Synthesis, antibacterial and antitubercular activities of some 7-[4-(5-amino-[1,3,4]thiadiazole-2-sulfonyl)-piperazin-1-yl] fluoroquinolonic derivatives.

In the present study, a series of 7-[4-(5-amino-1,3,4 thiadiazole-2-sulfonyl)]-1-piperazinyl fluoroquinolonic derivatives VIIa-d were synthesized in good yields and characterized by IR, (1)H-NMR, (13)C-NMR, FAB Mass spectral and elemental analyses. The compounds were evaluated for their preliminary in vitro antibacterial activity against some Gram-positive and Gram-negative bacteria and selected compounds VIIa, b were screened for antitubercular activity against Mycobacterium tuberculosis H(37)Rv strain by broth dilution assay method. The antibacterial data of the tested N-sulfonylfluoroquinolones VIIa-d indicated that all the synthesized compounds showed better activity against Gram-positive bacteria S. aureus, E. faecelis, Bacillus sp. (MIC=1-5 microg ml(-1), respectively) compared to reference drugs. The MIC values of tested derivatives connotes that the sparfloxacin and gatifloxacin derivatives VIIc, d were most active against the tested Gram-positive bacterial strains (MIC=1-5 microg ml(-1)). All the tested compounds VIIa-d showed poor activity against the Gram-negative bacteria. The in vitro antitubercular activity reports of selected compounds VIIa, b against M. tuberculosis strain H(37)Rv showed moderate activity at MIC of 10 microg ml(-1).

Insight into the structural requirements of urokinase-type plasminogen activator inhibitors based on 3D QSAR CoMFA/CoMSIA models

Urokinase-type plasminogen activator (uPA), a trypsin-like serine protease, has been implicated in large number of malignancies, tumor cell invasion, angiogenesis and metastasis; hence, the potent and selective inhibitors of uPA may therefore be therapeutically useful drugs for treatment of various forms of cancer. A three-dimensional quantitative structure-activity relationship (3D QSAR) study was performed on five different chemical series reported as selective uPA inhibitors employing comparative molecular field analysis (CoMFA)/comparative molecular similarity indices analysis (CoMSIA) techniques to investigate the structural requirements for substrates and derive a predictive model that may be used for the design of novel uPA inhibitors. ClogP has been used as an additional descriptor in the CoMFA analysis to study the effects of lipophilic parameters on activity. Inclusion of ClogP did not improve the models significantly and exhibited comparable correlation coefficients with CoMFA steric and electrostatic models. 3D QSAR models were derived for 2-pyridinylguanidines (training set N = 25, test set N = 8), 4-aminoarylguanidines and 4-aminoarylbenzamidines (training set N = 29, test set N = 8), thiophene-2-carboxamindines (training set N = 64, test set N = 19), 2-naphthamidines (training set N = 32, test set N = 8), and 1-isoquinolinylguanidines (training set N = 29, test set N = 7). 3D contour maps generated from these models were analyzed individually, which provides the regions in space where interactive fields may influence the activity. The superimposition of contour maps on the active site of serine proteases additionally helps in understanding the structural requirements of these inhibitors. Further, the predictive ability of 3D QSAR models was affirmed by predicting the activity of novel 2-naphthamidines. 3D QSAR models developed may be used in designing and predicting the uPA inhibitory activity of novel molecules.

3D-QSAR CoMFA/CoMSIA studies on Urokinase plasminogen activator (uPA) inhibitors: a strategic design in novel anticancer agents.

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) was performed on a series of indole/benzoimidazole-5-carboxamidines as urokinase plasminogen activator (uPA) inhibitors. The ligand molecular superimposition on template structure was performed by atom/shape-based RMS fit, multifit, and RMSD fit methods. The removal of two outliers from the initial training set of 30 molecules improved the predictivity of the models. The statistically significant model was established from 28 molecules, which were validated by evaluation of test set of nine compounds. The atom-based RMS alignment yielded best predictive CoMFA model (r2(cv) = 0.611, r2(cnv) = 0.778, F value = 43.825, r2(bs) = 0.842, r2(pred) = 0.616 with two components) while the CoMSIA model yielded (r2(cv) = 0.499, r2(cnv) = 0.976, F value=96.36, r2(bs) = 0.993, r2(pred) = 0.694 with eight components). The contour maps obtained from 3D-QSAR studies were appraised for the activity trends of the molecules analyzed. The results indicate that the steric, electrostatic, and hydrogen bond donor/acceptor substituents play significant role in uPA activity and selectivity of these compounds. The data generated from the present study can be used as putative pharmacophore in the design of novel, potent, and selective urokinase plasminogen activator inhibitors as cancer therapeutics.

Synthesis and biological activity of some 3-methyl/ethoxycarbonyl-6-arylimidazo[2, 1-b]thiazoles and their 5-bromo/5-formyl derivatives

Facile reaction of arylacylbromide 1 with 2-amino-4-methylthiazole 2 and its hindered reaction with 2-amino-4-ethoxycarbonylthiazole 3 during the synthesis of 3-methyl/ethoxycarbonyl-6-arylimidazo[2,1-b]thiazoles 8/9 are explained on the basis of electronic effects of the 4-substituent of thiazole substrate. Their bromination/formylation afforded the corresponding 5-bromo and 5-formyl derivatives. Results of preliminary screening of the target compounds reveal moderate anthelmintic and anti-inflammatory activity.

Synthesis and antibacterial activity of some 5-guanylhydrazone/thiocyanato-6-arylimidazo[2,1-b]-1,3, 4-thiadiazole-2-sulfonamide derivatives.

6-Arylimidazo[2,1-b]-1,3,4-thiadiazole-2-sulfonamides 3 on Vilsmeier-Haak reaction produced 5-formyl-6-arylimidazo[2,1-b]-1,3, 4-thiadiazole-2-[N-(dimethylaminomethino)]sulfonamides 4, while 3 on treatment with potassium thiocyanate in the presence of bromine in acetic acid produced 5-thiocyanato-2-sulfonamides 6. Interaction of 4 with aminoguanidine hydrochloride in ethanol produced the corresponding 5-guanylhydrazone derivatives 5. Compounds 5 and 6 showed a high degree of antibacterial activity against both Escherichia coli and Staphylococcus aureus comparable to that of sulfamethoxazole and Norfloxacin. However, they were found to show moderate activity against Salmonella typhi, Pseudomonas aeruginosa and Pneumococci.

Role of C-5 chiral center in R-(+)-pulegone-mediated hepatotoxicity: metabolic disposition and toxicity of 5, 5-dimethyl-2-(1-Methylethylidene)-cyclohexanone in rats.

Metabolic disposition of 5, 5-dimethyl-2-(1-methylethylidene)-cyclohexanone (I) was examined in rats. Compound (I) was administered orally (250 mg/kg of body weight/day) to rats for 5 days. The following urinary metabolites were isolated and identified: 4,5,6,7-tetrahydro-3,6, 6-trimethylbenzofuran (III), 3,3-dimethylcyclohexanone (VI), 5, 5-dimethyl-3-hydroxy-2-(1-methylethylidene)-cyclohexanone (X), 5, 5-dimethyl-2-(1-hydroxymethylethyl)-cyclohexanone (IX), 3-hydroxy-5-hydroxymethyl-5-methyl-2-(1-methylethylidene)-cyclo hexano ne (XI), 5,6-dihydro-3,6,6-trimethyl-2(4H)-benzofuranone (VIII), and 5,5-dimethyl-3-hydroxy-2-(1-carboxy ethylidene)-cyclohexanone (XIII). Incubation of compound (I) with phenobarbital (PB)-induced rat liver microsomes in the presence of NADPH resulted in the formation of a metabolite, tentatively identified as a furanoterpene (III) based on proton magnetic resonance, gas chromatography, and gas chromatography-mass spectroscopy analyses. The formation of III was inhibited to a significant extent by carbon monoxide, metyrapone, SKF 525-A, and cytochrome c, suggesting the participation of PB-induced microsomal cytochrome P-450 system in the conversion of I to III. Compound I gave type I spectral change in the PB-induced liver microsomes and the dissociation constant (Ks) for I was 38.5 microM. Intraperitoneal administration of a single dose (250 mg/kg) of I to rats resulted in 26, 23, and 41% decreases in the levels of cytochrome P-450, glucose-6-phosphatase, and aminopyrine N-demethylase, respectively, at the end of 24 h. During this period, a 11-fold increase in serum glutamate pyruvate transaminase level was also observed. However, a decrease in the level of cytochrome P-450 and glucose-6-phosphatase, and an increase in serum glutamate pyruvate transaminase values were comparatively more pronounced when R-(+)-pulegone (250 mg/kg) or CCl(4) (0.6 ml/kg) was administered to rats. Pretreatment of rats with PB potentiated the hepatotoxicity caused by I, whereas pretreatment with 3-methylcholanthrene protected from it. This suggests that PB-induced cytochrome P-450-catalyzed reactive metabolites may be responsible for the toxic effects caused by I.

Synthesis and biological evaluation of 5-formyl-6-arylimidazo(2,1-b)-1,3,4-thiadiazole-2-N-(dimethylaminomethi no) sulfonamides as antitumor agents.

In search for potential anti cancer drug candidates in imidazo (2,1-b)-1,3,4-thiadiazole series, two series of 5-formyl-6-arylimidazo(2,1-b)-1,3,4-thiadiazole-2-N- (dimethylaminomethino) sulfonamides and 5-bromo-6-aryl/ethylacetateimidazo(2,1-b)-1,3,4- thiadiazole-2-sulfonamides were synthesised. All compounds showed significant cytotoxic effects (log10 GI50 < -4.0, log molar drug concentration required to cause 50% growth inhibition) against a variety of human tumor cell lines of the National Cancer Institute in vitro screen, including cells derived from solid tumors such as non-small cell lung, colon, central nervous system, melanoma, ovarian, prostate and breast cancer, and also few cell lines of leukemia and renal cancer. Introduction of a formyl group at the 5- and substituted aromatic group at 6-position generated compounds with potent antitumor activity. Incorporation of a bromo at 5- and ester group at 6-position produced compounds with reduced activity.

Synthesis, analgesic and anti-inflammatory activities of some 1-acyl/aracyl-5-aminopyrazole derivatives.

A series of 1-acyl/aracyl-3, 4-disubstituted-5-aminopyrazoles (IV) were synthesized by the reaction of 1-acyl/aracylhydrazines (I) with an appropriately substituted ketenedithioacetal (II/III). Compounds IV were tested for their analgesic activity by rat caudal immersion test and anti-inflammatory activity by carrageenin induced edema in rat paw test. 1-Benzoyl-3-mercapto-4-carboxamido-5-aminopyrazole (IVk) proved to be the most active compound of the series in both tests.

Synthesis, anticonvulsant and analgesic activities of some 6-substituted imidazo(2,1-b)-1,3,4-thiadiazole-2-sulfonamides and their 5-bromo derivatives.

A series of 6-substituted imidazo(2,1-b)-1,3,4-thiadiazole-2-sulfonamides (V) were prepared by condensation of 2-amino-1,3,4-thiadiazole-5-sulfonamide (II) with an appropriate 2-bromo-ketone (III). Bromination of V in glacial acetic acid gave the corresponding 5-bromo derivatives (VI). Five selected compounds (15-18 and 28) were evaluated for their anticonvulsant and analgesic activities. Compounds 15-17 showed maximum protection (83%) against pentylene tetrazole induced convulsions and maximum electroshock induced seizures while the standard phenobarbital sodium and phenytoin sodium showed 100% protection, respectively. Compounds 15, 16 and 18 showed superior analgesic activity to acetylsalicylic acid in rat caudal immersion test.

Synthesis and antihyperlipaemic activity of some 2-aminomethyl-3-aryl-5,6,7,8-tetrahydrobenzo(b)/5,6-dimethylthieno++ +(2,3- d) -pyrimidin-4-ones.

A series of 2-aminomethyl-3-aryl-5,6,7,8-tetrahydrobenzo(b)/5,6-dimethylthieno (2,3-d) pyrimidin-4-ones (IX) were prepared by the displacement reaction between various amines and 2-chloromethyl-3-aryl-5,6, 7,8-tetrahydrobenzo(b)/5, 6-dimethylthieno(2, 3-d) pyrimidin-4-ones (VIII), which are obtained by the cyclization of corresponding chloroacetylamino derivatives (VII) under acidic condition. Compounds VII were obtained by the interaction of VI and chloroacetylchloride in glacial acetic acid. Compounds VIII were converted to corresponding 2-acetoxymethyl derivatives (X) with potassium acetate in glacial acetic acid. Selected compounds were screened for antihyperlipaemic activity in albino rats, whereby most of these compounds were found to be active. The serum cholesterol and triglyceride lowering activities exhibited by compounds 1 and 3 were found to be comparable to that of gemfibrozil. Compounds 1 and 3 were also found to be safe as indicated by their acute toxicity study.