Preparation, DFT calculations, docking studies, antioxidant, and anticancer properties of new pyrazole and pyridine derivatives.

Seven novel pyrazole derivatives (4a-g) and four novel starting compounds incorporating substituted pyridine moieties were synthesized successfully. Cell viability assay for the tested compounds was performed, and the inhibitory concentrationlogarithmic 50 (LogIC50 ) values of the compounds were calculated after a 24-h treatment. Four of the examined compounds (3d, 3g, 4f, and 4g) showed comparable cytotoxic activity against CaCo-2 compared to the standard drug docetaxel at 0.1 and 1 µM concentrations. Although the LogIC50  of docetaxel was -0.678 µM for CaCo-2 cells at 24 h, the LogIC50 values of compounds were -0.794, -0.567, -0.657, and -0.498 µM, respectively. Five of the compounds (2d, 2g, 3d, 3g, and 4e) showed comparable cytotoxic activity against MCF-7 at 0.1 µM concentration compared to docetaxel (p < 0.05). Docking studies revealed the compounds have a good affinity to the active site of the human topoisomerase II ß enzyme. The antioxidant capacities of all compounds were determined using both 1,1-diphenyl-2-picrylhydrazyl and metal chelation methods. Although the compounds did not show significant antioxidant activity, relatively effective are compounds 3c, 3d, and 3g, which are hydrazine derivatives with approximately 50% antioxidant activity of standard antioxidants at concentrations of 62.5 and 125 µg/ml.

Synthesis of new 7-amino-3,4-dihydroquinolin-2(1H)-one-peptide derivatives and their carbonic anhydrase enzyme inhibition, antioxidant, and cytotoxic activities.

Six new monopeptides, seven new dipeptides, and two deprotected monopeptide dihydroquinolinone conjugates were prepared by the benzothiazole-mediated method and their structures were confirmed by nuclear magnetic resonance, mass, infrared spectroscopy, and elemental analysis methods. The human carbonic anhydrase (hCA) I and hCA II enzyme inhibition activities of the compounds were determined using the stopped-flow instrument. The synthesized peptide-dihydroquinolinone conjugates 2, 3, 6, 10, 13, and 15 showed inhibition against the hCA II enzyme in the range of 15.7-65.7 µM. However, none of the compounds showed inhibition of hCA I at a concentration of 100 µM. The antioxidant activities of the compounds were also examined using the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging method at concentrations of 12.5-125 µg/ml, but when compared with the standard antioxidant compounds α-tocopherol and butylated hydroxyanisole (BHA), weak antioxidant activities were detected. The cytotoxic effects of four compounds against the A549 and BEAS-2B cell lines were also investigated. Among the compounds studied, compound 7 was found to be most effective, with the IC50 values on the A549 cells for 48 and 72 h being 26.87 and 9.979 µg/ml, respectively, and the IC50 values on the BEAS-2B cells being >100 µg/ml. None of the tested compounds showed antimicrobial activity in the concentration range (800-1.56 µg/ml) studied.

Cytotoxic and antimicrobial potential of benzimidazole derivatives.

New benzimidazole derivatives were synthesized and their structures were characterized by spectroscopic and microanalysis techniques. The cytotoxic properties of ten benzimidazole derivatives, five of which were synthesized in our previous studies, were determined against the lung cancer cell line, A549, and the healthy lung epithelial cell line, BEAS-2B. Among the ten compounds tested, based on the 72-h incubation results, compound 12 was the most cytotoxic against the A549 cell line, whereas against the BEAS-2B cell line, it was as cytotoxic as cisplatin. The IC50 values of compound 12 were 3.98 and 2.94 µg/ml for A549 and BEAS-2B cells, respectively. The cisplatin values were 6.75 and 2.75 µg/ml for A549 and BEAS-2B cells, respectively. Compounds 10, 8, 7, and 13 showed toxic effects against A549 cells, but were less toxic against BEAS-2B cells than cisplatin. The antimicrobial activity of these compounds against pathogenic bacteria and yeasts was also evaluated based on their minimum inhibitory concentration (MIC) values. The compounds, except 12 and 13, generally showed higher antimicrobial activity against yeasts, compared with bacteria. Compound 12 showed better activity against Pseudomonas aeruginosa and Staphylococcus aureus than against Escherichia coli. Compounds 7, 8, and 11 were the most effective ones against the microorganisms, and yeasts were highly sensitive to these compounds with MIC values of 25-100 µg/ml.

Moringa oleifera leaves: could solvent and extraction method affect phenolic composition and bioactivities?

This study was carried out to evaluate the effect of extraction methods (direct maceration (DM) and successive maceration (SM)) and solvents (dichloromethane (DCM), ethyl acetate (EAc), butanol (But), and aqueous extraction (Aqu)) on the phenolic composition and biological activities of Moringa oleifera leaves cultivated for the first time in Tunisia. Total polyphenol content (TPC), total flavonoid content (TFC) and LC-MS analysis were performed for all extracts. Antioxidant potential by DPPH, metal chelating, and FRAP assays, antibacterial activity against Staphylococcus aureus (ATCC 29213) and Escherichia coli (ATCC 25922) by the minimum inhibitory concentration method (MIC) and cytotoxic properties against lung cancer cells (A549), were determined. Phenolic compounds and biological activities of M. oleifera leaves depend on the method and the solvent used for the extraction of these bioactive substances. The But extract prepared by SM method exhibited the highest amounts of TPC (103.06 ± 0.5 mg GAE/g DE) and showed the strongest potential antioxidant (CI50 = 0.26 mg/mL on DPPH test), antibacterial (MIC = 250 µg/mL) and cytotoxic activities (GI50 = 69.9 µg/mL). LC-MS analysis showed that 28 phenolic compounds of 33 tested standards were found in M. oleifera leaves. The But extract obtained by SM method exhibited the highest amounts of rutin, quercetin and syringic acid.

Synthesis and anticancer properties of novel hydrazone derivatives incorporating pyridine and isatin moieties.

Nine novel hydrazone derivatives (4a-i) incorporating pyridine and isatin moieties were synthesized through one-pot, four-component heterocyclic condensation reactions. The structures of all new compounds (2a-e, 3a, 3c-e, and 4a-e) were identified by 1 H nuclear magnetic resonance (NMR), 13 C NMR, and Fourier-transform infrared spectroscopic techniques and elemental analysis. Cell viability assays for the tested hydrazone derivatives were performed and the log IC50 values of the compounds were calculated after a 24-h treatment. All hydrazide derivatives tested showed a promising antitumor activity against A-2780 cells as compared with the standard drug docetaxel with a log IC50 value of 0.2200 µM (p < .05). Seven of the examined compounds (4b-e, 4g-i) showed high cytotoxic activity against A-2780 cells as compared with the standard drug docetaxel. Whereas the log IC50 of docetaxel was 0.2200 µM for A-2780 cells at 24 h, the IC50 values of these compounds were -0.4987, -0.4044, -0.8138, -0.3868, -0.6954, -0.4751, and 0.1809 µM, respectively. Three of the compounds, 4b, 4d, and 4i, showed high cytotoxic activity against MCF-7 cells as compared with docetaxel (p < .05). Whereas the log IC50 of docetaxel was 0.2400 µM for MCF-7 cells at 24 h, the log IC50 values of compounds 4b, 4d, and 4i were -0.1293, -0.1700, and 0.2459 µM, respectively.

Preparation, carbonic anhydrase enzyme inhibition and antioxidant activity of novel 7-amino-3,4-dihydroquinolin-2(1H)-one derivatives incorporating mono or dipeptide moiety.

New dipeptide-dihydroquinolinone derivatives were successfully synthesised by benzotriazole mediated nucleophilic acyl substitution reaction and their structures were elucidated by spectroscopic and analytic techniques. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the new compounds was determined against four human (h) isoforms, hCA I, hCA II, hCA IX and hCA XII. While all compounds showed moderate to good in vitro CA inhibitory properties against hCA IX and hCA XII with inhibition constants in the micromolar level (37.7-86.8 and 2.0-8.6 µM, respectively), they did not show inhibitory activity against hCA I and hCA II up to 100 µM concentration. The antioxidant capacity of the peptide-dihydroquinolinone conjugates was determined using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging method. Most of the synthesised compounds showed low antioxidant activities compared to the control antioxidant compounds BHA and α-tocopherol.

Synthesis and human carbonic anhydrase I, II, VA, and XII inhibition with novel amino acid-sulphonamide conjugates.

A series of amino acid-sulphonamide conjugates was prepared through benzotriazole mediated coupling reactions and characterised by 1H-NMR, 13C-NMR, MS, and FTIR spectroscopic techniques as well as elemental analysis. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the new compounds was determined against four human (h) isoforms, hCA I, hCA II, hCA VA, and hCA XII. Most of the synthesised compounds showed effective in vitro CA inhibitory properties. The new amino acid-sulphonamide conjugates showed potent inhibitory activity against hCA II, some of them at subnanomolar levels, exhibiting more effective inhibitory activity compared to the standard drug acetazolamide. Some of these sulphonamides were also found to be effective inhibitors of hCA I, hCA VA, and hCA XII, with activity from the low to high nanomolar range.

Synthesis carbonic anhydrase enzyme inhibition and antioxidant activity of novel benzothiazole derivatives incorporating glycine, methionine, alanine, and phenylalanine moieties.

Thirteen novel benzothiazole derivatives incorporating glycine, methionine, alanine, and phenylalanine were synthesised by facile acylation reactions through benzotriazole or DCC mediated reactions and their structures were identified by 1H-NMR, 13C-NMR, and FT-IR spectroscopic techniques and elemental analysis. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the new compounds was assessed against four human (h) isoforms, hCA I, hCA II, hCA V, and hCA XIII. Some of the synthesised compounds showed good in vitro carbonic anhydrase inhibitory properties, with inhibition constants in the micromolar level. The new amino acid benzothiazole conjugates found to be more effective against hCA V and hCA II inhibition. In vitro antioxidant activities of the novel compounds were determined by DPPH method. Most of the synthesised compounds showed moderate to low antioxidant activities compared to the control antioxidant compounds (BHA and α-tocopherol).

Synthesis and carbonic anhydrase inhibitory properties of novel 4-(2-aminoethyl)benzenesulfonamide-dipeptide conjugates.

Thirty novel sulfonamide derivatives incorporating dipeptide were synthesized by facile acylation through benzotriazole mediated reactions and their structures were identified by 1H NMR, 13C NMR, MS and FT-IR spectroscopic techniques and elemental analysis. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the new compounds was assessed against four human (h) isoforms, hCA I, hCA II, hCA IV and hCA XII. Most of the synthesized compounds showed excellent in vitro carbonic anhydrase inhibitory properties comparable to those of the clinically used drug acetazolamide (AAZ). The new unprotected dipeptide-sulfonamide conjugates showed very effective inhibitory activity, in the low nanomolar range against II and XII, being less effective as hCA I and IV inhibitors. Four of the thirty compounds also showed strong inhibitory activity against hCA XII compared to AAZ.

Synthesis of novel dipeptide sulfonamide conjugates with effective carbonic anhydrase I, II, IX, and XII inhibitory properties.

Twenty-four novel sulfonamide derivatives incorporating dipeptide tails were synthesized by facile acylation reactions of homosulfanilamide through benzotriazole or dicyclohexyl carbodiimide (DCC) mediated coupling reactions. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the new compounds was assessed against four human (h) isoforms, hCA I, hCA II, hCA IX and hCA XII. Most of the synthesized compounds showed good in vitro carbonic anhydrase inhibitory properties, with inhibition constants in the low nanomolar range. Particularly, the new dipeptide-sulfonamide conjugates incorporating Ala, Phe and Met in the dipeptide sequence, showed the most effective inhibitory activity against to CA IX and XII.

Synthesis and carbonic anhydrase I, II, IV and XII inhibitory properties of N-protected amino acid - sulfonamide conjugates.

N-protected amino acids (Gly, Ala and Phe protected with Boc and Z groups) were reacted with sulfonamide derivatives, leading to the corresponding N-protected amino acid-sulfonamide conjugates. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the new compounds was assessed against four human (h) isoforms, hCA I, hCA II, hCA IV and hCA XII. Among them, hCA II, IV and XII are antiglaucoma drug targets, being involved in aqueous humor secretion within the eye. Low nanomolar inhibition was measured against all four isoforms with the 20 reported sulfonamides, but no selective inhibitory profiles, except for some CA XII-selective derivatives, were observed. hCA I, II and XII were generally better inhibited by sulfonamides incorporating longer scaffolds and Gly/Ala, whereas the best hCA IV inhibitors were homosulfanilamide derivatives, incorporating Phe moieties. The amino acid-sulfonamide conjugates show good water solubility and effective hCA II, IV and XII inhibition, and may be considered as interesting candidates for antiglaucoma studies.

Synthesis and carbonic anhydrase inhibitory properties of amino acid - coumarin/quinolinone conjugates incorporating glycine, alanine and phenylalanine moieties.

N-Protected amino acids (Gly, Ala and Phe) were reacted with amino substituted coumarin and quinolinone derivatives, leading to the corresponding N-protected amino acid-coumarin/quinolinone conjugates. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the new compounds was assessed against various human (h) isoforms, such as hCA I, hCA II, hCA IV and hCA XII. The quinolinone conjugates were inactive as enzyme inhibitors, whereas the coumarins were ineffective hCA I/II inhibitors (KIs > 50 µM) but were submicromolar hCA IV and XII inhibitors, with inhibition constants ranging between 92 nM and 1.19 µM for hCA IV, and between 0.11 and 0.79 µM for hCA XII. These coumarin derivatives, as many others reported earlier, thus show an interesting selective inhibitory profile for the membrane-bound over the cytosolic CA isoforms.

Synthesis, characterization and carbonic anhydrase inhibitory activity of novel benzothiazole derivatives.

N-protected amino acids were reacted with substituted benzothiazoles to give the corresponding N-protected amino acid-benzothiazole conjugates (60-89%). Their structures were confirmed by proton nuclear magnetic resonance ((1)H NMR), carbon-13 nuclear magnetic resonance ((13)C NMR), IR and elemental analysis. Their carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activities were determined against two cytosolic human isoforms (hCA I and hCA II), one membrane-associated (hCA IV) and one transmembrane (hCA XII) enzyme by a stopped-flow CO2 hydrase assay method. The new compounds showed rather weak, micromolar inhibitory activity against most of these enzymes.

Determination of pKa values of some novel benzimidazole salts by using a new approach with (1)H NMR spectroscopy.

Benzimidazoles and their derivatives including imidazole are studied widely because they exist in the structure of natural products and different drugs. pKa values are extremely important for drug discovery and improvement in order to determine pharmacokinetic and pharmacodynamic features such as permeation through biological barriers, interactions with the target area or side effects. Acid-base features (pKa ) have great importance not only for physiological characteristics but also for being used as a ligand or changing physico-chemical features by turning benzimidazoles into salts. Within the scope of this study, a variety of new benzimidazole salts were synthesized, and their characterizations were made by NMR spectroscopy, FTIR spectroscopy and element analysis techniques. The pKa values of synthesized benzimidazole salts were determined by inflection point approach using integration values obtained with (1) H NMR spectroscopy and Henderson-Hasselbalch analysis. pKa values of some benzimidazole salts were also determined by potentiometric methods in order to compare those of NMR spectroscopy results.

Microwave assisted Suzuki-Miyaura and Ullmann type homocoupling reactions of 2- and 3-halopyridines using a Pd(OAc)2/benzimidazolium salt and base catalyst system.

A number of novel benzimidazole derivatives 1-4 were synthesized and the catalytic activity of these compounds in a catalytic system consisting of a benzimidazolium salt/Pd(OAc)2/K2CO3 were investigated in the Suzuki-Miyaura and Ullmann type homocoupling reactions under microwave irradiation. We obtained both cross coupling and homocoupling products of pyridine and some side products such as dimethylaminopyridine and unsubstituted pyridine.

Synthesis and antimalarial bioassay of quinine - peptide conjugates.

Amino acid and peptide conjugates of quinine were synthesized using microwave irradiation in 52-95% yields using benzotriazole methodology. The majority of these conjugates retain in vitro antimalarial activity with IC50 values below 100 nm, similar to quinine.

Synthesis, characterization and microwave-promoted catalytic activity of novel N-phenylbenzimidazolium salts in Heck-Mizoroki and Suzuki-Miyaura cross-coupling reactions under mild conditions.

A number of novel benzimidazolium salts having aryl substituents such as N-phenyl, 4-chlorophenyl and various alkyl substituents were synthesized. Their microwave-assisted catalytic activities were evaluated in Heck-Mizoroki and Suzuki-Miyaura cross-coupling reactions using a catalytic system consisting of Pd(OAc)(2)/K(2)CO(3) in DMF/H(2)O under mild reaction conditions with consistent high yields, except those of 2-bromopyridine.

Evaluation of in vitro and in vivo toxic effects of newly synthesized benzimidazole-based organophosphorus compounds.

This paper reports the toxic properties of eight newly synthesized benzimidazole-based organophosphorus (OP) compounds in Xenopus laevis in both in vivo and in vitro conditions. For both experiments, a commercial solution of azinphos methyl (AzM, Gusathion M WP25) was used as a reference compound. The 24-h median lethal concentrations (LC50) of all tested compounds were determined for 46th stage tadpoles in the range of 9.54-140.0 µM. For evaluation of the lethality of the compounds, the activity of the enzyme biomarkers acetylcholinesterase (AChE), carboxylesterase, glutathione S-transferase (GST), glutathione peroxidase, glutathione reductase, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase were determined in vivo in X. laevis tadpoles exposed to three concentrations (LC50, LC50/2, and LC50/4) of tested compounds. All exposure concentrations of AzM and seven of eight tested compounds caused CaE inhibition in in vivo conditions. Furthermore, the AChE inhibition capacity of tested compounds in commercial electric eel AChE and in X. laevis homogenates and also CaE inhibition capacity in only X. laevis homogenates were assayed for a 30-min in vitro exposure period. Eight OP compounds did not inhibit AChE activity more than 23 percent, but AzM exposure inhibited AChE activity by 26 percent for X. laevis homogenates and 97 percent for electric fish AChE in in vitro conditions. Also, CaE inhibition levels in X. laevis tadpole homogenates were 46 percent for AzM and between 8 percent and 33 percent for other compounds in in vitro conditions.

1-{[Dimeth-yl(phen-yl)sil-yl]meth-yl}-3-(2-phenyl-eth-yl)-1H-benzimidazol-3-ium bromide monohydrate.

The title compound, C(24)H(27)N(2)Si(+)·Br(-)·H(2)O, was synthesized from 1-(dimethyl-phenyl-silylmeth-yl)-1H-benzimidazole and (2-bromo-eth-yl)benzene in dimethyl-formamide. The benzimidazole ring system is nearly planar, with a maximum deviation of 0.015 (5) Å, and forms dihedral angles of 73.0 (3) and 39.6 (2)°, with the phenyl rings. In the crystal, mol-ecules are linked by O-H⋯Br, C-H⋯Br and C-H⋯O hydrogen bonds. In addition, the structure features π-π stacking inter-actions, with a face-to-face separation of 3.644 (3) Šbetween parallel benzimidazole ring systems.

1,3-Bis(3-phenyl-prop-yl)-1H-1,3-benzimidazole-2(3H)-selone.

The title mol-ecule, C(25)H(26)N(2)Se, has mirror symmetry, with the mirror plane passing through the atoms of the C=Se bond and the mid-points of the two C-C bonds of the benzene ring of the benzimidazole group. The dihedral angle between the benzimidazole ring system and the phenyl ring is 71.62 (14)°.