ABSTRACT
The title compound, 2C14H14N4O·H2O, comprises a neutral mol-ecule containing a central pyrazol-3-one ring flanked by an N-bound phenyl group and a C-bound 5-methyl-1H-pyrazol-3-yl group (at positions adjacent to the carbonyl substituent), its zwitterionic tautomer, whereby the N-bound proton of the central ring is now resident on the pendant ring, and a water mol-ecule of crystallization. Besides systematic variations in geometric parameters, the two independent organic mol-ecules have broadly similar conformations, as seen in the dihedral angle between the five-membered rings [9.72â (9)° for the neutral mol-ecule and 3.32â (9)° for the zwitterionic tautomer] and in the dihedral angles between the central and pendant five-membered rings [28.19â (8) and 20.96â (8)° (neutral mol-ecule); 11.33â (9) and 11.81â (9)°]. In the crystal, pyrazolyl-N-Hâ¯O(carbon-yl) and pyrazolium-N-Hâ¯N(pyrazol-yl) hydrogen bonds between the independent organic mol-ecules give rise to non-symmetric nine-membered {â¯HNNHâ¯NC3O} and {â¯HNNâ¯HNC3O} synthons, which differ in the positions of the N-bound H atoms. These aggregates are connected into a supra-molecular layer in the bc plane by water-O-Hâ¯N(pyrazolide), water-O-Hâ¯O(carbon-yl) and pyrazolyl-N-Hâ¯O(water) hydrogen bonding. The layers are linked into a three-dimensional architecture by methyl-C-Hâ¯π(phen-yl) inter-actions. The different inter-actions, in particular the weaker contacts, formed by the organic mol-ecules are clearly evident in the calculated Hirshfeld surfaces, and the calculated electrostatic potentials differentiate the tautomers.
ABSTRACT
A set of 1,2,3-triazole incorporated quinolone antibiotic conjugates 10-15, 17-19 were synthesized via microwave assisted click chemistry technique. Some of the aryl-substituted conjugates 17-19 show promising antibacterial properties against the tested Gram-positive (S. aureus and S. pyogenes) and Gram-negative bacteria (S. typhi) with potency higher than that of the parent antibiotics 1-3. 2D-QSAR modeling supports the observed biological properties.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Quantitative Structure-Activity Relationship , Quinolones/chemistry , Triazoles/chemical synthesis , Triazoles/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/toxicity , Chemistry Techniques, Synthetic , Microbial Sensitivity Tests , Triazoles/chemistry , Triazoles/toxicityABSTRACT
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.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cyclooxygenase 1/metabolism , Cyclooxygenase 2/metabolism , Cyclooxygenase Inhibitors/pharmacology , Edema/drug therapy , Pyrazoles/pharmacology , Stomach Ulcer/drug therapy , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Carrageenan , Cyclooxygenase Inhibitors/chemical synthesis , Cyclooxygenase Inhibitors/chemistry , Dose-Response Relationship, Drug , Edema/chemically induced , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Rats , Sheep , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Quinine/chemistry , Triazoles/chemistry , Animals , Antimalarials/chemistry , Biological Assay , Carbon-13 Magnetic Resonance Spectroscopy , Drug Design , Inhibitory Concentration 50 , Plasmodium falciparum/drug effects , Proton Magnetic Resonance Spectroscopy , Quantitative Structure-Activity Relationship , Spectrometry, Mass, Electrospray IonizationABSTRACT
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.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/therapeutic use , Pyrazoles/therapeutic use , Thiourea/chemistry , Thiourea/therapeutic use , Animals , Blood Glucose/drug effects , Female , Hypoglycemic Agents/chemistry , Mice , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistryABSTRACT
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.
Subject(s)
Anti-Bacterial Agents/pharmacology , Antifungal Agents/pharmacology , Antineoplastic Agents/pharmacology , Pyrazoles/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Aspergillus niger/drug effects , Candida albicans/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Escherichia coli/drug effects , HT29 Cells , Hep G2 Cells , Humans , MCF-7 Cells , Microbial Sensitivity Tests , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Staphylococcus aureus/drug effects , Structure-Activity RelationshipABSTRACT
In the paper by Asiri et al. [Acta Cryst. (2012), E68, o1154], the title and the chemical name of one of the reagents used in the synthesis are corrected.[This corrects the article DOI: 10.1107/S1600536812011579.].
ABSTRACT
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.
ABSTRACT
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.
Subject(s)
Antineoplastic Agents/chemical synthesis , Oligopeptides/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Cell Line , Cell Proliferation/drug effects , Cell Survival/drug effects , HEK293 Cells , HL-60 Cells , Human Umbilical Vein Endothelial Cells , Humans , Oligopeptides/chemical synthesis , Oligopeptides/toxicityABSTRACT
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.
Subject(s)
Biological Products/chemical synthesis , Diketopiperazines/chemical synthesis , Porifera/chemistry , Proline/analogs & derivatives , Triazoles/chemistry , Animals , Biological Products/chemistry , Cyclization , Diketopiperazines/chemistry , Dipeptides/chemistry , Ethylamines/chemistry , Proline/chemical synthesis , StereoisomerismABSTRACT
A series of bipyrazoles functionalized with sulfonamide, N(1),N(3)-disubstituted sulfonylurea, sulfonylthiourea pharmacophores, and some derived thiazolidinone and thiazoline ring systems were synthesized. The structures of the newly synthesized compounds were substantiated by analytical and diverse spectroscopic data. The anti-inflammatory and antioxidant activity of some of the newly synthesized compounds were tested and the results reveled that compounds 14, 16, 20, 24 and 25 proved to be the most active anti-inflammatory agents according to the Carrageenan-induced rat paw edema bioassay. Whereas, the analogs 14, 16 and 24 were able to exhibit good to moderate antioxidant activity in the DPPH radical-scavenging assay. Hence, compounds 14, 16 and 24 can be considered as lead structures for dual anti-inflammatory and antioxidant activities.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Antioxidants/chemical synthesis , Chalcones/chemical synthesis , Pyrazoles/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antioxidants/chemistry , Antioxidants/pharmacology , Biphenyl Compounds/chemistry , Chalcones/chemistry , Chalcones/pharmacology , Edema/drug therapy , Free Radicals/chemistry , Male , Picrates/chemistry , Pyrazoles/chemistry , Pyrazoles/pharmacology , RatsABSTRACT
Two synthetic pathways were adopted to synthesize the target 2-oxo-1,4-disubstituted-1,2,5,6-tetrahydro-benzo[h]quinoline-3-carbonitriles. Structure of the synthesized compounds has been characterized based on FT-IR, (1)H NMR, (13)C NMR and elemental analyses. UV-Vis and fluorescence spectroscopy measurements provided that all compounds are good absorbent and fluorescent. Fluorescence polarity study demonstrated that these compounds were sensitive to the polarity of the microenvironment provided by different solvents. In addition, spectroscopic and physicochemical parameters, including singlet absorption, extinction coefficient, Stokes shift, oscillator strength and dipole moment were investigated in order to explore the analytical potential of synthesized compounds.
Subject(s)
Coloring Agents/chemistry , Nitriles/chemistry , Quinolines/chemistry , Coloring Agents/chemical synthesis , Magnetic Resonance Spectroscopy , Nitriles/chemical synthesis , Quinolines/chemical synthesis , Spectrometry, Fluorescence , Spectroscopy, Fourier Transform InfraredABSTRACT
Thirty thiazole compounds bearing chemotherapeutically-active pharmacophores were synthesized and evaluated for their preliminary in vitro antimicrobial and anticancer activities. Nineteen compounds displayed obvious antibacterial potential, with special bactericidal activity against Gram positive bacteria, whereas, nine analogs showed moderate to weak antifungal activity against Candida albicans. The analog 12f proved to be the most active antimicrobial member identified in this study being comparable to ampicillin and gentamicin sulfate against Staphylococcus aureus and Bacillus subtilis, together with a moderate antifungal activity. Additionally, nine derivatives were tested for their preliminary in vitro anticancer activity according to the current one-dose protocol of the NCI. Compound 9b revealed a broad spectrum of anticancer activity against 29 out of the tested 60 subpanel tumor cell lines. Collectively, compounds 4, 9b, 10b and 12f could be considered as promising dual anticancer antibiotics.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Phenylurea Compounds/chemical synthesis , Phenylurea Compounds/pharmacology , Thiazoles/chemical synthesis , Thiazoles/pharmacology , Thiourea/analogs & derivatives , Anti-Bacterial Agents/chemistry , Antineoplastic Agents/chemistry , Drug Screening Assays, Antitumor , In Vitro Techniques , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Structure-Activity Relationship , Thiourea/chemical synthesis , Thiourea/pharmacologyABSTRACT
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.
Subject(s)
Anti-Infective Agents/chemical synthesis , Antineoplastic Agents/chemical synthesis , Quinolines/chemical synthesis , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Aspergillus niger/drug effects , Aspergillus niger/growth & development , Candida albicans/drug effects , Candida albicans/growth & development , Cell Proliferation/drug effects , Cell Survival/drug effects , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/growth & development , Gram-Positive Bacteria/drug effects , Gram-Positive Bacteria/growth & development , HT29 Cells , Hep G2 Cells , Humans , MCF-7 Cells , Quantitative Structure-Activity Relationship , Quinolines/chemistry , Quinolines/pharmacologyABSTRACT
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.
Subject(s)
Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/pharmacology , Nitriles/chemistry , Phenanthrenes/chemical synthesis , Phenanthrenes/pharmacology , Bacteria/drug effects , Crystallography, X-Ray , Fungi/drug effects , Microbial Sensitivity Tests , Molecular ConformationABSTRACT
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.
Subject(s)
Acetamides/chemistry , Chloroacetates/chemistry , Oligosaccharides/chemistry , Thiourea/chemistry , Catalysis , Glycosylation , Oligosaccharides/chemical synthesis , StereoisomerismABSTRACT
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.
Subject(s)
Diazonium Compounds/chemistry , Enzyme Inhibitors/chemistry , Glycoside Hydrolase Inhibitors , Diazonium Compounds/chemical synthesis , Diazonium Compounds/metabolism , Enzyme Inhibitors/metabolism , Hydrogen-Ion Concentration , Kinetics , Protein Binding , Saccharomyces cerevisiae/enzymology , alpha-Glucosidases/metabolismABSTRACT
This study reports the synthesis of some novel isoxazolo[4,5-d]pyridazines and structurally related thiazolo[4,5-d]pyridazines, and their biological evaluation as antimicrobial agents. The proposed compounds were designed to contain pharmacophores such as urea, thiourea, sulfonylurea (thiourea) and some derived functionalities that are believed to contribute to the anticipated biological activities. The results revealed that 25 compounds displayed broad spectrum of antibacterial activity, with greater inhibitory effect on the growth of the tested Gram positive strains compared to Gram negative ones. Moreover, 14 compounds were able to produce appreciable growth inhibitory activity against Candida albicans fungus when compared to Clotrimazole. Most of the tested isoxazolo[4,5-d]pyridazines displayed better antimicrobial profile than their corresponding thiazolo[4,5-d]pyridazine congeners. Four compounds namely, p-(3,7-dimethyl-4-oxo-4H-isoxazolo [4,5-d]pyridazine-5-yl)benzenesulfonylthioureas (11c-d), 3-substituted-2-[p-(3,7-dimethyl-4-oxo-4H-isoxazolo[4,5-d]pyridazine-5-yl)-benzene-sufonylimino]-4-oxothiazolidines (13d) and p-(2,7-dimethyl-4-oxo-4H-thiazolo[4,5-d]pyridazin-5-yl)benzenesulfonylthiourea (24c) were found to be most active antimicrobial members in present study.
Subject(s)
Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/pharmacology , Pyridazines/chemical synthesis , Pyridazines/pharmacology , Thiourea/analogs & derivatives , Urea/analogs & derivatives , Anti-Infective Agents/chemistry , Microbial Sensitivity Tests , Molecular Structure , Pyridazines/chemistry , Structure-Activity RelationshipABSTRACT
The synthesis of some new tetrahydroquinolines, tetrahydropyrimido[4,5-b]quinolines, and tetrahydropentaazacyclopenta[a]anthracenes structurally related to some DNA intercalators is described. Fifteen compounds were evaluated for their antitumor activity by the National Cancer Institute (NCI), in vitro disease oriented antitumor screening. The most active tricyclic pyrimido[4,5-b]quinolines 3b, 6b, 7b and 8b were further subjected to DNA-binding investigation in an attempt to rationalize their activity. Compound 8b proved to be the most active member in this study as evidenced from its remarkable growth inhibitory potential against some individual cell lines, and its broad spectrum of antitumor activity (GI50, TGI and LC50 values 46.9, 85.3 and 97.4, respectively), together with a good DNA-binding affinity.
Subject(s)
DNA/chemistry , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 4 or More Rings/chemistry , Quinolines/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Binding, Competitive , Cell Line, Tumor , Cell Survival/drug effects , DNA/metabolism , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HCT116 Cells , HL-60 Cells , HT29 Cells , Heterocyclic Compounds, 3-Ring/metabolism , Heterocyclic Compounds, 3-Ring/pharmacology , Heterocyclic Compounds, 4 or More Rings/metabolism , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , K562 Cells , MCF-7 Cells , Molecular Structure , Quinolines/metabolism , Quinolines/pharmacology , Structure-Activity RelationshipABSTRACT
The first total synthesis of Rolloamide B, a cyclic proline-enriched heptapeptide, is reported. This work features solution phase benzotriazole-mediated peptide synthesis ligating native amino acids.