Synthesis and evaluation of 2-amino-5-sulfanyl-1,3,4-thiadiazoles as antidepressant, anxiolytic, and anticonvulsant agents

The purpose of this study was to evaluate the title compounds on central nervous system activity by varying the substituents in the thiadiazole moiety. The newly synthesized intermediates and compounds were characterized by spectral analysis. Two of the tested compounds (3a and 3b) exhibited excellent antidepressant, anxiolytic, and anticonvulsant activity in comparison with the reference drugs.     

Some substituted 1,3,4-thiadiazoles: a novel centrally acting agents

In the present study, a series of 2-amino-5-sulphanyl-1,3,4-thiadiazole derivatives were synthesized in good yields and the structure of these compounds were established by means of FT-IR, ¹H/¹³C NMR, mass, and elemental analysis. The synthesized compounds were screened pharmacologically to evaluate their central nervous system activity. The purpose of this study was to evaluate the title compounds on Central Nervous System activity by varying the substituents in the thiadiazole scaffold. Three of the tested compounds (centrally acting agents) 2a, 2d, and 2g exhibited excellent antidepressant, anxiolytic, and anticonvulsant activity in comparison to the reference drugs.     

5-Nitroimidazole-based 1,3,4-thiadiazoles: heterocyclic analogs of metronidazole as anti-Helicobacter pylori agents

A series of 5‐nitroimidazole‐based 1,3,4‐thiadiazoles were prepared and tested for antibacterial activity against Helicobacter pylori. The anti‐H. pylori activity of target compounds along with the commercially available antimicrobial metronidazole was evaluated by comparing the inhibition‐zone diameters determined by the paper disc diffusion bioassay. From our bioassay results against 20 clinical isolates it is evident that piperazinyl, 4‐methylpiperazinyl, 3‐methylpiperazinyl, and 3,5‐dimethylpiperazinyl analogs ( 6a , 6b , 6e , and 6f , respectively) and pyrrolidine derivative 7 had strong activity at 0.5 µg/disc (average of inhibition zone >20 mm) while metronidazole had no activity at this dose. Compound 6f containing the 3,5‐dimethylpiperazinyl moiety at the 2‐position of the 5‐(1‐methyl‐5‐nitro‐1H‐imidazol‐2‐yl)‐1,3,4‐thiadiazole skeleton was the most potent compound tested at low concentrations.     

Synthesis of novel 3-(5-sulfanyl-1,3,4-oxadiazol-2-yl)-2H-chromen-2-one condensed s-triazinyl piperazines and piperidines as antimicrobial agents

Synthesis and antimicrobial activity of a new series of 3-(5-sulfanyl-1,3,4-oxadiazol-2-yl)-2H-chromen-2-ones based on various substituted piperazines and piperidines incorporating a 1,3,5-triazine moiety are reported in this article. 3-{5-[(4,6-dichloro-1,3,5-triazin-2-yl)sulfanyl]-1,3,4-oxadiazol-2-yl}-2H-chromen-2-one 3 was obtained by the reaction of 2,4,6-trichloro-1,3,5-triazine 1 with 3-(5-sulfanyl-1,3,4-oxadiazol-2-yl)-2H-chromen-2-one 2 which was obtained by following the method reported in the literature. Intermediate 3 was then condensed with 8-hydroxyquinoline 4 to form 3-(5-{[4-chloro-6-(quinolin-4-yloxy)-1,3,5-triazin-2-yl]sulfanyl}-1,3,4-oxadiazol-2-yl)-2H-chromen-2-one 5. This was further treated with various substituted piperazines and piperidines to obtain the title compounds 7a–u, which were then subjected to determine their in vitro biological efficacy against bacterial and fungal strains as two Gram-positive bacteria (S. aureus, B. cereus), six Gram-negative bacteria (E. coli, P. aeruginosa, K. pneumoniae, S. typhi, P. vulgaris, and S. flexneria) and two fungal species (A. niger, and C. albicans) with an intent to develop novel class of antimicrobial agents. The results indicate that some of the novel s-triazines have noteworthy activity in MIC (μg/ml) and zone of inhibition (mm) indicating potential leads for further drug discovery study. All the final compounds were structurally elucidated on the basis of IR, ¹H NMR, ¹³C NMR, ¹⁹F NMR spectroscopy, and elemental analysis.     

Synthesis and biological evaluation of 2-amino-5-sulfanyl-1,3,4-thiadiazole derivatives as antidepressant, anxiolytics and anticonvulsant agents

A new series of 2-amino-5-sulfanyl-1,3,4-thiadiazole derivatives has been synthesized. The newly synthesized compounds were characterized by analytical and spectral methods. Compounds were screened for central nervous system activity. Compounds 1, 5, 7, 10, 14 exhibited significant antidepressant, anxiolytic and anticonvulsant activity in comparison to the reference drugs.     

Synthesis of novel 1-pyrazolylpyridin-2-ones as potential anti-inflammatory and analgesic agents

A new series of 4-alkyl/aryl-2-oxo-1-pyrazolyl-1,2-dihydropyridine-3-carbonitriles, pyrazolo[3,4-b]pyridine-5-carbonitriles and pyrido[2,3-d]pyrimidine-6-carbonitriles have been synthesized and tested for their anti-inflammatory and analgesic activities. Among the tested compounds, 3e and 8b exhibited comparable anti-inflammatory activity to the standard (indomethacin). Compounds 5, 7a, and 8b displayed potent analgesic activity. Detailed syntheses, spectroscopic and biological data are reported.     

Zur Kenntnis der 2-Amino-1,3,4-oxdiazole Mitt.: 2-Amino-5-aryloxy(thio)alkyl-1,3,4-oxdiazole

By action of cyanogen bromide on aryloxy(thio)acylhydrazines (I) 2-amino-5-aryloxy(thio)alkyl-1,3,4-oxdiazoles (II) are formed. Some reactions of II are described, for instance the addition of phenylisocyanate and the alcoholysis as well as the opening of the ring with acylhydrazines. Characteristic bands of infrared spectra are given.     

Studies on novel 7-acyl-5-chloro-2-oxo-3H-benzoxazole derivatives as potential analgesic and anti-inflammatory agents

In this study, a series of (7-acyl-5-chloro-2-oxo-3H-benzoxazol-3-yl)alkanoic acid derivatives were synthesized and evaluated for their analgesic and anti-inflammatory activities by using the p-benzoquinone-induced writhing test and the carrageenan hind paw edema model, respectively. Acetic acid-induced peritoneal capillary permeability test and serotonin-induced hind paw edema test were also employed for the most active compounds. The test results indicated that (7-acyl-2-oxo-3H-benzoxazol-3-yl)alkanoic acids (Compounds 6 a-c, 8 a-c, 10 a-c) were equally or more potent analgesic and anti-inflammatory agents than aspirin and indomethacin respectively. The compounds 8a and 8c, but not 8b have the longest carbon chain on alkanoic acid moiety did not induce gastric lesion in mice.     

Synthesis of some new 2-(6-methoxy-2-naphthyl)- 5-aryl-1,3,4-oxadiazoles as possible non-steroidal anti-inflammatory and analgesic agents

The synthesis of some new 2-(6-methoxy-2-naphthyl)-5-aryl-1,3,4-oxadiazoles (4a-k) has been described. Ethyl-6-methoxy-2-naphthoate (1) yielded on treatment with hydrazine hydrate to 6-methoxy-2-naphthoic acid hydrazide (2). Compound 2 reacted with substituted aromatic carboxylic acids (3a-k) in phosphorus oxychloride yielded 2-(6-methoxy-2-naphthyl)-5-aryl-1,3,4-oxadiazoles (4a-k). Newly synthesized compounds were characterized by IR, (1)H-NMR and mass spectral data. All the compounds were screened for their anti-inflammatory and analgesic activity. Compound 4j exhibited promising anti-inflammatory and analgesic activities.     

Synthesis of some new 2-(substituted-phenyl)-5-(N,N-diphenylaminomethyl)-1,3,4-oxadiazoles: a safer anti-inflammatory and analgesic agents

A series of 2-(substituted-phenyl)-5-(N,N-diphenylaminomethyl)-1,3,4-oxadiazoles (3-15) were synthesized. The compounds were evaluated for their anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation actions. The percentage inhibition in edema at different time intervals indicated that compounds 8, 11, 12, 14 and 15 exhibited good anti-inflammatory potential. The results illustrate that 2-(2-acetoxyphenyl)-5-(N,N-diphenylaminomethyl)-1,3,4-oxadiazole (15) and 2-(3,4-dimethoxyphenyl)-5-(N,N-diphenylaminomethyl)-1,3,4-oxadiazole (12) showed best anti-inflammatory activity among the series tested. Furthermore, activity is higher in case of chloro substitution as compared to methyl substitution. The compounds synthesized were also evaluated for their ulcerogenic and lipid peroxidation action and showed superior GI safety profile along with reduction in lipid peroxidation as compared to that of ibuprofen.     

Synthesis and biological evaluation of novel benzyl piperazine derivatives of 5-(5-nitroaryl)-1,3,4-thiadiazoles as Anti-Helicobacter pylori agents

Background and the purpose of the study

Helicobacter pylori is recognized as the main cause of gastritis and gastroduodenal ulcers and classified as class 1 carcinogen pathogen. Different 1,3,4-thiadiazole derivatives bearing 5-nitroaryl moiety have been shown considerable anti- H. pylori activity. In attempt to find new and potent derivatives of described scaffold, a new series of 1-(substituted benzyl)-4-(5-(5-nitroaryl-2-yl)-1,3,4-thiadiazol-2-yl)piperazine derivatives were synthesized and evaluated against three metronidazole-resistant isolates of H. pylori using paper disk diffusion bioassay test.

Methods

The title compounds were prepared through the reaction of 1-(5-(5-nitroaryl-2-yl)-1,3,4-thiadiazol-2-yl) piperazine 5a-b and substituted benzyl chloride in DMF. The inhibitory activity of the new derivatives 6a-q against three metronidazole-resistant isolates of H. pylori was evaluated by the disc diffusion method and compared with the commercially available standard drug metronidazole.

Results and discussion

The results of SAR study indicated that the potency and anti-H. pylori activity profile of synthesized derivatives is mainly attributed to the substituted nitroaryl moiety at the C-5 position of 1,3,4-thiadiazole ring. Most of 1,3,4-thiadiazole derivatives bearing 5-nitrofuran moiety at C-5 position of central thiadiazole ring, demonstrated more promising anti-H. pylori than the 5-nitrothiophen counterpart.

Conclusion

The most potent nitrofuran derivative containing 3-methoxybenzyl piperazine pendant at the C-2 position of 1,3,4-thiadiazole ring (compound 6i), demonstrated strong anti-H. pylori potential at studied concentrations 100-25 μg/disk (IZD > 20 mm) against all studied metronidazole- resistant isolates of H. pylori.     

Synthesis and biological evaluation of novel 2-[substituted acetly]-amino-5-alkyl]-amino-5-alkyl-1,3,4-thiadiazoles

Sixteen novel 2-substituted acetyl amino-5-alkyl-1,3,4-thiadiazole were synthesized and screened for their pharmacological activities. A few of the compounds namely 11, 12 and 16 showed anti-inflammatory activities comparable to phenylbutazone. Compound 12 also showed significant non-specific spasmolytic activity. Diuretic activity of compound 15 at a dose level of 90 mg/kg p.o. was two fold higher compared to 50 mg/kg p.o. of furosemide. Comparable diuresis was also produced by compounds 9, 10 and 16. Division of Medicinal Chemistry, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya [Formerly University of Saugor] Sagar 470003 (MP), India     

Zur Kenntnis der 2-Amino-1,3,4-oxidiazole 27. Mitt.: Hydroxyalkyl-substituierte 2-Amino-1,3,4-oxdiazole

2-Amino-1,3,4-oxdiazoles. PART XXVII 5-[Hydroxyalkyl]-2-amino-1,3,4-oxdiazoles are accessible from aliphatic hydroxy acid hydrazides and cyanogen bromide. Their reactive behaviour is studied in some examples. Characteristic infrared bands are given.     

Synthesis of novel pyrazole and dihydropyrazoles derivatives as potential anti-inflammatory and analgesic agents

Novel dihydropyrazole 5-8, 10 and pyrazole derivatives 12, 14, 15, 17 were synthesized. The structures of the newly synthesized compounds were elucidated by spectral and elemental analyses. The anti-inflammatory activity of all new compounds was evaluated using the carrageenan-induced rat paw edema test using indomethacin and celecoxib as reference drugs. The most active derivatives as anti-inflammatory agents were accordingly tested for their analgesic activity using the p-benzoquinone-induced writhing method in mice and results revealed that these compounds had also good analgesic activity. The ulcerogenic liability of the selected compounds was also evaluated. Results showed that the selected derivatives had anti-inflammatory activity comparable to or slightly lower than the reference drugs, reaching about 82% inhibition with a considerable gastric safety profile.     

Synthesis and analgesic activity of some novel 2-substituted 1,3,4-thiadiazolo

An ecofriendly synthesis for 1,2,3,4,5,6,8-octahydro- 3-amino-2-thioxo-benzothieno[2,3-d]pyrimidin-4-one (7A, B) has been developed. A series of hitherto unreported compounds (2a-i, 3a-c) have been synthesized by treating 3-Amino-2-mercaptopyrimidinones (7A, B) with one carbon donors like chloroacetyl chloride or chloroacetic acid and subsequently replacing the chloro group by various nucleophiles. Compound 2f was successfully synthesized by an alternate route. All the new compounds were characterized by elemental and spectral analyses. They were screened for analgesic activity in mice. Compounds 2a, b, 3a, b, and 2e, showed very good activity.     

Synthesis and anti-inflammatory activity of 1-acylthiosemicarbazides, 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazole-3-thiones

Sixteen 1-(2-naphthyloxyacetyl)-4-substituted-3-thiosemicarbazide, 2-(2-naphthyloxymethyl)-5-substitutedamino-1,3,4-oxadiazole, 2-(2-naphthyloxymethyl)-5-substitutedamino-1,3,4-thiadiazole and 5-(2-naphthyloxymethyl)-4-substituted-1,2,4-triazole-3thione derivatives have been prepared and evaluated as orally active anti-inflammatory agents with reduced side-effects. The structures of the compounds were confirmed by IR and 1H NMR spectral data and microanalysis. The anti-inflammatory and ulcerogenic activities of the compounds were compared with naproxen, indomethacin and phenylbutazone. In carrageenan-induced foot pad edema assay, 2-(2-naphthyloxymethyl)-5-methylamino-1,3,4-oxadiazole, 5-(2-naphthyloxymethyl)-4-methyl-1,2,4-triazole-3-thione and 5-(2-naphthyloxymethyl)-4-ethyl-1,2,4-triazole-3-thione showed an interesting anti-inflammatory activity. In the air-pouch test, 1,3,4-oxadiazole and 1,2,4-triazole-3-thione derivatives reduced total number of leukocytes of the exudate that indicates excellent inhibition of prostaglandin production. Side effects of the compounds were examined on gastric mucosa, liver and stomach and none of the compounds showed significant side effects compared with reference nonsteroidal anti-inflammatory drugs (NSAIDs).     

Synthesis of 2-amino-5-sulfanyl-1,3,4-thiadiazole derivatives and evaluation of their antidepressant and anxiolytic activity

Recently a series of 2-amino-5-sulfanyl-1,3,4-thiadiazole derivatives bearing different substituents were synthesized and screened pharmacologically in order to evaluate their central nervous system activity. The purpose of this study was to evaluate the effects of the title compounds on CNS activity by varying the substituents in the thiadiazole moiety. It was found that some of these compounds possess marked antidepressant and anxiolytic properties comparable in efficiency to the reference drugs Imipramine and Diazepam. The most potent compound 3k was further investigated to complete its pharmacological profile with respect to undesired side effects. Behavioral results showed that 3k is a very promising compound, characterized by a mixed antidepressant-anxiolytic activity accompanied by a therapeutic dose range that is essentially 2 orders of magnitude less than that at which side effects such as sedation and amnesia are evident.     

Zur Kenntnis der 2-Amino-1,3,4-oxdiazole 39. Mitt.: Darstellung und Reaktionen von [2-Amino-1,3,4-oxdiazolyl-(5)]-carbinolen

2-Amino-1,3,4-oxdiazoles. Part 39 [2-Amino-1,3,4-oxdiazolyl-(5)]-carbinols possess the typical properties of amino-oxdiazoles. They can be acylated easily and transformed into the 1,2,4-triazolyl-(5)-carbinols. Diphenyl-[2-amino-1,3,4-oxidiazylyl-(5)]-carbinol is analogous to triphenylcarbinol. It can be reduced and produces together with phenols, phenol ethers and aromatic amines condensation products. IR and UV spectra establish the described structure of the compounds.     

Licofelone--a novel analgesic and anti-inflammatory agent

Dual inhibitors that block both cyclooxygenase (COX) and lipoxygenase (LOX) metabolic pathways of arachidonic acid are expected to possess clinical advantages over the selective inhibitors of COX enzyme. One of the most promising compounds belonging to this category is licofelone ([2,2 -dimethyl -6-(4-chloropheny-7-phenyl-2,3-dihydro-1H-pyrrazoline-5-yl] acetic acid). Originally discovered by Merckle GmbH and developed by EuroAllaince, licofelone (IC(50) COX=0.21 microM, IC(50) 5-LOX=0.18 microM) possesses significant analgesic, anti-inflammatory, and antiasthmatic effects at doses that cause no gastrointestinal (GI) side effects. The pharmacodynamic profile of licofelone has been assessed and compared with widely used NSAIDs in different animal models. The ED(50) value of licofelone is reported to be 11.22-27.07 mg/kg, po and 39.5-55-8 mg/kg, po against carrageenan-induced paw oedema and Randal Selitto hyperalgesic assay in rats, respectively. Licofelone showed analgesic effect (ED(50) = 31.33 mg/kg) against acetic acid-induced writhing in mice. Licofelone has long duration of action and more effective than indomethacin and zileuton with ED(50) values of 2.92 mg/kg, po and 36.77 mg/kg, po, in the mechanical hyperalgesia and cold allodynia testing, respectively, against rat model of incisional pain. Licofelone significantly ameliorated indomethacin-induced gastric ulceration, neutrophil adhesion in mesentery, and lipid peroxides in rat gastric mucosa. Also, licofelone reversed the altered vascular permeability, morphological changes, and prevented NSAIDs-related increase in leukotriene levels in gastric mucosa. The preclinical studies have shown that licofelone not only has convincing pharmacodynamic effect but also it is well tolerated. It is currently under clinical evaluation in osteoarthritis (OA), the most common form of arthritis. The present review describes pharmacological and clinical development of licofelone as a dual inhibitor.