fibroblast (healthy) cells using MTT assay and all these compounds were defined as non-cytotoxic agents against L929 cells. Molecular docking studies, which were employed to determine the affinity of compounds 1-12 into the active site of AR, highlighted that the thiazole scaffold of all these compounds presented π-π stacking interactions with Trp20 and Phe122. According to both in vitro and in silico assays, these potential AR inhibitors may have great importance in the prevention of diabetic microvascular conditions.

Design, synthesis and biological evaluation of a new series of thiazolyl-pyrazolines as dual EGFR and HER2 inhibitors.

Epidermal growth factor receptor (EGFR, also known as HER1) and HER2, prominent members of receptor tyrosine kinase (RTK) superfamily, have been reported as diagnostic or prognostic markers in tumor progression. Based on the importance of molecular hybridization of pyrazoline and thiazole scaffolds in the discovery of potent anticancer agents, new thiazolyl-pyrazoline derivatives (3a-v) were synthesized and screened for their cytotoxic effects on A549 human lung adenocarcinoma, MCF-7 human breast adenocarcinoma and A375 human melanoma cell lines. 1-(4-(4-Fluorophenyl)thiazol-2-yl)-3-(4-morpholinophenyl)-5-(4-chlorophenyl)-2-pyrazoline (3c),1-(4-(4-cyanophenyl)thiazol-2-yl)-3-(4-morpholinophenyl)-5-(4-chlorophenyl)-2-pyrazoline (3f) and 1-(4-(4-cyanophenyl)thiazol-2-yl)-3-(4-piperidinophenyl)-5-(4-chlorophenyl)-2-pyrazoline (3q) were found as the most potent anticancer agents against A549 and MCF-7 cell lines compared to erlotinib. Compound 3q also showed moderate cytotoxic activity against A375 cell line. Moreover, these compounds exert a cancer cell-selective action against Jurkat cell line posing no toxicity on peripheral blood mononuclear cells (PBMCs). In order to enlighten the mechanism of action underlying anticancer activity, compounds 3c, 3f and 3q were investigated for their apoptotic effects on A549 and MCF-7 cell lines and inhibitory potencies against eight different RTKs including EGFR and HER2 compared to erlotinib. The results indicated that compounds 3f and 3q induced apoptosis in both cell lines and showed significant EGFR inhibitory activity with IC50 values of 4.34 ±â€¯0.66 µM and 4.71 ±â€¯0.84 µM, respectively when compared with erlotinib (IC50 = 0.05 ±â€¯0.01 µM). Besides, compound 3f also inhibited HER2 notably with an IC50 value of 2.28 ±â€¯0.53 µM making it a dual EGFR and HER2 inhibitor. Molecular docking studies, which were conducted to support the in vitro assays, pointed out that compound 3f showed high affinity into the ATP binding sites of EGFR and HER2.

In silico Molecular Docking and ADME Studies of 1,3,4-Thiadiazole Derivatives in Relation to in vitro PON1 Activity.

BACKGROUND: Paraoxonase 1 (PON1) is a paraoxonase, arylesterase and lactonase associated with protection of lipoproteins and cell membranes against oxidative modification. OBJECTIVE: Based on antioxidative properties of PON1 and significance of 1,3,4-thiadiazoles in pharmaceutical chemistry, herein we aimed to evaluate the potentials of 1,3,4-thiadiazole derivatives as PON1 activators. METHODS: 2-[[5-(2,4-Difluoro/dichlorophenylamino)-1,3,4-thiadiazol-2-yl]thio]acetophenone derivatives (1-18) were in vitro evaluated for their activator effects on PON1 which was purified using ammonium sulfate precipitation (60-80%) and DEAE-Sephadex anion exchange chromatography. Molecular docking studies were performed for the detection of affinities of all compounds to the active site of PON1. Moreover, Absorption, Distribution, Metabolism and Excretion (ADME) properties of all compounds were also in silico predicted. In silico molecular docking and ADME studies were carried out according to modules of Schrodinger's Maestro molecular modeling package. RESULTS: All compounds, particularly compounds 10, 13 and 17, were determined as promising PON1 activators and apart from compound 1, all of them were detected in the active site of PON1. Besides, ADME results indicated that all compounds were potential orally bioavailable drug-like molecules. CONCLUSION: PON1 activators, compounds 10, 13 and 17 stand out as potential drug candidates for further antioxidant studies and these compounds can be investigated for their therapeutic effects in many disorders such as atherosclerosis, diabetes mellitus, obesity, chronic liver inflammation and many more.

Comprehensive Study on Thiadiazole-Based Anticancer Agents Inducing Cell Cycle Arrest and Apoptosis/Necrosis Through Suppression of Akt Activity in Lung Adenocarcinoma and Glioma Cells.

OBJECTIVES: Akt is considered as an attractive target for anticancer drug discovery and development and therefore extensive efforts have been devoted to the discovery of new potent anticancer agents targeting Akt. MATERIALS AND METHODS: Due to the importance of thiadiazoles for anticancer drug discovery, herein eight 1,3,4-thiadiazole derivatives were investigated for their cytotoxic effects on C6 rat glioma and A549 human lung adenocarcinoma cell lines using the MTT assay. The effects of the most promising anticancer agents on apoptosis, caspase-3 activation, mitochondrial membrane potential, and cell cycle arrest were determined on a BD FACSAria (I) flow cytometer. Akt activity was measured in the C6 and A549 cell lines using an ELISA colorimetric method. Schrödinger's Maestro molecular modeling package was used to explore the possible binding modes of compounds 3 and 8 in the active site of Akt enzyme (PDB code: 3OW4). RESULTS: N-(4-Chlorophenyl)-2-[(5-((4-nitrophenyl)amino)-1,3,4-thiadiazol-2-yl)thio]acetamide (3) and N-(6-nitrobenzothiazol-2-yl)-2-[(5-((4- nitrophenyl)amino)-1,3,4-thiadiazol-2-yl)thio]acetamide (8) induced apoptosis and cell cycle arrest in the C6 cell line through inhibition of Akt activity (92.36% and 86.52%, respectively). The docking results of compounds 3 and 8 indicated that π-π interactions, H bonds, and salt-bridge formation were responsible for the observed Akt inhibitory activity. CONCLUSION: According to in vitro and docking studies, compounds 3 and 8 stand out as promising antiglioma agents.

Design, Synthesis, and Neuroprotective Effects of a Series of Pyrazolines against 6-Hydroxydopamine-Induced Oxidative Stress.

Parkinson's disease (PD) is a chronic, progressive, and age-related neurodegenerative disorder characterized by the loss of midbrain dopaminergic neurons caused by the accumulation of free radicals and oxidative stress. Based on the neuroprotective properties of 2-pyrazoline derivatives, in the current work, 1-(phenyl/4-substituted phenyl)-3-(2-furanyl/thienyl)-5-aryl-2-pyrazolines (3a⁻i, 4a⁻i) were synthesized via the cyclization of the chalcones (1, 2) with suitable phenylhydrazine hydrochloride derivatives. All these compounds were investigated for their neuroprotective effects using an in vitro 6-hydroxydopamine (6-OHDA)-induced neurotoxicity model of PD in the rat pheochromocytoma (PC-12) Adh cell line. In addition, some different pharmacokinetic parameters of all compounds were in silico predicted by the QikProp module of Schrödinger's Maestro molecular modeling package. 4-Methylsulfonylphenyl substituted compounds 3h (20%) and 4h (23%) were determined as the most promising neuroprotective agents related to their inductive roles in cell viability when compared with the 6-OHDA-positive control group (43% and 42%, respectively). Moreover, in silico pharmacokinetic results indicated that all compounds were within the acceptable range intended for human use. According to both in vitro and in silico studies, compounds 3h and 4h draw attention as potential orally bioavailable therapeutic drug candidates against neurodegeneration in PD.