Design and Synthesis of 1,2,4-Triazolo[3,2-b]-1,3,5-thiadiazine Derivatives as a Novel Template for Analgesic/Anti-Inflammatory Activity.

Previously, we demonstrated that certain heterocyclic compounds derived from 3-substituted-1,2,4-triazole-5-thiones had promising analgesic/anti-inflammatory activities together with low ulcerogenic properties. Therefore, we sought to design and synthesize new derivatives of triazol-5-thiones-fused heterocycles. In the present study, a series of novel bis-Mannich bases, namely 2,6-disubstituted-6,7-dihydro-5H-1,2,4-triazolo[3,2-b]-1,3,5-thiadiazines (1a-d, 2a-c, and 3a-d), were synthesized and characterized to assess their possible anti-inflammatory/analgesic properties. Additionally, their ability to induce gastric toxicity was also evaluated. Several of the condensed compounds produced a degree of analgesic activity comparable to reference drugs in both the hot plate and tail-flick tests. A strong anti-inflammatory effect was observed for the derivatives carrying a benzyl group at the second position (2a-c). The majority of the prepared compounds caused comparatively less gastrointestinal (GI) side effects than the reference drugs naproxen and indomethacin did. These results showed that 1,2,4-triazolo[3,2-b]-1,3,5-thiadiazine derivatives might afford a safer alternative to currently available analgesic/anti-inflammatory agents for the treatment and management of inflammatory disease and pain.

Novel thiazolo[3,2-b]-1,2,4-triazoles derived from naproxen with analgesic/anti-inflammatory properties: Synthesis, biological evaluation and molecular modeling studies.

3-Substituted-1,2,4-triazole-5-thiones are versatile synthetic intermediates for the preparation of several biologically active N-bridged heterocyclic compounds, given that they have two reactive sites, thiocarbonyl and an amine nitrogen (N1/N4). For several years, our interest has focused on the synthesis of novel heterocyclic systems derived from 3-substituted-1,2,4-triazole-5-thiones having analgesic/anti-inflammatory activity. In this study, a series of novel thiazolo[3,2-b]-1,2,4-triazole-6(5H)-one derivatives bearing naproxen was synthesized and evaluated for their in vivo analgesic and anti-inflammatory properties in acute experimental pain and inflammation models. The compounds were also tested for their ulcerogenic potential. Our findings showed that all the newly synthesized derivatives attenuate nociception and inflammation compared with a control. All the synthesized compounds exhibited much lower ulcerogenic risk than the standard drugs indomethacin and naproxen. Some compounds with significant analgesic and/or anti-inflammatory activities as well as low ulcer scores were further evaluated for in vitro COX-1 and COX-2 inhibitory potential in a COX-catalyzed prostaglandin biosynthesis assay. Among the tested compounds, compound 1q showed the highest selectivity index (SI) of 4.87. The binding mode for some of the tested compounds to the cyclooxygenase (COX) enzymes was predicted using docking studies.

Thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one substituted with ibuprofen: novel non-steroidal anti-inflammatory agents with favorable gastrointestinal tolerance.

In an effort to establish new candidates with improved analgesic and anti-inflammatory activities and lower ulcerogenic risk, a series of thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one derivatives of ibuprofen were synthesized. All compounds were evaluated for their in vivo anti-inflammatory and analgesic activities in mice. Furthermore, the ulcerogenic risks of the compounds were determined. In general, none of the compounds represent a risk for developing stomach injury as much as observed in the reference drugs ibuprofen and indomethacin. The compounds carrying a 3-phenyl-2-propenylidene (1a), (biphenyl-4-yl)methylidene (1f) and (1-methylpyrrol-2-yl)methylidene (1n) at the 6th position of the fused ring have been evaluated as potential analgesic/anti-inflammatory agents without a gastrointestinal side effect. These new compounds, therefore, deserve further attention to develop new lead drugs.

Investigation of antioxidant properties of some 6-(alpha-aminobenzyl)thiazolo[3,2-b]-1,2,4-triazole-5-ol compounds.

Promising antiinflammatory activity together with low ulcerogenic properties of some Michael addition products of thiazolo[3,2-b]-1,2,4-triazole-5(6H)-ones which have been synthesized in our previous study, prompted us to investigate their antioxidant properties. Since compound Ib has both antioxidant and antiinflammatory activities beside the lowest ulcerogenic incidence, it was selected for investigation of its inhibitory effect on various cyclooxygenase ezymes. It was found that while it did not inhibit cyclooxygenase-1 (COX-1) enzyme, there was a small inhibitory effect (17%) on COX-2 enzyme. We concluded that the diminished harmful effects on the stomach of this novel antiinflammatory compound were related to its antioxidant properties since it is ineffective on COX-1 enzyme. In conclusion, the compounds having both antioxidant and antiinflammatory activities with a lack of COX-1 enzyme inhibitory effect may improve the gastrointestinal safety profile of such compounds.

Development of nonsurfactant cyclodextrin nanoparticles loaded with anticancer drug paclitaxel.

In the current formulation of clinical use paclitaxel (PCX) is associated with solubilizers that may produce severe side effects. In this study, PCX was complexed to an amphiphilic cyclodextrin (CD), 6-O-CAPRO-beta-CD, capable of forming nanoparticles spontaneously in order to mask its physicochemical properties via the formation of inclusion complexes of the drug with amphiphilic CD before the nanoparticle is formed. Complexes have been characterized with various techniques such as (1)H NMR, Fourier Transform Infrared (FTIR), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM) confirming the formation of inclusion complex between PCX and 6-O-CAPRO-beta-CD. Nanospheres and nanocapsules were prepared directly from the preformed PCX/6-O-CAPRO-beta-CD inclusion complex by the nanoprecipitation technique, showing a size from 150 to 250 nm for nanospheres and from 500 to 500 nm for nanocapsules. Zeta potentials of the nanospheres and nanocapsules indicate stable colloidal dispersions within the range of -18 to -39 mV. A 12-month physical stability was demonstrated for blank nanoparticles. PCX encapsulation was high with three-fold increase in loading when nanoparticles are prepared directly from preformed inclusion complexes of the drug with 6-O-CAPRO-beta-CD. In vitro liberation profiles of PCX from CD nanoparticles show a prolonged release profile for this drug up to 12 h for nanospheres and 24 h for nanocapsules.

Synthesis of 3-substituted-5-(4-carb oxycyclohexylmethyl) - tetrahydro-2H-1,3,5-thiadiazine-2-thione derivatives as antifibrinolytic and antimicrobial agents.

A series of 3-substituted-5-(4-carboxycyclohexylmethyl)-tetrahydro-2H-1,3,5thiadiazine-2-thione derivatives was prepared and examined for antifibrinolytic and antimicrobial activities. Their structures were elucidated by spectral methods. Antifibrinolytic activities of these compounds, were investigated in vitro and compared to tranexamic acid (CAS 1197-18-8). Among the synthesized compounds, 3-methyl-5-(4-carboxycyclohexylmethyl)-tetrahydro-2H-1,3,5-thiadiazine-2-thione (Ia) was the most prominent one (104%) when compared to tranexamic acid. Besides, 3-ethyl-5-(4-carboxycyclohexyl-methyl)-tetrahydro-2H-1,3,5-thiadiazine-2-thione (Ib), 3-iso-propyl-5-(4-carboxycyclohexylmethyl)-tetrahydro-2H-1,3,5-thiadiazine-2-thione (Id) and 3-isobutyl-5-(4-carboxycyclohexyl-methyl)-tetrahydro-2H-1,3,5-thiadiazine-2-thione (Ig) showed antifibrinolytic activity similar to tranexamic acid. Antibacterial activities of these compounds against Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis), Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa) and yeast-like fungi (Candida albicans, Candida tropicalis) were investigated by the micro-dilution method and compared with the activity of tranexamic acid, ofloxacin and fluconazole. By this way their minimal inhibitory concentration (MIC), minimal bactericidal concentration (MBC) and minimal fungicidal concentration (MFC) values were determined. Compound Ia exhibited almost equally potent activity against B. subtilis (MIC and MBC: 6.25 microg/mL). Compounds Ib-Id, If-Ig and In exhibited similar bactericidal activity against B. subtilis (MBC: 12.5 microg/mL). Compounds Ik and Im showed bacteriostatic activity against S. aureus. None of the compounds exhibited activity against Gram-negative bacteria. On the other hand, all compounds had potent antifungal activities against the yeast utilized. Among the synthesized compounds, 3-methyl-5-(4-carboxycyclohexylmethyl)-tetrahydro-2H-1,3,5-thiadiazine-2-thione (Ia) seems to be the most effective compound with antifibrinolytic and antimicrobial activity.

Design and synthesis of some new thiazolo [3,2-b]-1,2,4-triazole-5(6H)-ones substituted with flurbiprofen as anti-inflammatory and analgesic agents.

In the course of our ongoing studies, a series of thiazolo[3,2-b]-1,2,4-triazole-5(6H)-ones substituted with flurbiprofen (CAS 5104-49-4) has been prepared. The compounds were synthesized by the cyclization of the 3-[(2-fluoro-4-biphenyl)ethyl]-5-mercapto-1,2,4-triazole (3) with chloroacetic acid and relevant benzaldehydes in the presence of acetic acid, acetic anhydride and anhydrous sodium acetate in one step. The product of this one-pot synthesis that precipitated on cooling of the reaction mixture was identified undoubtedly by X-ray crystallographic analysis as thiazolo[3,2-b]-1,2,4-triazole. In-vivo anti-inflammatory and analgesic activities of the compounds were assessed by carrageenan-induced hind paw edema and p-benzoquinone-induced abdominal constriction tests in mice, respectively. In addition, the ulcerogenic risks were evaluated. It is worthy of saying that the compounds which maintained analgesic/antiinflammatory activity of the starting compound were found to be safer with regard to gastric lesion risks at 100 mg/kg oral dose when compared with flurbiprofen. Among the synthesized compounds 3d showed the highest analgesic and antiinflammatory activity without inducing any gastric lesion and deserves further attention in order to develop new lead drug candidates.

Preparation of 5-aryl-3-alkylthio-l,2,4-triazoles and corresponding sulfones with antiinflammatory-analgesic activity.

In this study, a series of 5-aryl-3-alkylthio-1,2,4-triazoles and corresponding sulfones were prepared with the objective of developing better analgesic-antiinflammatory compounds with minimum ulcerogenic risk. The structures of the compounds were elucidated by spectral and elemental analysis. The compounds were assayed per os in mice for their antiinflammatory and analgesic activity as well as the ulcerogenic risk and acute toxicity. Several of these compounds showed significant activity. Alkylsulfone derivatives were found to be much more potent analgesic-antiinflammatory agents than the corresponding alkylthio analogs. Compounds 9 and 11 were the most active of the series in both analgesic and antiinflammatory activity tests. In contrast to reference compound acetyl salicylic acid, these compounds did not induce gastric lesions in the stomach of experimental animals at the doses that exhibited analgesic/antiinflammatory activity.

Synthesis and evaluation of analgesic/ anti-inflammatory and antimicrobial activities of 3-substituted- 1,2,4-triazole-5-thiones.

In this study, the synthesis of a novel series of Mannich bases of 5-mercapto-3-aryl-1,2,4-triazoles is described. The structures attributed to compounds la-5e were elucidated using IR and 1H-NMR spectroscopic techniques besides elemental analysis. The formation of 1-aminomethyl-3-substituted-1,2,4-triazole-5-thiones - not the isomeric 3-substituted-4-aminomethyl-1,2,4-triazole-5-thiones was unambiguously confirmed by X-ray crystallographic analysis of 1c. The compounds were examined for their in vivo anti-inflammatory and analgesic activity in two different bioassays, namely carrageenan-induced hind paw edema and p-benzoquinone-induced abdominal constriction tests in mice, respectively. In addition, the ulcerogenic effects of the compounds were determined. Among the tested derivatives most promising results were obtained for the compounds bearing a nonsubstituted phenyl group at C-3 position of the triazole ring (1a-e). The compounds were also evaluated for their in vitro antimicrobial activity against a series of gram positive bacteria [Staphylococcus aureus (ATCC 29213), Enterococcus faecalis (ATCC 29212)], gram negative bacteria [Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853)] and yeast-like microorganisms [Candida albicans (ATCC 90028), C. krusei (ATCC 6258), C. parapsilosis (ATCC 22019)]. One series of the examined compounds (3a-e) exhibited better antibacterial activity especially against gram positive bacteria than against gram negative bacteria. Compounds 2c, 3b, and 3e were found to be more effective against C. parapsilosis compared with the other derivatives (MIC: 16 microg/mL).

Protective effects of thiazolo[3,2-b]-1 ,2,4-triazoles on ethanol-induced oxidative stress in mouse brain and liver.

A series of 3-[1-(4-(2-methylpropyl) phenyl) ethyl]-1 ,2,4-triazole-5-thione (I) and its bicyclic condensed derivatives 6-benzylidenethiazolo[3,2-b]-1,2,4-triazole-5(6H)-ones (IIa-IIf) were investigated for the prevention of ethanol-induced oxidative stress in liver and brain of mice. Administration of ethanol (0.1 mL/mice, p.o.) resulted in a drop of total thiol groups (T-SH) and non-protein thiol groups (NP-SH), and an increase in thiobarbituric acid reactive substances (TBARS) in both liver and brain tissue of mice (p < 0.001). Among the compounds investigated (at a dose of 200 mg/kg, p.o.), I and IId ameliorated the peroxidative injury in these tissues effectively. Compounds IIa, IIc and IIe improved the peroxidative tissue injury only in brain. These findings suggest that certain condensed thiazolo-triazole compounds may contribute to the control of ethanol-induced oxidative stress in an organ selective manner.

Chiral capillary electrophoresis: facts and fiction on the reproducibility of resolution with randomly substituted cyclodextrins.

Comparative enantioseparation of the enantiomers of 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate was performed with cyclodextrin (CD)-modified capillary electrophoresis (CE). Two single isomers, beta-CD, heptakis(2,3,6-tri-O-methyl)-beta-CD (TM-beta-CD), and heptakis(2,6-di-O-methyl)-beta-CD (DM-beta-CD) of 98% purity as well as heptakis(2,3-di-O-acetyl)-beta-CD were used and compared in terms of resolution power to randomly methylated and corresponding acetylated beta-CDs, which were synthesized in our laboratory. The methylated ones were characterized by means of matrix-assisted laser desorption/ionization-time of flight-(MALDI-TOF) mass spectrometry. By testing defined mixtures of single isomers and comparing their resolution power to randomly substituted CDs of similar degree of substitution we could show, that a simple characterization by the average molecular degree of substitution (DS) is not sufficient. In order to get reproducible results, a clearly defined substitution pattern is necessary, which is not given using randomly substituted CDs. Taken together, a validation of a chiral separation with "undefined" CD derivatives is almost impossible.

6-(2-Fluorobenzylidene)-2-[1-(2-fluoro-4-biphenyl)ethyl]thiazolo[3,2-b][1,2,4]triazol-5(6H)-one.

The title compound, C(25)H(17)F(2)N(3)OS, was synthesized from 6-(benzylidene)thiazolo[3,2-b][1,2,4]triazol-5(6H)-one. The fused thiazolo[3,2-b][1,2,4]triazole system is essentially planar, and bifurcated C-H.O, C-H.N and C-H.F interactions are present between molecules.

Synthesis, characterization and antiinflammatory-analgesic properties of 6-(alpha-amino-4-chlorobenzyl)thiazolo [3,2-b]-1,2,4-triazol-5-ols.

A series of 6-(alpha-amino-4-chlorobenzyl)-thiazolo[3,2-b]-1,2,4-triazol-5-ols (2a-j) were synthesized from 6-(4-chlorobenzylidene) thiazolo[3,2-b]-1,2,4-triazolo-5(6H)-one (2) by applying Michael addition reaction. All the compounds were characterized by their melting points, elementary analysis, IR and 1H-NMR spectra and screened for their anti-inflammatory and analgesic activities. Among the derivatives compound 2i bearing 4-(4-acetylphenyl)piperazine showed the highest and dose-dependent analgesic and anti-inflammatory activity without inducing any gastric lesion.

Synthesis, enantioseparation and pharmacological activity of 4-aryl-7,7-dimethyl-5-oxo-1,2,3,4,5,6,7,8-octahydroquinazoline-2-thiones.

4-Aryl-7,7-dimethyl-5-oxo-1,2,3,4,5,6,7,8-octahydroquinazoline-2-thione derivatives (1-8) have been prepared by modified Biginelli reaction from 5,5-dimethyl-1,3-cyclohexanedione, the aromatic aldehydes and thiourea. The structures of the compounds were confirmed by spectroscopic and elemental analysis. Racemic compounds were resolved into their enantiomers by HPLC using an amylose tris-(3,5-dimethylphenylcarbamate) chiral stationary phase in the normal phase mode. The calcium antagonist activities of the compounds were determined by the tests performed on isolated rat ileum and lamb carotid artery. Compounds 2, 3, 4 and 6 were the most active compounds on isolated rat ileum. Compounds 2 and 3 were significantly active on lamb carotid artery.