Novel Bis(1,2,4-oxadiazolyl) Fused Thiazole Derivatives: Synthesis and Anticancer Activity

A novel series of bis-1,2,4-oxadiazole fused benzothiazole derivatives 9a–9j are synthesized, and their structures are confirmed by ¹H and ¹³C NMR, and mass spectral data. All products are evaluated in vitro for their anticancer potential against a panel of four human cancer cell lines such as lung cancer (A549), breast carcinoma (MCF-7), melanoma (A375), and colon cancer (HT-29). The combretastatin-A4 is used as standard drug. All compounds 9a–9j exhibit significant anticancer activity with IC₅₀ values ranging from 0.11±0.01 to 14.6±3.89 μM. Among these, compounds 9a–9d, 9h, 9i demonstrate more potent activity than the control.

     

Amide derivatives of 4-azaindole: Design,synthesis, and EGFR targeting anticancer agents

Abstract

A series of amide derivatives of azaindole-oxazoles (11a-n) were designed and synthesized and their structures were confirmed by ¹HNMR, ¹³CNMR and mass spectral analysis. Further, these derivatives were screened for their anticancer activity against human cancer cell lines viz; MCF7 (breast), A549 (lung) and A375 (melanoma). In vitro anticancer activity screening indicated that most of the hybrids exhibited potent inhibitory activities in a variety of cancer cell lines. Among the compounds 11d, 11e, 11f, 11j, 11k, 11l, 11m, and 11n were exhibited more potent activity than standard, in those mainly two compounds 11m and 11j were exhibited excellent activity in MCF-7 cell line with IC₅₀ values 0.034 and 0.036?µM. Moreover, all these compounds were carried out their molecular docking studies on EGFR receptor results indicated that two potent compounds 11m and 11j were strongly binds to protein EGFR (PDB ID: 4hjo). It was found that the energy calculations were in good agreement with the observed IC₅₀ values.     

Synthesis of spirooxindoles promoted by the deep eutectic solvent,ZnCl2+urea via the pseudo four-component reaction: anticancer,antioxidant, and molecular docking studies

Abstract

Various spirooxindoles (7a–c, 8a–c, 9a–c, and 10a–c) were efficiently synthesized using deep eutectic solvent ZnCl₂+urea and well characterized using IR, ¹H NMR, and ¹³C NMR spectroscopic techniques. The biological screening results showed that the compound 9a exhibited potent anticancer activity against MCF7 and HeLa cell lines with IC₅₀ values 6.47?±?0.01 and 9.14?±?0.32?µM, respectively. The compound 7c exhibited potent activity against the HeLa cell line with IC₅₀ value 6.81?±?0.01?µM. The compound 9a exhibited a potent antioxidant activity with IC₅₀ value 7.34?±?0.17?µM. The comparative molecular docking study against the cancer proteins EGFR and HER2 revealed that the EGFR was the best target protein receptor for the target compounds. Among all the compounds, the compound 9a exhibited the least binding energy ?10.72?kcal/mol against the protein EGFR (PDB ID: 4HJO).     

Synthesis,characterization and pharmacological evaluation of some new 1,3,4-oxadiazole derivatives bearing 3-chloro-2-fluoro phenyl moiety

A new series of 2-(3-chloro-2-fluorophenyl)-5-aryl-1,3,4-oxadiazole (3a–j) and 2-(aryl sulfanyl)-5-(3-chloro-2-fluorophenyl)-1,3,4-oxadiazole (5a–e) were synthesized via a multistep reaction from 3-chloro-2-fluoro benzoic acid. The newly synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR, mass spectral data and elemental analysis. They were also screened for their in vivo anti-convulsant and anti-inflammatory activities. Some of them exhibited significant biological activities and were well supported by in silico molecular docking studies for the inhibition of cyclooxygenase-2 (PDB ID: 1CX2) and voltage-gated sodium channels (PDB ID: 4F4L) comparable with the standard drugs. Thus, they were believed to be good inhibitors of cyclooxygenase-2 (PDB ID: 1CX2) and voltage-gated sodium channels (PDB ID: 4F4L).     

1,2-Benzisoxazole-3-acetamide derivatives as dual agents for DPP-IV inhibition and anticancer activity

Abstract

Herein, we have designed various benzisoxazole acetamide derivatives with and without glycine spacer as DPP-IV inhibitors. Compounds 9a–d and 11a–e were synthesized and screened for their in vitro DPP-IV inhibition. Compounds 11a and 11c showed moderate activity for DPP-IV inhibition, whereas other remained inactive at 25–200?µM concentrations. DPP-IV inhibition can be a good strategy for modulating diabetes and cancer; hence, we have screened compounds 9a–d and 11a–e for their anticancer activity using MTT assay against A549 and MCF7 cell lines. Compounds 9a–d without glycine spacer have shown good anticancer activity compared to compounds 11a–e with glycine spacer. Compound 9b has shown moderate activity with IC₅₀ values 4.72?±?0.72 and 4.39?±?0.809?µM against A549 and MCF7 cell lines, respectively. Interestingly, compound 9c with cyano group has shown very good anticancer activity with IC₅₀ 2.36?±?0.34?µM against MCF7 cell line as compared to fluorouracil with IC₅₀ 45.04?±?1.02?µM.     

Synthesis and Anticancer Activity of 1,2,3-Triazole Fused N-Arylpyrazole Derivatives

A novel series of triazole derivatives 11a–11j is synthesized. Structures of the products are confirmed by ¹H and ¹³C NMR, and mass spectral data. The anticancer activities of compounds 11a–11j are evaluated against three human cancer cell lines (MCF-7, A549, and A375) using the standard MTT assay in vitro, using doxorubicin as the positive control. All the compounds exhibit significant activity against cancer cell lines. The compounds 11a, 11d, 11e, 11g, and 11j demonstrate more potent activity than the positive control.

     

Click synthesis of new 7-chloroquinoline derivatives by using ultrasound irradiation and evaluation of their biological activity

This study describes the click synthesis of new 7-chloroquinoline derivatives by using ultrasound irradiation and evaluation of their activity as antimicrobial, antimalarial and the anticancer. All the compounds show moderate antimalarial activity with IC₅₀?<?100?μM, six of them showed high antimalarial activity (2, 3, 4, 6, 8 and 9) with IC₅₀?<?50?μM. The most active 7-chloroquinoline derivative is a compound (9). Also, the newly synthesized compounds were screened for their antitumor activity towards three lines of cancer cells, MCF-7 (human breast cancer), HCT-116 (colon carcinoma) and Hela (Cervical carcinoma) cell lines. Compounds (3) and (9) exerted the highest activity on all cell lines and showed special selectivity toward MCF-7 cells and the antibacterial screening data showed moderate to good inhibition zone (12.5?±?0.63–23.8?±?1.5) towards all the tested compounds. Elucidation of the structures of these new pure compounds was based on, IR, ¹H NMR, ¹³C NMR, MS and their elemental analysis.     

Design and synthesis of fluorescent symmetric bis-triazolylated-1,4-dihydropyridines as potent antibreast cancer agents

Herein, we report the synthesis of fluorescent 1,4-dihydropyridine-linked bis-triazoles (2a–2n) through Hantzsch synthesis by the condensation of o/m-chloro-substituted benzaldehyde, ethyl 3-oxo-4(prop-2-yn-1-yloxy)butanoate, and ammonium acetate in the presence of Ba(NO₃)₂ as a catalyst followed by the click reaction of resultant Hantzsch product (1) with various aromatic as well as aliphatic azides. All the synthesized compounds were well characterized by ¹H-NMR, ¹³C-NMR, FTIR, and HRMS spectral techniques. Antibreast cancer evaluation of all the synthesized derivatives revealed that the compounds 2f (IC₅₀?=?7?±?0.02?µM) and 2g (IC₅₀?=?5?±?0.03?µM) showed better anticancer activity (lower IC₅₀) than the standard drug tamoxifen (IC₅₀?=?11.2?±?0.01?µM) against breast carcinoma (MDA-MB-231) cell line. The synthesized compounds were also screened against normal human embryonic kidney (HEK-293) cell line and found to be nontoxic. The fluorescent nature and cytotoxicity assay of these newly synthesized hybrids recommend their utility in tumor cell imaging.     

Synthesis,biological evaluation and computational studies of fused acridine containing 1,2,4-triazole derivatives as anticancer agents

A novel series of fused acridine containing 1,2,4-triazole derivatives (13a-j) have been synthesized and their structures were confirmed by ¹HNMR, 13CNMR and mass spectral data. Further, all these derivatives were tested for their anticancer activity against four human cancer cell lines A549 (Lung), MCF7 (Breast), A375 (Melanoma) and HT-29 (Colon). The IC₅₀ values range of target compounds shown 0.11 ± 0.02 to 13.8 ± 0.99 µM as compared with standard drug range 0.11 ± 0.02 to 0.93 ± 0.056 µM. Among them, compounds 13d, 13f, 13g, 13h, 13i, and 13j were exhibited more potent activity. Docking simulation was performed as a trial to study the mechanisms and binding modes of these compounds towards the DNA target. The results showed these compounds have intercalated placement in the active sites and stable interactions similar to the co-crystallized reference ligand. Further, these compounds (13a-j) were investigated for Drug-likeness, ADME properties and Toxicity risk assessment.     

Synthesis and antitumor activity of novel pyridazinone derivatives containing 1,3,4-thiadiazole moiety

Abstract

A series of novel pyridazinone derivatives containing the 1,3,4-thiadiazole moiety were synthesized and characterized by ¹H NMR, 13C NMR, spectroscopies HRMS and IR. Among them, the structure of compound 5c (2-(Tert-butyl)?4-chloro-5-((5-((2-ethylphenyl)amino)?1,3,4-thiadiazol-2-yl)thio)pyridazin-3(2H)-One) was unambiguously confirmed via single crystal X-ray diffraction analysis. The inhibitory activity of all the target compounds against MGC-803 and Bcap-37 was determined by MTT assay, with doxorubicin (the inhibition rates were 95.5?±?0.4% and 95.7?±?1.0% respectively) as a control. The preliminary results showed that the inhibitory activity of compound 5n (2-(Tert-butyl)?4-chloro-5-((5-((3-fluorophenyl)amino)?1,3,4-thiadiazol-2-yl)thio)pyridazin-3(2H)-One) was superior to the others. The inhibition rates of MGC-803 and Bcap-37 cells were 86.3?±?2.2% and 92.3?±?0.6% at a concentration of 10?μmol/L, respectively. The preliminary structure-activity relationship showed that when the 2-position of the benzene ring was substituted by a methyl group, such as compound 5j (2-(Tert-butyl)?4-chloro-5-((5-((2,3-dimethylphenyl)amino)?1,3,4-thiadiazol-2-yl)thio)pyridazin-3(2H)-One), it exhibited good anticancer activity on MGC-803 cells. Besides, introducing fluorine, chlorine, or trifluoromethyl group onto the benzene ring, such as compound 5?m (2-(Tert-butyl)?4-chloro-5-((5-((4-(trifluoromethoxy)phenyl)amino)?1,3,4-thiadiazol-2-yl)thio)pyridazin-3(2H)-One), displayed good anticancer activity on MGC-803 and Bcap-37 cells.     

Synthesis,EGFR-TK inhibition and anticancer activity of new quinoxaline derivatives

Abstract

Ethyl 4-substituted-3-oxo-quinoxaline-2-carboxylates 3–5 were obtained via alkylation of ethyl 3-oxo-3,4-dihydroquinoxaline-2-carboxylate (1). Compound 1 was heterocyclized using hydrazines, ethylenediamine, and ethanolamine to give pyrazoloquinoxalines 6, 7, diazepinoquinoxaline 8, and oxazepinoquinoxaline 10. The quinoxaline-2-carboxamides 9, 11, 12 were prepared via condensation of compound 1 with different amines. Compound 1 was thiated using Lawesson’s reagent affording quinoxaline-3-thione 13, in fair yield. In addition, the reaction of 4-methyl-3-oxoquinoxaline 3 with some binucleophiles led to a series of new oxoquinoxaline derivatives 14–18. The molecular structure of compounds 1, 3, and 9 was confirmed by X-ray crystallography.

The anti-proliferative activity showed that among all the tested compounds, compounds 3, (IC₅₀ 2.51?±?3.0, 4.22?±?1.6 and 2.27?±?1.9?µM), 11 (IC₅₀ 1.32?±?2.61, 1.41?±?1.23 and 1.18?±?1.91?µM) and 17 (IC₅₀ 1.72?±?1.32, 1.85?±?0.94 and 1.92?±?4.83?µM) showed noteworthy anti-proliferative effects against the three cancer cell lines, HCT116, HePG2 and MCF7, respectively, compared to the reference drugs doxorubicin (IC₅₀ 1.41?±?0.58, 0.90?±?0.62 and 1.01?±?3.02?µM) and erlotinib (IC₅₀ 1.63?±?0.81, 1.57?±?0.62 and 1.49?±?0.54?µM). Compounds 3 (0.899?nM), 11 (0.508?nM) and 17 (0.807) showed strong EGFR inhibitory activity compared to Erlotinib (0.439?nM) and these results are in agreement with the docking study. These results suggest that compounds could probably be promising anticancer agents with EGFR inhibitory activity.     

Diorganotin(IV) carboxylates of 3-methylphenyl ethanoic acid: Synthesis,crystal structure,antibacterial, anticancer and molecular docking studies

Abstract

Di-n-butyl- (1) and diethyltin(IV) (2) derivatives of 3-methylphenylethanoic acid were synthesized and characterized by elemental analysis, atomic absorption, IR, ¹H and 13C NMR spectroscopy and mass spectrometry. The spectroscopic data and single crystal X-ray diffraction studies for complex 2 have confirmed a bidentate coordination mode of the carboxylate ligand and the presence of hexacoordinated tin atoms in the complexes. The complexes were screened for their in vitro antibacterial activity against selected gram positive and gram negative bacterial strains. The anticancer potential was assessed against prostate cancer cell lines. Both complexes have shown higher activities than the ligand acid. Complex 1 with an IC₅₀ value of 4.97?±?0.27?μg/mL was found to be better anti prostate cancer agent than complex 2 (IC₅₀ = 11.26?±?2.18?μg/mL). Molecular docking study has suggested antibacterial action of the complexes in terms of their ability to develop hydrogen bonding and hydrophobic interactions with vital residues of the target proteins like tyrosyl-tRNA synthase from Staphylococcus aureus (gram-positive bacteria) and undecaprenyl diphosphate synthase from Escherichia coli (gram-negative bacteria).     

Synthesis and monoamine oxidase A/B inhibitory evaluation of new benzothiazole-thiazolylhydrazine derivatives

Abstract

In this study, a novel series of benzothiazole-thiazolylhydrazine (3a–3i) was synthesized and their structures were characterized by ¹H-NMR, ¹³C-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?µM). 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?µM.     

Heterocyclic 1,3,4-oxadiazole as columnar core

The synthesis, characterization and mesomorphic properties of a new type of liquid crystalline compound, the 2,5-bis(3,4,5-trialkoxyphenyl)-1,3,4-oxadiazoles, 3a-3h, are reported. These heterocyclic compounds are derived from unsaturated 1,3,4-oxadiazole as the core group, and obtained by the condensation reaction of 3,4,5-trialkoxybenzoic acid N-(3,4,5-trialkoxybenzoyl)-hydrazides and phosphorus oxychloride in toluene under reflux. All compounds were characterized by ¹H and ¹³C NMR spectroscopy, and elemental analysis. The mesomorphic properties of these and the related compounds 1, 2 were characterized and studied by differential scanning calorimetry and polarizing optical microscopy. The formation of columnar mesophases was found to be dependent on the numbers of alkoxy sidechains. The compounds 3 exhibited hexagonal columnar (Col_h) phases, however compounds 1, 2 formed crystalline phases. Compounds 3b-3e with shorter carbon chains were room temperature liquid crystals. Polar induction by nitrogen and/or oxygen atoms on the heterocyclic core ring might be responsible for the formation and better observed mesomorphic properties in this type of compound.     

Synthesis and in vitro antibacterial activity of new oxoethylthio-1,3,4-oxadiazole derivatives

In the present investigation, a series of 2(4-pyridyl)-5[(aryl/heteroarylamino)-1-oxoethyl]thio-1,3,4-oxadiazole were synthesized using isonicotinohydrazide and substituted aryl/heteroaryl amines using pyridine as solvent. Newly synthesized compounds were tested for their in vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv using the BACTEC 460 radiometric system. Among the synthesized compounds, compounds 2(4-pyridyl)-5((2-nitrophenylamino)-1-oxoethyl)thio-1,3,4-oxadiazole (5e), 2(4-pyridyl)-5((4-nitrophenylamino)-1-oxoethyl)thio-1,3,4-oxadiazole (5g) and 2(4-pyridyl)-5((2-pyrrolylamino)-1-oxoethyl)thio-1,3,4-oxadiazole (5k) produced highest efficacy and exhibited >90% inhibition at a concentration of 0.0077, 0.0052 and 0.0089 μM, respectively. All the new compounds were pharmacologically evaluated for their in vitro Antimicrobial activity.     

Synthesis,anticancer activity and molecular docking studies of novel pyrido[1,2-a]pyrimidin-4-one derivatives

A series of novel triazolothione, thiadiazole, triazole, and oxadiazole-functionalized pyrido[1,2-a]pyrimidin-4-ones 6a–6l and 7a–7f were prepared, starting from pyridine derivatives 1a and 1b. All the compounds 6a–6l and 7a–7f were screened against four human cancer cell lines (HeLa, COLO205, Hep G2, and MCF 7), among which compounds 6d, 6h, 6j, 7b, and 7e showed promising anticancer activity. Molecular docking studies showed good binding energy and exhibited interactions and better lower free energy values, indicating more thermodynamically favored interaction.     

Synthesis,biological evaluation and molecular docking studies of novel 2-(2-cyanophenyl)-N-phenylacetamide derivatives

A series of novel 2-(2-cyanophenyl)-N-phenylacetamide derivatives 3(a-u) were designed and synthesized via selective amidation of methyl-2-(2-cyanophenyl)acetates over amidine formation by using AlMe₃ as catalyst in good yields. All the newly synthesized derivatives were well characterized by ¹H NMR, ¹³C NMR, FTIR and HRMS spectral techniques. All the synthesized title compounds were evaluated for their in vitro anticancer activity against three cancer cell lines. Among all compounds, 3i (IC₅₀?=?1.20 μM, IC₅₀?=?1.10 μM), 3j (IC₅₀?=?0.11 μM, IC₅₀?=?0.18 μM), 3o (IC₅₀?=?0.98 μM, IC₅₀?=?2.76 μM) showed excellent inhibitory activity than the standard Etoposide (IC₅₀?=?2.11 μM, IC₅₀?=?3.08 μM) against MCF-7 and A-549 cell lines, respectively. Docking analysis of all the compounds with the human topoisomerase II revealed that the compound 3j fitted well in the active site pocket, showing the best docking score of 158.072 kcal/mol.

     

Synthesis and biological evaluation of 5-methyl-4-phenyl thiazole derivatives as anticancer agents

Abstract

New N-(5-methyl-4-phenylthiazol-2-yl)-2-(substituted thio)acetamides were synthesized and studied for their anticancer activity. The title compounds were procured by reacting 2-chloro-N-(5-methyl-4-phenylthiazol-2-yl)acetamide with some mercapto derivatives. The structural elucidation of the compounds was performed by ¹H-NMR, ¹³C-NMR and LC-MS/MS spectral data and elemental analyses. The synthesized compounds were investigated for their antitumor activities against A549 human lung adenocarcinoma cells and NIH/3T3 mouse embryoblast cell line for determining their selective cytotoxicity. 2-[(1-methyl-1H-tetrazol-5-yl)thio]-N-(5-methyl-4-phenylthiazol-2-yl)acetamide (4c) showed high selectivity, and whose IC₅₀ value was determined as 23.30?±?0.35?µM and >1000?µM against A549 human lung adenocarcinoma cells and NIH/3T3 mouse embryoblast cell lines, respectively. 2-[(1-Methyl-1H-imidazol-2-yl)thio]-N-(5-methyl-4-phenyl thiazol-2-yl)acetamide (4a) and 2-[(1-Methyl-1H-tetrazol-5-yl)thio]-N-(5-methyl-4-phenyl thiazol-2-yl)acetamide (4c) exhibited the highest apoptosis percentage among those tested, but not as high as the standard, cisplatin.     

Synthesis,characterization, and hypoglycemic efficacy of nitro and amino acridines and 4-phenylquinoline on starch hydrolyzing compounds: an in silico and in vitro study

α-Amylase and α-Glucosidase are important therapeutic targets for type II diabetes. The present focus of our study is to elucidate the hypoglycemic activity of novel compounds through in vitro and in silico studies. Here, we synthesized the nitro acridines (3a–3c), amino acridines (4a–4c), and nitro phenylquinoline (3d) and amino phenylquinoline (4d) using a multi-step reaction protocol in good yields. All the above derivatives were screened for molecular docking, α-Amylase and α-Glucosidase inhibitory activities utilizing acarbose as standard drug. In silico studies were performed to explore the binding ability of compounds with the active site of α-Amylase and α-Glucosidase enzymes. The in vitro antihyperglycemic report of 3c exhibits the maximum inhibitory activity with IC₅₀ values of 200.61?±?9.71 μmol/mL and 197.76?±?8.22 μmol/mL against α-Amylase and α-Glucosidase, respectively. Similarly, the compound 3a exhibits IC₅₀ values of 243.78?±?13.25 μmol/mL and 296.57?±?10.66 μmol/mL, and 4c exhibits IC₅₀ values of 304.28?±?3.51 μmol/mL and 278.86?±?3.24 μmol/mL with a significant p?<?0.05 in both enzyme inhibitions. In addition, the presence of diverse functional moieties in synthesized compounds may provide a strong inhibitory action against the abovementioned enzymes compared with standard acarbose inhibition (IC₅₀, 58.74?±?3.68 μmol/mL and 49.39?±?4.94 μmol/mL). Also, the docking studies provided an excellent support for our in vitro studies. The outcome of these studies recommends that the tested compounds might be treated as potential inhibitors for the starch hydrolyzing enzymes in type II diabetes.

     

Optimized POCl3-assisted synthesis of 2-amino-1,3,4-thiadiazole/1,3,4-oxadiazole derivatives as anti-influenza agents

Although recent decades have witnessed the synthesis of 1,3,4-thiadiazoles via phosphorus POCl₃-promoted cyclization reaction, simultaneous access to 2-amino-1,3,4-thiadiazole and 2-amino-1,3,4-oxadiazole analogs remains unexpected and elusive. Herein, a detailed regiocontrolled synthesis of 2-amino-1,3,4-thiadiazoles in good to high yields with good regioselectivities from readily available thiosemicarbazides using POCl₃ was disclosed. Meantime, to establish a comprehensive structure–activity relationship, 2-amino-1,3,4-oxadiazole derivatives as single regioisomers were prepared via EDCI·HCl-triggered cyclization of the thiosemicarbazide intermediates. The in vitro anti-influenza assays proved that the selected compounds with the pyrazine/pyridine ring exhibited certain inhibitory activities against influenza A virus strains A/HK/68 (H3N2) and A/PR/8/34 (H1N1) in MDCK cells. Among them, N-(adamantan-1-yl)-5-(5-(azepan-1-yl)pyrazin-2-yl)-1,3,4-thiadiazol-2-amine (4j) was the most active compound, and exhibited favorable activity with EC₅₀ values of 3.5 μM and 7.5 μM, respectively. In addition, the molecular docking results explained the reason why compound 4j had dual inhibitory activity and revealed the reasonable binding mode of this compound with the M2-S31N and M2-WT ion channels. This compound had the potential to be further developed as an anti-influenza drug.