Compounds 4a-f Research Articles

Synthesis of new N-(3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl)pyridine-3-carboxamide derivatives and evaluation of their anti-influenza virus and antitubercular activities.

We here report the synthesis, structural characterization, and evaluation of the antiviral and antitubercular activities of a novel series of hybrid spirothiazolidinone derivatives (2a-f and 3a-f) containing the nicotinohydrazide moiety, which is an isomer form of the approved antitubercular drug isoniazid. When evaluated for activity against influenza A/H1N1, A/H3N2, and B viruses, three of the new compounds proved to possess specific antiviral activity against the influenza A/H3N2 virus. The most active analog 3a, bearing a 2,8-dimethyl group at the spiro ring, displayed an antiviral EC50 value of 5.2 µM. Compound 3a produced no cytotoxicity at 100 µM, the highest concentration tested, giving a selectivity index of at least 19. Structure-activity relationship analysis indicated that the absence of the methyl substituent at the 2-position and the presence of a bulky substituent at the 8-position of the spirothiazolidinone system caused a significant decrease in antiviral activity. The in vitro antitubercular activity of compounds 2a-f and 3a-f was determined for six different drug-sensitive/drug-resistant laboratory strains and clinical isolates of Mycobacterium tuberculosis. Compounds 2c, 2d, 3b, 3c, and 3d showed weak antitubercular activity against different strains, with MIC values of 125-250 μM.

Design, synthesis, docking study, and anticancer evaluation of novel bis-thiazole derivatives linked to benzofuran or benzothiazole moieties as PI3k inhibitors and apoptosis inducers

A molecular hybridization approach was used to construct and develop a variety of new bis-thiazoles coupled to benzofuran or benzothiazole moieties as anticancer drugs. The target compounds 6a-f and 7a-f were synthesized by reacting the respective bis-thiosemicarbazones 5a–f with bromoacetylbenzofuran or bromoacetybenzothiazole. Several analytical and spectroscopic techniques were used to characterize all of the products. Using the MTT assay, compounds 6a-f and 7a-f were tested for cytotoxicity against three human tumor cell lines: hepatocellular carcinoma (HEPG-2), colorectal carcinoma colon cancer (HCT-116), and human breast cancer (MCF7). The results showed that 6c and 7e had strong antitumor activity against HePG2, MCF7, and HCT-116, with IC50 values of 6.89, 9.94, and 12.67 µM for 6c and 8.37, 7.31, and 24.86 µM for 7e, respectively, when compared to the standard reference drug, doxorubicin (IC50 =5.50, 5.23 and 8.87 µM, respectively). The most active drugs' enzyme inhibition and cell cycle apoptosis properties were investigated further. Compound 6c's apoptotic and necrotic properties were promising. P53 and cyclinB1 gene expressions were also examined using Western Blot to investigate changes in apoptosis and cell cycle-related protein expression. The results showed up-regulation of P53 and down-regulation of cyclinB1 and were found to be inconsistent with those obtained by chemotherapeutics sorafenib, fluorouracil, and methotrexate. Interestingly, the molecular docking study indicated that chemicals 6c, 6d, and 7e could all be lodged in the active pocket of the 4JPS enzyme via various interactions.

Synthesis, Characterization and In Vitro Pharmacological Screening of 3, 4-Dihydropyrimidin-2-one Derivatives

Reaction of ethyl-6-methyl–2-oxo-4-phenyl-1, 2, 3, 4- tetrahydropyrimidin-5-carboxylates (1) with hydrazine hydrate yielded 6-methyl-2-oxo-4-phenyl-1, 2, 3, 4- tetrahydropyrimidin-5-carbohydrazide (2). These products on reaction with cyanogen bromide gave 5- (5-amino 1, 3, 4-oxadiazol-2-yl)-6-methyl-4-phenyl- 3,4-dihydropyrimidin-2 (1H)-ones (3). The resultant amino-oxadiazolylpyrimidinones were condensed with substituted aromatic aldehyde to obtain various 5-(5- {[-(4-substituted phenyl) methylidene]-amino}-1, 3, 4- oxadiazol-2-yl)-6-methyl-4-phenyl-3, 4-dihydropyrimidin- 2-one (4a-f). These products were characterized by IR, 1H NMR, mass spectra and elemental analysis. The synthesized compounds (4a-f) were evaluated for their antimicrobial activity against two gram positive and two gram negative bacteria along with two fungal species /yeast strains. All the synthesized compounds showed good antimicrobial activity. In addition, the newly synthesized compounds were screened for their antioxidant properties. The results showed that the compounds 5-{5-[(4-chlorobenzylidene)-amino]-1, 3, 4- oxadiazol – 2 –yl } -6 – methyl – 4 - phenyl-3, 4 dihydropyrimidin -2 (1H) -one (4b) and 5-{5-[(4- hydroxybenzylidene)-amino]-1,3,4-oxadiazol-2-yl}-6- methyl-4-phenyl-3,4-dihydro pyrimidin- 2 (1H)-one (4d) revealed the highest antimicrobial and antioxidant activity throughout this work.

1,3,5-Tris[(2H-tetrazol-5-yl)methyl]isocyanurate and Its Tricationic Salts as Thermostable and Insensitive Energetic Materials

Various energetic salts (3a-f) were obtained from 1,3,5-tris[(2H-tetrazol-5-yl)methyl]isocyanurate (3), while N2,N4,N6-tri(1H-tetrazol-5-yl)-1,3,5-triazine-2,4,6-triamine (5) and N,N'-{6-[(1H-tetrazol-5-yl)amino]-1,3,5-triazine-2,4-diyl}bis[N-(1H-tetrazol-5-yl)nitramide] (6) were obtained from cyanuric chloride via a simple, efficient two-step synthetic route from inexpensive starting materials. Compounds 3a-f and 6 show excellent detonation properties (VOD = 7876-8832 m s-1, and DP = 20.73-30.0 GPa), a high nitrogen content (>62%), and high positive heats of formation (205.2-1888.9 kJ mol-1) with excellent thermostability and remarkable insensitivity.

Molecular docking and anticancer evaluation of some newly synthesized 4-aryl-2-(2-oxopropoxy)-6-(cyclohexyl)nicotinonitrile and their furo[2,3-b]pyridine derivatives

1-(3-Amino-6-cyclohexylfuro[2,3-b]pyridin-2-yl)ethan-1-one derivatives 3a-f carrying aryl substituents at position 4 were synthesized in two steps. The 6-cyclohexyl-2-oxo-1,2-dihydropyridine-3-carbonitriles 1a-f, as key compounds, were converted to the corresponding 6-cyclohexyl-2-(2-oxopropoxy)nicotinonitriles 2a-f, followed by the Thorpe-Ziegler ring cyclization to compounds 3a-f. Moreover, the in vitro cytotoxicity evaluation of the new compounds has been assessed against four cancer cell lines: A549 (lung carcinoma), HCT116 (colon), PACA2 (Pancreatic cancer) and MCF7 (Human Caucasian breast adenocarcinoma), utilizing doxorubicin as a reference drug. The results revealed that the nicotinonitrile derivatives 2a-f were the most potent and selective for the lung carcinoma (A549) inhibition, in particular compounds 2d and 2f, while the furo[2,3-b]pyridine derivatives 3b,c,e,f represented selective promising inhibition activity against the breast cancer (MCF7) cell line. Finally, a good correlation was obtained between the observed cytotoxicity evaluation of compounds 2d and 2f against A549 (lung carcinoma), from one side, and the molecular descriptors from another side.

Synthesis, antimicrobial, and antitubercular evaluation of new Schiff bases with in silico ADMET and molecular docking studies

Schiff bases are a proven moiety in antitubercular drug discovery and the antitubercular drug development. Drug discovery is a never-ending process due to evolving drug resistance by the bacteria, as a result, there is a need of developing new antitubercular drugs. In this continuous process of antitubercular drug discovery, new series of Schiff bases are synthesized using quinoline carbohydrazide upon coupling with different aldehydes in ethanolic media through multistep synthesis. These synthesized compounds were purified and characterized by different spectroscopic techniques. The molecules were in vitro screened for antifungal and antibacterial potential by Agar well diffusion assay, antitubercular activity by using microplate Alamar blue assay, and an attempt has been made to study the in-silico relationship between new Schiff base derivatives 4a-f and the crystal structure of M. tuberculosis (5V3Y) protein by molecular docking studies. Synthesized compounds 4a-f show good interaction with the crystal structure of M. tuberculosis protein (5V3Y) and fulfill ADMET characteristics in silico experiments. Among the compounds tested, compound 4d was found to be active against bacteria and fungi. Compound 4b was found to be sensitive against M. tuberculosis at 50 µg/mL concentration.

Synthesis, solubility and antitumor activity of maslinic acid derivatives

Maslinic acid (MA), a pentacyclic triterpenoid obtained from olives that is characterized by its antiproliferative activity in tumor cells, has become a promising molecule that could be modified to improve cancer treatment. In this work we have synthesized in good yields several new MA conjugates, including glycerin, oligo(ethylene glycol), and amino acid derivatives (compounds 3a-f). The synthesis offers the possibility of recovering unreacted MA, and thus the scaling up of the process. For the tyramine-MA conjugate, compound 3f or TMA, the preparation has been optimized to a one-pot reaction. Solubility of conjugates in polar solvents has been measured, showing a marked increase of solubility with respect to MA. Moreover, we selected the tyramidyl maslinic acid conjugate (3f or TMA) to determine antitumor capacity over a wide range of cancer cell lines, including glioblastoma, melanoma, breast, lung, colorectal and pancreatic cancer. Our results clearly demonstrated that TMA induced higher cytotoxicity in all cancer cell types compared to MA. TMA was more effective than MA, especially in breast cancer cells (MCF-7) and melanoma cells (B16–F10) where IC50 reductions of 4.12 and 4.72, respectively, was detected. Interestingly, TMA showed a remarkable antitumor ability against the resistant HCT-15 colon cancer cell line. Furthermore, we demonstrated for the first time a relevant effect of a MA derivative against glioblastoma cells (A172 and SF-268). These results suggest that TMA is able to improve the antitumor characteristics of MA in a wide range of cancers and that it may be a promising compound for various tumor types, including resistant cancer.

Synthesis, Characterization and Biological Activities of Pyrazole Based Heterocycles

In this work, a unique pyrazolyl compounds comprising flourine and thiophene were synthesized. In brief, esters 3a-f were synthesized by reacting thiophene and pyrazolyl acid (1) with various 2-hydroxyacetophenones (2a-f). The 1,3-diketones 4a-f were formed by Baker- Venkataraman rearrangement of esters 3a-f. Compounds 4a-f were cyclized to form chromene derivatives 5a-f, which further converted into pyrazolyl derivatives 6a-f. The majority of the compounds in series 3a-f, 4a-f, 5a-f and 6a-f showed promising antibacterial activity against S. typhii, S. aureus, B. subtilis and E. coli. Compounds 4e and 4f exhibited considerable antifungal activity against A. niger, while the majority of the compounds had promising activity against T. viride. At 1 mg/mL concentration, some of the synthesized compounds shown potential α-amylase inhibitory action.

Synthesis and alpha-glucosidase inhibition of some novel quinazolin-4(3H)-one derivatives bearing a 2-thioxothiazolidine-4-one heterocycle

Aimed at finding new compounds capable of inhibiting the enzyme glucosidase, six new N-(5-aryliden-4-oxo-2-thioxothiazolidin-3-yl)-2-{[4-oxo-3-(p-tolyl)-3,4-dihydro quinazolin-2-yl]thio}acetamides 5a-f were synthesized by the reaction of N-(4-oxo-2-thioxothiazolidin-3-yl)-2-{[4-oxo-3-(p-tolyl)-3,4-dihydroquinazolin-2-yl]thio}acetamide 4 and appropriate aromatic aldehydes. The structural features of all synthesized compounds were confirmed based on their spectral data, including HR-MS, IR, 1H-NMR and 13C-NMR spectra. The results of the evaluation of the α-glucosidase enzyme inhibitory activity of acetamide compounds 5a-f showed that these compounds possess good inhibitor activity against the α-glucosidase enzyme, in which compound 5a containing the 4-methylbenzylidene moiety exhibited the best activity. Furthermore, molecular docking was conducted to better comprehend the binding properties of the compounds. The results indicated that synthesized quinazoline derivatives are potential antidiabetic compounds.

N,N-Bis(Substituted benzyl)-β-Carbolineum Bromides as Potential Anticancer Therapeutics: Design, Synthesis, Cytotoxicity, Drug-DNA Intercalation and In-Silico Binding Properties

• Synthesized of novel N 2 ,N 9 - bis(substituted benzyl)- β -carbolineum bromide derivatives • In-vitro cytotoxicity against human cancer cell lines HT-29, HeLa, HepG2 and K562 • In-vitro cytotoxicity against non-cancer cell lines BALB/c3T3 and Hs-27 • 2,9-Bis(3-methoxybenzyl)- β -carbolineum bromides showed potent cytotoxicity • It's having less cytotoxicity against non-cancer cell lines tested • It's intercalated with calf thymus DNA • Molecular docking results revealed its binding ability to DNA through intercalation The present study reports a series of novel N 2 , N 9 -bis(substituted benzyl)- β -carbolineum bromides ( 4a-f ) synthesized from L-tryptophan in three steps with excellent yields (>80%). The structures of synthesized compounds 4a-f were confirmed by 1 H- and 13 C-NMR, FT-IR, LC-MS (ESI-MS) spectrum and elemental analysis. Meanwhile, the crystal structure for compound 4f was determined by X-ray single-crystal diffraction. The crystal belongs in monoclinic space group in P12 1 /c 1 space group with a = 13.253(6) Å, b = 20.809(10) Å, c = 9.116(6) Å, β = 107.215(13)°, V = 2401.4(19) Å 3 and Z = 4, F(000) = 1048, D c = 1.403 Mg/m 3 and µ = 1.743 mm −1 . Compounds 4a-f were evaluated for their in-vitro anticancer activity against selected human cancer cell lines, such as HT-29 (colorectal adenocarcinoma), HeLa (cervical carcinoma), HepG2 (hepatocellular carcinoma) and K562 (chronic myelogenous leukaemia, CML). Results showed that compounds 4a-f exerted excellent cytotoxicity effect with IC 50 values ranging from 0.36-1.08 µM against K562 human CML cell line. It was found that synthesized β -carbolines are much less toxic towards non-cancer cell lines BALB/c3T3 and Hs-27, in comparison to cisplatin and doxorubicin, which were employed as positive controls. To investigate the binding mode of these compounds against DNA, spectroscopic studies were conducted. Subsequent UV-Visible and in-silico (molecular docking) studies revealed that compound 4f interacts with DNA through intercalation. Based on the present findings, it was suggested that compound 4f has a great potential to be developed as a novel anticancer agent.

Synthesis, Crystal Structure, Biological Evaluation, DFT Calculations and Third Order Nonlinear Optical Studies of Pyrazolines

• Synthesis of a novel series of pyrazolines. • Chemical structures were confirmed by crystal study and spectral techniques. • In-silico and anticancer properties of compounds were tested against MCF-7 and HCT116 cell lines. • DFT computational studies were carried out to understand structural, absorption, and first static hyperpolarizability properties. • NLO properties were studied using open/closed aperture z-scan techniques. Novel pyrazoline derivatives were synthesized and characterized by FTIR, NMR, UV-visible, and mass spectral studies. All the synthesized compounds 6a-f were screened for anticancer activity against MCF-7 and HCT 116 cell lines via SRB assay. Among the synthesized pyrazolines 6b and 6f showed appreciable anticancer activity. The molecular docking study was done with two proteins (PDB No: 1M17 and 5ZTO) to study the binding interactions of the compounds with proteins. ADME study showed that the compounds exhibited drug-likeness properties, following Lipinski's rule of five. The molecular structure of compound 6b was studied using the single-crystal X-ray diffraction method. The structural, absorption and first static hyperpolarizability properties of the compound 6b were studied using density functional theory (DFT) calculations. The experimental data and calculated FTIR and UV-visible spectral data are in good agreement. The third order nonlinear optical properties were studied using open and closed aperture z-scan techniques. The compound 6b showed nonlinear absorption ( β ) of 1.94 × 10 − 11 m/W at intensity ( I 0 ) is 4.49 GW / c m 2 . Third order nonlinear susceptibility is of the order of 10 −12 esu and this indicates the molecule has the potential to be used in nonlinear optical device applications.

Bile-Acid-Appended Triazolyl Aryl Ketones: Design, Synthesis, In Vitro Anticancer Activity and Pharmacokinetics in Rats.

A library of bile-acid-appended triazolyl aryl ketones was synthesized and characterized by detailed spectroscopic techniques such as 1H and 13C NMR, HRMS and HPLC. All the synthesized conjugates were evaluated for their cytotoxicity at 10 µM against MCF-7 (human breast adenocarcinoma) and 4T1 (mouse mammary carcinoma) cells. In vitro cytotoxicity studies on the synthesized conjugates against MCF-7 and 4T1 cells indicated one of the conjugate 6cf to be most active against both cancer cell lines, with IC50 values of 5.71 µM and 8.71 µM, respectively, as compared to the reference drug docetaxel, possessing IC50 values of 9.46 µM and 13.85 µM, respectively. Interestingly, another compound 6af (IC50 = 2.61 µM) was found to possess pronounced anticancer activity as compared to the reference drug docetaxel (IC50 = 9.46 µM) against MCF-7. In addition, the potent compounds (6cf and 6af) were found to be non-toxic to normal human embryonic kidney cell line (HEK 293), as evident from their cell viability of greater than 86%. Compound 6cf induces higher apoptosis in comparison to 6af (46.09% vs. 33.89%) in MCF-7 cells, while similar apoptotic potential was observed for 6cf and 6af in 4T1 cells. The pharmacokinetics of 6cf in Wistar rats showed an MRT of 8.47 h with a half-life of 5.63 h. Clearly, these results suggest 6cf to be a potential candidate for the development of anticancer agents.

Synthesis, anticancer activity and mechanism of action of new phthalimido-1,3-thiazole derivatives

In this work, 22 new compounds were obtained and evaluated for their cytotoxic activity on peripheral blood mononuclear cells (PBMC) and eight different tumor cell lines. All compounds displayed IC50 values above 100 μM when assayed against PBMCs. The cytotoxic assays in tumor cell lines revealed that sub-series of phthalimido-bis-1,3-thiazoles (5a-f) exhibited the best anti-tumor activity profile, presenting viability values below 59 %. As a result, the IC50 value was calculated for compounds 5a-f and 4c, and compounds 5b and 5e were selected for further assays due to their best IC50s. Considering the results presented by the sub-series 5a-f, the importance of the 1,3-thiazole ring in improving the anti-tumor activity was pointed out. Together, the results highlighted the anti-tumor activity of phthalimido-bis-1,3-thiazole derivatives.

English

In the search for new drugs possessing the activities we have sought to synthesize new quinoline derivatives which constitute a basic heterocyclic support of some drugs such as quinine, chloroquine marketed under the name Nivaquine®, Mefloquine®, used in the treatment of malaria. The objective of this work is to contribute to the synthesis of new derivatives of quinoline. It consists in introducing heterocycles such as benzimidazole in its 3-position. The introduction of heterocyclics, aryls or alkyls on the pyrrolic nitrogen of benzimidazole, allowed us to obtain compounds 3a-f. The chemical structures of all these compounds were determined by NMR (1H, 13C) and electron impact mass spectrometry. Key words: Quinoline, benzimidazole, aryls, alkyls.

A Piperine-Based Scaffold as a Novel Starting Point to Develop Inhibitors against the Potent Molecular Target OfChtI.

The insect chitinase OfChtI from the agricultural pest Ostrinia furnacalis (Asian corn borer) is a promising target for green insecticide design. OfChtI is a critical chitinolytic enzyme for the cuticular chitin degradation at the stage of molting. In this study, piperine, a natural amide compound isolated from black pepper, Piper nigrum L., was discovered for the first time to have inhibitory activity toward OfChtI. The compound-enzyme interaction was presumed to take place between the piperine benzo[d][1,3] dioxole skeleton and subsite -1 of the substrate-binding pocket of OfChtI. Hence, on the basis of the deduced inhibitory mechanism and crystal structure of the substrate-binding cavity of OfChtI, compounds 5a-f were designed and synthesized by introducing a butenolide scaffold into the lead compound piperine. The enzymatic activity assay indicated that compounds 5a-f (Ki = 1.03-2.04 μM) exhibited approximately 40-80-fold higher inhibitory activity than the lead compound piperine (I) (Ki = 81.45 μM) toward OfChtI. The inhibitory mechanism of the piperonyl butenolide compounds was elucidated by molecular dynamics, which demonstrated that the introduced butenolide skeleton improved the binding affinity to OfChtI. Moreover, the in vivo activity assay indicated that these compounds also displayed moderate insecticidal activity toward O. furnacalis. This work introduces the natural product piperine as a starting point for the development of novel insecticides targeting OfChtI.

Nitrogen and selenium containing heterocycles: Part-2: Synthesis and antimicrobial activities of novel S-5-(2-oxo-2H-selenopyrano [2,3-b]quinolin-3-yl)-1,3,4-oxadiazol-2-yl-2-cyanoethanethioates

Abstract Synthesis and antimicrobial activities of novel S-5-(2-oxo-2H-selenopyrano [2,3-b]quinolin-3-yl)-1,3,4-oxadiazol-2-yl-2-cyanoethanethioates derivatives was undertaken employing a convenient and easily accessible procedure. A Series of S-5-(2-oxo-2H-selenopyrano[2,3-b]quinolin-3-yl)-1,3,4-oxadiazol-2-yl 2-cyanoethanethioates are synthesized by a simple and efficient one-pot reaction of substituted 3-(5-mercapto-1,3,4-oxadiazol-2-yl)-2H-selenopyrano[2,3-b]quinolin-2-ones with 2-cyanoacetyl chloride and potassium carbonate in the presence dimethyl formamide as a solvent. This reaction sequence involves a nucleophilic substitution of -S-H of 1,2,3-oxadiazole with 2-cyanoacetyl chloride. The structures of all the synthesized products were confirmed with their elemental analysis, IR,1H NMR and mass spectral analysis. All the newly synthesized compounds (2a-f) were screened for in vitro antimicrobial activities (Minimum Inhibitory Concentration (MIC) of three (Staphylococcus aureus, Micrococcus roseus) and (Escherichia coli) by disk diffusion method using ampicillin as positive and Dimethylformamide (DMF) as negative control. The tested, compounds 2d and 2e were highly active against S. aureus-ATCC 25953 and M. roseus-NCTC 07523 (gram positive) and moderately active against E. coli-ATCC 25922 (gram negative), compound 2c was slightly active against M. roseus and E. coli. Compound 2e was slightly active against S. aureus and M. roseus and compounds 2a and 2b were slightly active against M. roseus.

Synthesis, Characterisation and Mesophase Transition of Hexasubstituted Cyclotriphosphazene Molecules with Schiff Base and Azo Linking Units and Determination of Their Fire Retardant Properties

Hexakis(oxy-4-benzaldehyde)cyclotriphosphazene, 1 was successfully synthesised by nucleophilic substitution reaction between hexachlorocyclotriphosphazene, HCCP and 4-hydroxybenzaldehyde. Azotization reaction of p-nitroaniline with phenol formed 4-(4-nitrophenylazo)phenol, 2 which was alkykated with heptyl, nonyl, decyl, dodecyl and tetradecylbromide to give a series of nitro compounds, 3a-e. Reduction of 3a-e and 2 formed the subsequent amine compounds 4a-f, 4-(4-alkyloxyphenylazo)phenylamine. Another similar reaction of protected aniline with a series of substituted aniline formed a series of compounds 4g-i. A series of hexasubstituted cyclotriphosphazene molecules containing Schiff base and azo linking units, 5a-i were synthesised from the reaction between intermediates 1 and 4a-i. Further reduction of compound 5i afford compound 5j with amino terminal end. All the synthesised intermediates and compounds were characterised using Fourier Transform Infrared spectroscopy (FT-IR), 1H and 13C Nuclear Magnetic Resonance spectroscopy (NMR) and CHN elemental analysis. The liquid crystal properties of intermediates and final compounds were determined using Polarised Optical Microscope (POM) and their phase transitions confirmed using Differential Scanning Calorimetry (DSC). Only intermediates 3a-e showed mesophase of smectic A and compounds 5a-e with alkoxy chain were mesogenic with smectic A and nematic phases. In addition, compound 5h exhibited nematic phase only. However, all the other intermediates and compounds were found to be non-mesogenic. Furthermore, the fire retardant of final compounds were determined using Limiting Oxygen Index (LOI) testing. The LOI value of pure polyester resin was increased from 22.53 to 24.71% when incorporated with 1 wt% of HCCP. Moreover, all the final compounds showed a positive in LOI value the highest LOI value was belonged to compound 5i with 27.90%.

Synthesis, molecular modeling and biological evaluation of new benzo[4,5]thieno[3,2-b]pyran derivatives as topoisomerase I-DNA binary complex poisons

A series of new benzo[b]thiophenes 2a-f and benzo[4,5]thieno[3,2-b]pyran derivatives 3a-f and 4a-f were synthesized and their structures were confirmed by elemental analyses and spectral data. All synthesized compounds were evaluated by the National Cancer Institute (NCI, USA) against 60 human tumor cell lines. Compounds 3a-f and 4a-f showed potent cytotoxic effects in one dose assay with mean growth inhibition ranging from 62% to 80%. Six compounds 3a, 3d, 3e, 3f, 4d and 4e were selected by NCI, USA for five dose evaluation against 60 human tumor cell lines. Compounds 3a, 3d, 3e and 3f exhibited very potent and broad spectrum cytotoxicity against almost all cancer cell lines with mean concentration that yield 50% growth inhibition (MG-MID GI50) of 0.1–0.58 µM and mean concentration that produce 100% growth inhibition (MG-MID TGI) of 6.03–10.00 µM. Compounds 4d and 4e exhibited very potent and selective cytotoxic activity against MDA-MB-435 subpanel (melanoma cancer) with GI50 of 0.45 µM and 0.59 µM, respectively. The mechanism of antiproliferative activity was determined for the most active compounds 3a, 3d, 3e, 3f, 4d, and 4evia measuring their half maximal inhibitory concentration (IC50) against topoisomerase I enzyme at different concentrations. Compounds 3a and 3e exhibited excellent activity compared with reference drugs with IC50 of 0.295 µM and 0.219 µM, respectively. Plasmid DNA nicking assay verified that these compounds are topoisomerase I poisons not suppressors. The active compound 3e induced a significant disruption in the cell cycle profile parallel to its effect on apoptosis induction.

N-(5-Morpholino-2-arylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)carboxamides as Potential Fer/FerT Kinase Inhibitors. Homology Modeling, Molecular Docking Studies and In Silico ADMET Profiling

This study has comparatively evaluated the degree of affinity of N-(5-morpholino-2-arylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)carboxamides 2a-f and 6-(4-isopropylphenyl)-2-(4-((4-methylpiperazin-1-yl)methyl)piperidin-1-yl)imidazo[2,1-b][1,3,4]thiadiazole (E260) to Fer kinase using molecular modeling methods. The Fer kinase model has been generated by homology modeling. It has been shown that compounds 2a-f predominantly form stronger complexes with this enzyme than the reference drug E260. In silico ADMET prediction of the properties of compounds 2a-f and E260 has been carried out. Comparative analysis of the obtained results has shown that compounds 2a-f are not inferior to the reference drug - E260 and even surpass it in most parameters. All examined compounds 2a-f have shown good results under in silico experimental conditions and can be recommended for further study on tumor cell cultures.

Design, synthesis, PASS prediction, in-silico ADME and molecular docking studies of substituted-(Z)-3-benzylidine-5-aza-2-oxindole derivatives (Part-1)

Abstract In this research article we report a simple protocol for the synthesis of series novel of substituted (Z)-3-benzylidine-5-aza-2-oxindole derivatives (5a-f) by employing optimized reaction condition of Knoevenagel condensation. Among the reaction conditions attempted, the reaction in ethanol and piperidine at 80 °C afforded the desired products (5a-f) in satisfactory yields and enhanced purity via trituration and recrystallization. The physicochemical as well as spectroscopic evidences established the assigned structures of the compounds without any ambiguity. The anti-inflammatory proficiency assessment for the synthesized compounds has been carried out on the basis of Prediction of Activity Spectra for Substances (PASS) technique and compared with standard tenidap. Furthermore, to validate the results of PASS prediction, molecular docking studies of the synthesized compounds (5a-f) were carried out on the TNF-α target protein (PDB ID: 2AZ5 ). The compounds displayed less docking energies in the range of -6.9 to -7.5 Kcal/mol than tenidap (-8.8 Kcal/mol). Additionally, in silico ADME analysis was carried out to check drug ability and toxicity issues.