Muscle relaxant activities of pistagremic acid isolated from Pistacia integerrima.

The aim of the current work was to explore the muscle relaxant effect of pistagremic acid (PA) isolated from Pistacia integerrima in various animal paradigms. In a rotarod test, PA caused a significant (p<0.05) muscle relaxant potential in a dose-dependent manner. When studied in the inclined plane test, pretreatment with PA (5 and 10 mg/kg) caused promising activity (p<0.05) after treatment for 30, 60 and 90 min. The muscle relaxant potential of PA was strongly complimented by the traction and chimney tests, showing a dominant effect after 60 min of treatment. In conclusion, PA possesses strong muscle relaxant activity in various animal-based models.

Multidrug resistance reversal activity of extract and a rare dimeric naphthoquinone from Diospyros lotus.

A dimeric naphthoquinone namely dihydrodyspyrole R (1) was purified once more from Diospyros lotus. Dihydrodyspyrole R and chloroform fractions were evaluated for their effects on the reversion of multidrug resistance (MDR). The compounds (1) and extract exhibited promising MDR reversing effect in a dose-dependent manner against mouse T-lymphoma cell line. Molecular docking of compound 1 revealed the correlation between in-silico with in-vitro results. The molecular docking results showed that compound 1 is bind closely where co-crystal ligand of P-gp is present. But usually, computational investigation predicts that, if a compound gives lesser score then compound will exhibit good activity. Hence, the docking scores of compound 1 are the near to the Rhodamine. It is conclude that there are certain important structural features of compound 1which are responsible for the inhibiting potency of P-gp from mice. The computational Petra/Osiris/Molinspiration (POM) analysis confirms the possibility of use of compound 1 without side effect or less toxicity risks.

Isolation and characterization of three new anti-proliferative Sesquiterpenes from Polygonum barbatum and their mechanism via apoptotic pathway.

BACKGROUND: The emergence of chemoresistant cancers and toxicity related to existing chemotherapeutic agents, demand the search for new pharmacophore with enhanced anti-cancer activity and least toxicity. For this purpose, three new sesquiterpenes were isolated from ethyl acetate fraction of the aerial parts of the plant Polygonum barbatum and evaluated for their anti-cancer potential. METHODS: The structural elucidation and characterization of the isolated compounds 1-3 were performed using various spectroscopic techniques such as mass, UV, IR, and extensive 1D/2D-NMR spectroscopy. Furthermore, the compounds 1-3 were subjected to screening of anti-cancer activity against different cell lines followed by brief analysis of apoptotic and anti-angiogenic potentials of the potent hit against non-small cell lung carcinoma cell line. RESULTS: All the compounds 1-3 were subjected to anti-proliferative potential against non-small cell lung carcinoma (NCI-H460), breast cancer (MCF-7), cervical cancer (HeLa) and normal mouse fibroblast (NIH-3 T3) cell lines. Among these, compound 3 was found to be more cytotoxic against NCI-H460 and MCF-7 cells (IC50 = 17.86 ± 0.72 and 11.86 ± 0.46 µM respectively). When compared with the standard drug cisplatin compound 3 was found to have more potent activity against NCI-H460 (IC50 = 19 ± 1.24 µM) as compared to MCF-7 cell lines (IC50 = 9.62 ± 0.5 µM). Compound 3 induced apoptosis in NCI-H460 cells in a dose dependent manner. It significantly downregulated, the expression of anti-apoptotic (BCL-2 L1 and p53) and increased the expression of pro-apoptotic (BAK and BAX) genes. Besides apoptosis, it also significantly reduced the cell migration and downregulated the angiogenic genes (i.e. VEGF and COX-2), thereby, inhibiting angiogenesis in NCI-H460 cells. CONCLUSION: Compound 3 possesses potent anti-proliferative potential as well as induced apoptosis and inhibited the cell migration of the cancerous cells by altering the gene expression, responsible for it.

Microwave-Assisted Synthesis of some Novel Azoles and Azolopyrimidines as Antimicrobial Agents.

In this study, new derivatives of pyrazole, isoxazole, pyrazolylthiazole, and azolopyrimidine having a thiophene ring were synthesized under microwave irradiation. Their pharmacological activity toward bacteria and fungi inhibition was screened and compared to the references Chloramphenicol and Trimethoprim/sulphamethoxazole. The antimicrobial results of the investigated compounds revealed promising results and some derivatives have activities similar to the references used.

Facial Regioselective Synthesis of Novel Bioactive Spiropyrrolidine/Pyrrolizine-Oxindole Derivatives via a Three Components Reaction as Potential Antimicrobial Agents.

This article presents the synthesis of new derivatives of spirooxindole-spiropiperidinone- pyrrolidines 6a-j and spirooxindole-spiropiperidinone-pyrrolizines 8a-j, through a 1,3-dipolar cycloaddition reaction of azomethineylides generated from isatin, sarcosine, and l-proline, through a decarboxylative route with dipolarophile 4a-j. All of the newly synthesized compounds were evaluated for their antimicrobial activities and their minimum inhibitory concentration (MIC) against most of the test organisms. The tested compounds displayed excellent activity against all of the tested microorganisms.

The Search for Covalently Ligandable Proteins in Biological Systems.

This commentary highlights the recent article published in Nature, June 2016, titled: "Proteome-wide covalent ligand discovery in native biological systems". They screened the whole proteome of different human cell lines and cell lysates. Around 700 druggable cysteines in the whole proteome were found to bind the electrophilic fragments in both active and inactive states of the proteins. Their experiment and computational docking results agreed with one another. The usefulness of this study in terms of bringing a change in medicinal chemistry is highlighted here.

Synthesis and Structure-Activity Relationship of Some New Thiophene-Based Heterocycles as Potential Antimicrobial Agents.

Several new pyrazole, pyridine, [1,2,4]triazolo[1,5-α]pyrimidine, benzimidazo[1,2-a]pyrimidine and 1,2,4-triazolo[3,4-c][1,2,4]triazine derivatives incorporating a thiophene moiety were synthesized from (E)-ethyl 5-(3-(dimethylamino)acryloyl)-4-phenyl-2-(phenylamino)thiophene-3-carboxylate (1). The structures of the newly synthesized compounds were confirmed by IR, ¹H-, (13)C-NMR, mass spectral data and elemental analysis. The antibacterial and antifungal activities of all the synthesized compounds were evaluated. The results indicated that compounds 9, 12, and 19 were found to be more potent than the standard drug Amphotericin B against Aspergillus fumigates. Additionally, compound 12 exhibited higher activity than the standard drug Amphotericin B against Syncephalastrum racemosum.

Antimicrobial Activity of Some Novel Armed Thiophene Derivatives and Petra/Osiris/Molinspiration (POM) Analyses.

Tetrasubstituted 2-acetylthiophene derivative 5 was synthesized and then condensed with various nitrogen nucleophiles such as 5-amino-1,2,4-triazole, 2-aminobenzimidazole, aniline or p-chloroaniline to afford the corresponding iminothiophene derivatives 6-8a,b. Condensation of thiophene 5 with malononitrile as carbon nucleophile afforded compound 9, which underwent nucleophilic addition with DMF-DMA to afford compound 10. The newly synthesized products were characterized by elemental analysis, IR, MS, ¹H-(13)C-NMR and CHN analysis and then evaluated for their antimicrobial activity. Results of the in vitro antibacterial activity showed that thiophene derivative 7 was found to be more potent than the standard drug gentamicin against Pseudomonas aeruginosa. Some of these compounds showed potential antimicrobial activities. Molecular docking and Osiris/Molinspiration analyses show the crucial role and impact of substituents on bioactivity and indicate the unfavorable structural parameters in actual drug design: more substitution with electronic donor group doesn't guarantee more effective bioactivity. This study should greatly help in an intelligent and a controlled pharmacomodulation of antibiotics.

Synthesis, spectroscopic investigations (X-ray, NMR and TD-DFT), antimicrobial activity and molecular docking of 2,6-bis(hydroxy(phenyl)methyl)cyclohexanone.

The synthesis of 2,6-bis(hydroxy(phenyl)methyl)cyclohexanone 1 is described. The molecular structure of the title compound 1 was confirmed by NMR, FT-IR, MS, CHN microanalysis, and X-ray crystallography. The molecular structure was also investigated by a set of computational studies and found to be in good agreement with the experimental data obtained from the various spectrophotometric techniques. The antimicrobial activity and molecular docking of the synthesized compound was investigated.

Synthesis, in-vitro antibacterial, antifungal, and molecular modeling of potent anti-microbial agents with a combined pyrazole and thiophene pharmacophore.

Ethyl 5-acetyl-4-methyl-2-(phenylamino)thiophene-3-carboxylate (2) and there derivatives 3a-c, 4, 6a-c and 9a-f were synthesized. The structure of compound 2 was deduced by 1H-NMR, 13C-NMR, FT-IR, MS, microanalysis, and single-crystal X-ray crystallography. The compound crystallized in the monoclinic system, with space group P21/c and cell coordinates a = 8.5752(16) Å, b = 21.046(4) Å, c = 8.2941(12) Å, ß = 101.131(6)°, V = 1468.7(4) Å3, and Z = 4. Compounds 2, 3a-c, 4, 5a-c and 9a-f were subjected into in vitro antimicrobial activity tests. Compounds 3a and 3c were more potent than standard drug amphotericin B, showing MIC values of 23.8 ± 0.42 and 24.3 ± 0.68, respectively, against Aspergillus fumigatus while the standard drug MIC was 23.7 ± 0.1. Compound 3c was also more potent (MIC 24.8 ± 0.64) than the standard drug amphotericin B (MIC 19.7 ± 0.2) against Syncephalastrum racemosum. Compounds 4 and 9f also showed promising anti-microbial activity. Molecular modeling was performed for the most active compounds.

Substituted thieno[2,3-b]thiophenes and related congeners: Synthesis, ß-glucuronidase inhibition activity, crystal structure, and POM analyses.

A series of 15 novel compounds incorporating the thieno[2,3-b]thiophene moiety were synthesized. The chemical structures of these compounds were deduced from elemental analyses, (1)H NMR, (13)C NMR, and ESI-mass spectral data. The enzyme inhibition potential of these compounds was evaluated, in vitro, against ß-glucuronidase, xanthine oxidase, and α-chymotrypsin enzymes. The cytotoxicity was evaluated by a cell viability assay utilizing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) dye. Among the compounds tested, compound 3 was the most potent ß-glucuronidase inhibitor with an IC50 value of 0.9 ± 0.0138 µM; it was much more active than the standard, d-saccharic acid 1,4-lactone (IC50=45.75 ± 2.16 µM). Compound 12, on the other hand, was the most potent as a xanthine oxidase inhibitor with an IC50 of 14.4 ± 1.2 µM. With the characterization of their mechanism of action and with further testing, these compounds could be useful candidates as anticancer drugs. In addition, the newly synthesized compounds were subjected to POM analyses to get insights about their degree of their toxicity.

Synthesis, anti-microbial and molecular docking studies of quinazolin-4(3H)-one derivatives.

In this work, synthesis, antimicrobial activities and molecular docking studies of some new series of substituted quinazolinone 2a-h and 3a-d were described. Starting form 2-aminobenzamide derivatives 1, a new series of quinazolinone derivatives has been synthesized, in high yields, assisted by microwave and classical methods. Some of these substituted quinazolinones were tested for their antimicrobial activity against Gram-negative bacteria (Pseudomonas aeruginosa and Esherichia coli) and Gram-positive bacteria (Staphylococcus aureus, and Bacillus subtilis), and anti-fungal activity against (Aspergillus fumigatus, Saccharomyces cervevisiae, and Candida albicans) using agar well diffusion method. Among the prepared products, 3-benzyl-2-(4-chlorophenyl)quinazolin-4(3H)-one (3a) was found to exhibits the most potent in vitro anti-microbial activity with MICs of 25.6±0.5, 24.3±0.4, 30.1±0.6, and 25.1±0.5 µg/mL against Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa and Esherichia coli, respectively. Compound 3a was found to exhibits the most potent in vitro anti-fungal activity with MICs of 18.3±0.6, 23.1±0.4, and 26.1±0.5 µg/mL against Aspergillus fumigatus, Saccharomyces cervevisiae, and Candidaal bicans, respectively.

Synthesis of Thieno[2,3-b]thiophene Containing Bis-Heterocycles-Novel Pharmacophores.

Thioenethiophene derivatives represent an important class of compounds with diverse biological activities. We describe here the synthesis of a new series of thieno[2,3-b]thiophene containing bis-heterocyclic compounds 3-7. All the compounds were evaluated for their in vitro antioxidant potential, α-glucosidase and ß-glucuronidase inhibiton and anticancer activity against PC-3 cell lines. Compounds 2b (IC50 = 1.3 ± 0.2 µM), 5a (IC50 = 2.3 ± 0.4 µM) and 5b (IC50 = 8.7 ± 0.1 µM) showed a potent inhibition of ß-glucuronidase enzyme, more active than the standard d-saccharic acid 1,4-lactone (IC50 = 45.8 ± 2.5 µM). Compounds 5a (IC50 = 22.0 ± 0.3 µM) and 5b (IC50 = 58.4 ± 1.2 µM) were also found to be potent α-glucosidase inhibitors as compared to standard drug (acarbose, IC50 = 841 ± 1.7 µM).

Synthesis and antimicrobial activity of some new thieno[2,3-b]thiophene derivatives.

A series of thieno[2,3-b]thiophene moiety-containing bis-cyanopyrazoles 5a-c, bis-aminopyrazole 9 and bis-pyridazine derivatives 11 were synthesized and evaluated in vitro for their antimicrobial potential. The antimicrobial activity of some selected products was evaluated and showed good results. 5,5'-(3,4-Dimethylthieno[2,3-b]thiophene-2,5-diyl)bis(3-acetyl-1-(4-chlorophenyl)-1H-pyrazole-4-carbonitrile) (5d) was found to be more potent than the standard drug amphotericin B against Geotricum candidum and equipotent to amphotericin B against Syncephalastrum racemosum. In addition, it was found to be equipotent to the standard drug Penicillin G against Staphylococcus aureus. Moreover, it was more potent than the standard drug streptomycin against Pseudomonas aeruginosa and Escherichia coli.

(E)-Ethyl 2-anilino-5-[3-(dimethyl-amino)-acrylo-yl]-4-phenyl-thio-phene-3-carboxyl-ate.

In the title compound, C24H24N2O3S, the phenyl rings form dihedral angles of 55.65 (11) and 79.60 (11)° with the plane of the thio-phene ring. The mol-ecular conformation is stabilized by an intra-molecular N-H⋯O hydrogen bond, generating an S(6) ring motif. In the crystal, centrosymmetrically related mol-ecules are linked into dimers by two pairs of C-H⋯O inter-actions.

Ethyl 4-acetyl-5-anilino-3-methyl-thio-phene-2-carboxyl-ate.

In the title compound, C16H17NO3S, a thio-phene derivative with amino phenyl, acetyl, methyl and ethyl carboxyl susbtituents attached to a central thio-phene ring, the phenyl and thio-phene rings form a dihedral angle of 36.92 (9) Å. The mol-ecular conformation is stabilized by an intra-molecular N-H⋯O hydrogen bond, which forms an S(6) ring motif.

3,4-Di-methyl-thieno[2,3-b]thio-phene-2,5-dicarbo-nitrile.

The asymmetric unit of the title compound, C10H6N2S2, contains two crystallographically independent but conformationally similar mol-ecules. The fused thio-phene ring cores are almost planar [maximum deviation = 0.027 (3) Å] with the thio-phene rings forming dihedral angles of 0.5 (4)° in one mol-ecule and 1.91 (4)° in the other. The crystal packing is stabilized only by van der Waals inter-actions.

Dimethyl 2-(4-methyl-benzyl-idene)malonate.

In the mol-ecule of the title compound, C13H14O4, the benzene ring forms dihedral angles of 18.60 (7) and 81.36 (8)° with the two arms of the malonate moiety. The crystal structure features C-H⋯O inter-actions, which form chains running parallel to the b axis.

Synthesis and antimicrobial studies of some novel bis-[1,3,4]thiadiazole and bis-thiazole pendant to thieno[2,3-b]thiophene moiety.

The synthetic utility of 3,3'-(3,4-dimethylthieno[2,3-b]thiophene-2,5-diyl)bis (3-oxopropanenitrile) (1) in the synthesis of some novel bis-[1,3,4-thiadiazole] 6a-g and bis-thiazole 10 and 13 derivatives with thieno[2,3-b]thiophene moiety is reported. Antimicrobial evaluation of some selected examples from the synthesized products was carried out and showed promising results.

A novel and expedient approach to new thiazoles, thiazolo[3,2-a]pyridines, dihydrothiophenes, and hydrazones incorporating thieno[2,3-b]thiophene moiety.

This paper reports details about the synthesis of a series of novel functionalized symmetrical bis-heterocyclic compounds containing a thieno[2,3-b]thiophene motif. Bis-thiazole derivatives 2, 3a-c and thiazolo[3,2-a]pyridine derivatives 4a-c are achieved. The hitherto unknown dihydrothiophene derivatives 6a-dvia bis-pyridimium salt 5 are obtained. Additionally, the novel hydrazonothieno[2,3-b]thiophene derivatives 10a-c are obtained via bis-tosylacetylthieno[2,3-b]thiophene derivative 9. All compounds are characterized by (1)H-, (13)C-NMR, GCMS, IR, and UV-vis spectrometry. These compounds represent a new class of sulfur and nitrogen containing heterocycles that should also be of interest as new materials.