Synthesis, Anti-Inflammatory Activity, and COX-1/2 Inhibition Profile of Some Novel Non-Acidic Polysubstituted Pyrazoles and Pyrano[2,3-c]pyrazoles.

The synthesis and evaluation of the anti-inflammatory activity of some structure hybrids comprising basically the 5-hydroxy-3-methyl-1-phenyl-4-substituted-1H-pyrazole scaffold directly linked to a variety of heterocycles and functionalities, or annulated as pyrano[2,3-c]pyrazoles, is described. According to the in vivo results and a comprehensive structure-activity relationship study, five analogs (5, 10, 17, 19, and 27) displayed remarkable anti-inflammatory profiles showing distinctive % protection and ED50 values, especially 10 and 27 (ED50 35.7 and 38.7 µmol/kg, respectively) which were nearly equiactive to celecoxib (ED50 32.1 µmol/kg). Compounds 10, 17, and 27 exhibited distinctive COX-2 inhibition with a noticeable COX-2 selectivity (SI values 7.83, 6.87, and 7.16, respectively), close to that of celecoxib (SI 8.68). Additionally, 5, 10, 17, 19, and 27 proved to be gastrointestinal tract safe (0-20% ulceration) and non-toxic, being well tolerated by the experimental animals up to 250 mg/kg orally and 80 mg/kg parenterally. Collectively, the in vivo ED50 values for the most potent five derivatives agree with their in vitro COX-2 selectivity indices, suggesting their usefulness as selective anti-inflammatory COX-2 inhibitors. The bipyrazole 10 and the pyranopyrazole 27 could be considered as the most active members in this study, being nearly equiactive to celecoxib, besides their obvious selective COX-2 inhibition, high safety margin, and predicted pharmacokinetic (ADME-T) suitability for oral use.

Synthesis, antimalarial properties and 2D-QSAR studies of novel triazole-quinine conjugates.

Click chemistry technique led to novel 1,2,3-triazole-quinine conjugates 8a-g, 10a-o, 11a-h and 13 utilizing benzotriazole-mediated synthetic approach with excellent yields. Some of the synthesized analogs (11a, 11d-h) exhibited antimalarial properties against Plasmodium falciparum strain 3D7 with potency higher than that of quinine (standard reference used) through in vitro standard procedure bio-assay. Statistically significant BMLR-QSAR model describes the bio-properties, validates the observed biological observations and identifies the most important parameters governing bio-activity.

1-Substituted carbamoyl and thiocarbamoyl-4,5-dihydro-1H-pyrazoles as possible cytotoxic and antimicrobial agents.

Two series of 1-substituted carbamoyl and thiocarbomoyl derivatives were prepared by either treating the corresponding pyrazole with the appropriate isocyanate and isothiocyanate respectively, or alternatively by condensing the appropriate diketone with the proper substituted semicarbazide or thiosemicarbazide. The structures of the prepared compounds were fully determined by analytical and spectral methods. Preliminary biological screening of the prepared compounds revealed significant antibacterial and cytotoxic activities for some compounds. Compounds 4a2 and 4a3 were found to be the most active against the human colon carcinoma HT29 (11.8 and 7.5 µg/mL, respectively) and human breast cancer MCF 7 (3.4 and 2.6 µg/mL, respectively) cell lines. The structure-activity relationship (SAR) and in silico drug relevant properties (HBD, HBA, tPSA, cLog P, molecular weight, % ABS, drug-likeness and drug score) further confirmed that the compounds are potential lead compounds for future drug discovery study.

Synthesis and biological evaluation of fluoropyrazolesulfonylurea and thiourea derivatives as possible antidiabetic agents.

Fluorinated pyrazoles, benzenesulfonylurea and thiourea and their cyclic sulfonylthiourea derivatives were prepared as hypoglycemic agents. The chemistry involves the condensation of 4-hydrazino benzenesulfonamide hydrochloride with fluorochalcones to give pyrazoline derivatives which upon oxidation with bromine water afforded corresponding pyrazoles. Reaction of pyrazolines with isocyanates and isothiocyanates give the corresponding ureas and thioureas. Subsequent cyclization of these thiourea derivatives with ethyl bromoacetate and α-bromoacetophenone yielded the 4-oxothiazolidines and thiazolines, respectively. Preliminary biological screening of the prepared compounds revealed significant antidiabetic activity. Molecular and biological properties calculations revealed favorable drug-like profiles of six compounds. The structure-activity relationship (SAR) and in silico drug relevant properties calculations (HBD, HBA, tPSA, miLogP, molecular weight, % ABS, drug-likeness and drug score) endorse that these compounds are potential leads for future drug discovery study.

A benzotriazole-mediated route to protected marine-derived hetero-2,5-diketopiperazines containing proline.

A procedure for the cyclization of dipeptidoyl benzotriazolides containing proline derivatives promoted by triethylamine under MW activation is introduced. The reaction is general for a variety of dipeptidoyl benzotriazolides and represents a very practical and convenient method for the preparation of Pro- or Hyp-derived 2,5-diketopiperazines (2,5-DKPs) and bis-DKPs with a disulfide linker. This method can be used for the construction of 2,5-DKP compound libraries and for the synthesis of natural products with diketopiperazine cores.

Synthesis and bioactivity of a Goralatide analog with antileukemic activity.

Natural tetrapeptide Goralatide (AcSDKP) is a selective inhibitor of primitive haematopoietic cell proliferation. It is not stable in vivo and decomposes within 4.5min when applied to live cells. In this work we developed an analog of Goralatide that exhibits cytotoxicity towards human myeloid HL-60, HEL, Nalm-6 leukemia cells, endothelial HUVEC, glioblastoma U251 and transformed kidney 293T cells. The Goralatide analog showed significant stability in organic solution with no tendency to degrade oxidatively.

Synthesis of Some 1,4,6-Trisubstituted-2-oxo-1,2-dihydropyridine-3-carbonitriles and Their Biological Evaluation as Cytotoxic and Antimicrobial Agents.

A series of novel 1,4,6-trisubstituted-2-oxo-1,2-dihydropyridine-3-carbonitriles supported with some functionalities reported to contribute to significant chemotherapeutic potential were synthesized and evaluated for their antimicrobial and/or cytotoxic activities. Thirteen compounds exhibited cytotoxic potential against a panel of three human tumor cell lines. Compounds 15, 23, and 24 proved to be the most active agents with a broad spectrum of cytotoxic activity. Analog 24 was considered as the most active cytotoxic agent, being 2.5 times more active than doxorubicin against the colon HT29 carcinoma cell line. Seventeen compounds were able to exert a variable antimicrobial profile, among which analogs 15, 20, 21, 23, and 24 were prominently active. The highest antimicrobial potential was displayed by analog 24, being equipotent to ampicillin against Staphylococcus aureus and Escherichia coli, together with a considerable antifungal activity comparable with clotrimazole. Collectively, compounds 15, 23, and 24 could be considered as possible dual antimicrobial-anticancer candidates.

Synthesis and biological evaluation of some novel tetrahydroquinolines as anticancer and antimicrobial agents.

This study reports the synthesis of a series of new 2-amino-3-cyano-8-methyl-4-substituted-5,6,7,8-tetrahydroquinolines along with some derived fused-ring systems. Ten compounds have shown remarkable cytotoxic activity against human colon carcinoma HT29, hepatocellular carcinoma HepG2 and Caucasian breast adenocarcinoma MCF7 cell lines. Six compounds showed considerable broad-spectrum cytotoxic activity among which two proved to be the most active derivatives. Likewise, seven compounds from the series were found to exhibit significant antimicrobial activity and three of them proved to be the most active candidates. Two alkylthio-pyrimido quinolines are suggested as possible antimicrobial and anticancer candidates in the present series.

C-(α-d-Glucopyranosyl)-phenyldiazomethanes-irreversible inhibitors of α-glucosidase.

Several C-(α-d-glucopyranosyl)-phenyldiazomethanes, with different substituent groups at the para-position of the phenyl ring, were prepared. The stabilities of these diazo compounds were investigated through NMR and UV monitoring. The para-cyano substituted diazo compound was found to be stable in neutral media (pH 7.0 buffer) and could be isolated. Inhibitory activity investigations indicated that this compound is an irreversible inhibitor against α-glucosidase from Saccharomyces cerevisiae.

Synthesis and in vitro antitumor and antimicrobial activity of some 2,3-diaryl-7-methyl-4,5,6,7-tetrahydroindazole and 3,3a,4,5,6,7-hexahydroindazole derivatives.

The synthesis of a series of 2,3-diaryl-7-methyl-4,5,6,7-tetrahydroindazole and 3,3a,4,5,6,7-hexahydroindazole derivatives substituted with various biologically-active function groups with anticipated chemotherapeutic activity is described. 4-(7-methyl-3-aryl-3,3a,4,5,6,7-hexahydro-indazol-2-yl)benzenesulfonamides 2a-c, which were employed as key intermediates in this study, were synthesized by cyclocondensation of 6-arylidene-2-methylcyclohexanones 1a-c with 4-hydrazinobenzenesulfonamide hydrochloride. A detailed discussion of the reactions utilized in the preparation of the intermediate and target compounds is reported, and the structures of the newly synthesized compounds were substantiated with IR, (1)H and (13)C NMR spectral data and elementary microanalyses. Twenty of the newly synthesized compounds were selected by National Cancer Institute (NCI), Maryland, USA, to be evaluated for their antitumor activity and the results revealed that six compounds 3c, 4d,e, 5a,d and 8c exhibited broad spectrum of antitumor activity against most of the tested tumor cell lines. In addition, the in vitro antibacterial and antifungal activities of a number of the target compounds were also tested using the Agar-diffusion method. Some of these compounds have shown significant antibacterial and mild to moderate antifungal activities.

Synthesis and characterization of some hydroxypyridone derivatives and their evaluation as antimicrobial agents.

The synthesis, in vitro antimicrobial activities of some novel hydroxy pyridines supported with various pharmacophores is described. Twenty-six out of the tested 58 compounds exhibited variable inhibitory effects on the growth of the tested Gram positive and Gram negative bacteria. The tested compounds revealed better activity against the Gram positive rather than the Gram negative strains. The synthesized hydroxypyridones have shown very significant inhibitory effect against Staphylococcus aureus and Bacillus subtilis. Twelve compounds namely; 5d, 5f, 6a, 6b, 8b, 18b, 18c, 19c, 21d, 22b, 22d and 23d were able to produce appreciable growth inhibitory activity against Candida albicans when compared to Clotrimazole. Among these, 22d proved to be the most potent antifungal agent.

3-cyano-8-methyl-2-oxo-1,4-disubstituted-1,2,5,6,7,8-hexahydroquinolines: synthesis and biological evaluation as antimicrobial and cytotoxic agents.

The synthesis, in vitro antimicrobial and cytotoxic activities of some novel hexahydroquinolines supported with various pharmacophores are described. The results revealed that 18 compounds displayed pronounced activity against Staphylococcus aureus and Escherichia coli bacteria beside a moderate antifungal activity. Compound 25 is the most active candidate with equipotency to ampicillin against S. aureus, E. coli and Pseudomonas aeruginosa, together with an obvious antifungal activity. Additionally, 12 compounds showed remarkable cytotoxic efficiency against human colon carcinoma HT29, hepatocellular carcinoma Hep-G2 and Caucasian breast adenocarcinoma MCF7 cell lines. Among these, the analogs 22 and 25 proved to be the most active cytotoxic members. Collectively, the results would suggest that compounds 22 and 25 could be considered as possible dual antimicrobial-anticancer agents.

An efficient approach to the synthesis of highly congested 9,10-dihydrophenanthrene-2,4-dicarbonitriles and their biological evaluation as antimicrobial agents.

An efficient and novel method for the synthesis in moderate to good yield (72%-84%) of a series of 3-amino-1-substituted-9,10-dihydrophenanthrene-2,4-dicarbonitriles 1-5 via one-pot multi-component reactions of aldehydes, malononitrile, 1-tetralone and ammonium acetate has been delineated. Cyclocondensation attempts of aminocyanophenanthrene derivatives 1, 2, 4 and 5 with acetic anhydride in the presence of conc. H2SO4 failed and instead the diacetylamino derivatives 10-13 were obtained. All prepared compounds were structurally elucidated by various spectroscopic methods and X-ray crystallography. N,N-diacetylamino-derivatives of phenanthrene have shown good antimicrobial activity.

Cooperative catalysis in glycosidation reactions with O-glycosyl trichloroacetimidates as glycosyl donors.

Thiourea mediates cooperative glycosidation through hydrogen bonding. N,N'-Diarylthiourea as cocatalyst enforces an SN2-type acid-catalyzed glycosidation even at room temperature (see scheme; Bn=benzyl). From O-(α-glycosyl) trichloroacetimidates as glycosyl donors and various acceptors, ß-glycosides are preferentially or exclusively obtained.

4-{(4Z)-4-[(2Z)-3-(4-Fluoro-anilino)-1-hy-droxy-but-2-en-1-yl-idene]-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl}-benzene-sulfonamide.

In the title compound, C(20)H(19)FN(4)O(4)S, the pyrazole and benzene-sulfonamide rings are coplanar [dihedral angle = 5.02 (15)°] but this planarity does not extend over the entire mol-ecule, the dihedral angle between the terminal six-membered rings being 33.24 (14)°. Intra-molecular hy-droxy-hy-droxy O-H⋯O and amine-hy-droxy N-H⋯O hydrogen bonds, as a well as a tight C-H⋯O(carbon-yl) inter-action, lead to a sequence of three fused S(6) rings. Supra-molecular chains along the a axis feature in the crystal packing; these chains are stabilized by amine-sulfonamide N-H⋯O and amine-pyrazole N-H⋯N hydrogen bonds.

(2Z)-3-(4-Fluoro-anilino)-1-(5-hy-droxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)but-2-en-1-one.

The central carbonyl group in the title compound, C(20)H(18)FN(3)O(2), forms amine-hy-droxy N-H⋯O and hy-droxy-hy-droxy O-H⋯O hydrogen bonds, leading to two S(6) rings. The N-bound phenyl ring is coplanar with the five-membered ring to which it is attached [dihedral angle = 6.27 (10)°], but an overall twist in the mol-ecule is evident, the dihedral angle between the terminal phenyl and benzene rings being 27.30 (10)°. Mol-ecules aggregate into a three-dimensional architecture via C-H⋯F, C-H⋯O and C-H⋯π inter-actions.

(2Z)-3-(3-Bromo-anilino)-1-(5-hy-droxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)but-2-en-1-one.

In the title compound, C(20)H(18)BrN(3)O(2), the central carbonyl group forms amine-N-H⋯O and hy-droxy-O-H⋯O hydrogen bonds, which lead to two fused S(6) rings. The N-bound phenyl ring is coplanar with the five-membered ring to which it is attached [dihedral angle = 5.22 (18)°], but the dihedral angle [33.87 (17)°] between the terminal phenyl and bromo-benzene rings indicates an overall twist in the mol-ecule. In the crystal packing, mol-ecules assemble into dimeric aggregates via C-H⋯π inter-actions.

N,N'-Bis[(E)-1-(thio-phen-3-yl)ethyl-idene]ethane-1,2-diamine.

The complete mol-ecule of the title compound, C(14)H(16)N(2)S(2), is generated by a crystallographic inversion centre. The thio-phene residue is close to being coplanar with the imine group [C-C-C-N torsion angle = 6.5 (2)°], and the conformation about the imine C=N bond [1.281 (2) Å] is E. In the crystal, the three-dimensional architecture is consolidated by C-H⋯N, C-H⋯π and S⋯S [3.3932 (7) Å] inter-actions.

1-Phenyl-1H-pyrazole-4-carbaldehyde.

In the title mol-ecule, C(10)H(8)N(2)O, the five- and six-membered rings form a dihedral angle of 10.14 (9)°. The aldehyde group is almost coplanar with the pyrazole ring to which it is connected [O-C-C-C torsion angle = -179.35 (17)°]. In the crystal, inversion dimers are linked by four C-H⋯O inter-actions as the carbonyl O atom accepts two such bonds. The dimeric aggregates are linked into supra-molecular layers in the ac plane by C-H⋯π and π-π [ring centroid(pyrrole)⋯ring centroid(phen-yl) = 3.8058 (10) Å] inter-actions.

3-Amino-1-(3,4-dimeth-oxy-phen-yl)-9,10-dihydro-phenanthrene-2,4-dicarbonitrile.

In the title compound, C(24)H(19)N(3)O(2), the partially saturated ring adopts a distorted half-chair conformation with the methyl-ene-C atom closest to the amino-benzene ring lying 0.664 (3) Šout of the plane defined by the five remaining atoms (r.m.s. deviation = 0.1429 Å. The dihedral angle [32.01 (10)°] between the benzene rings on either side of this ring indicates a significant fold in this part of the mol-ecule. The dimeth-oxy-substituted benzene ring is almost orthogonal to the benzene ring to which it is attached [dihedral angle = 72.03 (9)°]. The mol-ecule has been observed previously as the major component of a 1:19 co-crystal with 2-amino-4-(3,4-dimeth-oxy-phen-yl)-5,6-dihydro-benzo[ha]quinoline-3-carbonitrile [Asiri et al. (2011). Acta Cryst. E67, o2873-o2873]. Supra-molecular chains with base vector [201] are formed in the crystal structure via N-H⋯O hydrogen bonds between the amino H atoms of one mol-ecule inter-acting with the meth-oxy O atoms of a neighbouring mol-ecule. The chains are linked into a three-dimensional architecture by C-H⋯π inter-actions.