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A series of new 4-arylpiperazine derivatives of isothiazolopyridine of Mannich base type and their non-4-arylpiperazine analogues (3 and 4) were synthesized and assayed as potential analgesic agents. Pharmacological assay demonstrated that all the compounds prepared, without exception, displayed significant activity in the mouse writhing assay. The analgesic action, expressed as ED50, was found to be 2-10 times more potent than that of acetylsalicylic acid and 1.5-10 times weaker than that of morphine, these being used as standards. The toxicities (LD50) of the investigated derivatives varied and ranged from 250 to 2000 mg/kg. Additionally, the computational investigations were performed in order to find correlation between molecular structure and biological effects (toxicity, analgesic action) of discussed compounds. Useful model was found for toxicity assessment.

A series of thiazolyl-N-phenyl piperazines has been synthesised and tested for anti-inflammatory activity. Their R(M) values were determined as an expression of their lipophilicity. Theoretical calculation of their lipophilicity, as clog P and logPsk also performed. The effect of the synthesised compounds on inflammation, using the carrageenin induced mouse paw oedema model was studied. In general, the studied compounds were found to be potent anti-inflammatory agents (44-74.1%). Anti-inflammatory activity was influenced by some structural characteristics of the synthesised compounds. An attempt was made to correlate their biological activity with some physicochemical parameters using a quantitative structure-activity relationship approach (QSAR).

The synthesis of 3-methoxy-1,2-benzisothiazole derivatives, substituted in position 5- (compounds 1-7) or 7- (compounds 8-14), with oxypropanolaminic side chains and the pharmacological investigation on their activity at beta-adrenoceptors are described. Compounds were prepared in an attempt to explore the ability of the benzisothiazole ring to interact with the beta-adrenoceptor site and to establish whether oxypropanolaminic derivatives recognise the beta3-adrenoceptor subtype. All the products were tested on rat atria, bladder and small intestine, which preferentially (but not exclusively) express beta1-, beta2- and beta3-adrenoceptors, respectively. When compared with the reference, non-specific, beta-adrenoceptor agonist isoprenaline, the products tested did not show any consistent beta-adrenoceptor agonistic activity in the different models. Most compounds relaxed smooth muscle preparations, but such effect was resistant to the blockade by propranolol (1 micromol/l), ICI 118,551 (1 micromol/l) or bupranolol (1-10 micromol/l), thus excluding that the spasmolytic effect involves any beta-adrenoceptors. When tested as antagonists, some of these products showed a concentration-dependent attenuation of the isoprenaline-induced effects in rat atria, without affecting beta-adrenoceptor-mediated relaxation in smooth muscle. These data confirm the ability of the benzisothiazole ring to interact with beta-adrenoceptors, but the substitution in 5- or 7-positions with oxypropanolaminic groups does not generate compounds endowed with specific activity at beta3-adrenoceptors. Conversely, most of these compounds behave as (specific) antagonists at beta1- (cardiac) adrenoceptors. At the maximum concentrations tested (1-100 micromol/l), these compounds also exert direct spasmolytic and negative chronotropic effects, which could be related to a blockade of Ca2+-dependent mechanisms at an intracellular level and/or an anaesthetic-like activity at plasma membranes.

A series of N-cycloalkenyl-2-acylalkylidene-2,3-dihydro-1,3-benzothiazoles 5a-j, N-cycloalkyl-2-acylalkylidene-2,3-dihydro-1,3-benzothiazoles 8a-e, and N-alkyl-2-acylalkylidene-2,3-dihydro-1,3-benzothiazoles 8f-h, were synthesized and tested for in vitro antibacterial and antifungal activities against four gram-positive and five gram-negative bacteria (Bacillus subtilis 6633, Enterococcus faecalis 29212, Staphylococcus aureus 6538, Staphylococcus aureus 25923, Escherichia coli 25922, Acinetobacter calcoaceticus a1, A. calcoaceticus a2, Pseudomonas aeruginosa 27835, Klebsiella oxytoca 49131), four yeast-like fungi and one fungus (Candida tropicalis 750, C. albicans 14053, C. albicans 10231, Cryptococcus laurentii 18803, and Saccharomyces cerevisiae). Microdilution broth and agar dilution methods were used for antimicrobial tests. The findings obtained showed that some of the tested compounds 5 and 8 were effective against some of the bacterial strains used, whereas, only compounds 8b-g exhibited a moderate antifungal activity against the yeast strains evaluated.

The multistep synthesis of a series of new substituted-benzothiazoles as hydrochloride or quaternary salts is described. 6-Amidino substituted 2-aminobenzothiazoles (5, 6), N-methyl-2-(4-cyanostyryl)benzothiazolium iodide (8), cyano-substituted-2-styrylbenzothiazoles (9-11) and amidino and bis-amidino-substituted 2-styrylbenzothiazoles (12-17) were prepared. The crystal structure of amidino derivative (6) was determined by single crystal X-ray analysis. All new prepared compounds were tested on the cytostatic activities against malignant cell lines: (SW620, colon carcinoma; Hep2, laryngeal carcinoma; HBL, melanoma; HeLa, cervical carcinoma and WI38, human normal fibroblasts). The compounds exerted a different inhibitory effect, depended on concentration and type of the cells. The best inhibitory effect was achieved with compounds (12-15), with slight differences among them. All of them inhibited the growth of examined tumor cell lines and also normal fibroblasts. Other examined compounds exhibited a moderate inhibitory effect, depending on type of the cells. Majority of them inhibited the growth of HeLa cells and WI38.

Several 2,3-diaryl-1,3-thiazolidin-4-ones were synthesized and evaluated as anti-HIV agents. The results of the in vitro tests showed that some of them were highly effective inhibitors of HIV-1 replication at 30-50 nM concentrations with minimal cytotoxicity, thereby acting as non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs).

[5-(pyridin-2-yl)-1,3,4-thiadiazol-2-ylthio]acetic acid (3,4-diaryl-3H-thiazol-2-ylidene)-hydrazide derivatives were synthesized and tested for their in vitro antimycobacterial activity. Some compounds showed an interesting activity against a strain of Mycobacterium tuberculosis H(37)Rv and three clinical isolates of M. tuberculosis.

Cefpodoxime proxetil, a third-generation cephalosporin for oral administration, was synthesized by a method based on the following sequence of reactions: acylation of 7-aminocephalosporanic acid (7-ACA) with S-benzothiazol-2-yl(2-amino-4-thiazolyl)(methoxyimino)thioacetate (MAEM), chloroacetylation of the cefotaxime formed with chloroacetyl chloride, esterification of the acid function with 1-iodoethyl isopropyl carbonate and final cleavage of chloroacetamide protective group by treatment with thiourea in N,N-dimethylacetamide. The developed procedure allows us to obtain better yields of cefpodoxime proxetil and to eliminate the final purification step by column chromatography, necessary during the synthesis of this antibiotic by the previously reported methods.

Several 1,3-thiazolidin-4-ones bearing a 2,6-dihalophenyl group at C-2 and a variously substituted phenyl ring at N-3 have been synthesized and tested as anti-HIV agents. The results of the in vitro tests showed that some of them proved to be effective inhibitors of HIV-1 replication., (Copyright 2003 Editions scientifiques et médicales Elsevier SAS)

A new series of 3-benzyl(p-substituted benzyl)-5-[3'-(4H-4-oxo-1-benzopyran-2-yl)-benzylidene]-2,4-thiazolidinediones (8a-e) were synthesized. These products were prepared by Knoevenagel reaction from 3'-flavone carboxaldehyde and 3-substituted 2,4-thiazolidinediones. In vitro insulinotropic activity was determined for compounds 6a-e, 7a-e, 8b and 8c.

The synthesis of some pyridinyliminothiazoline derivatives starting from N-pyridine-N'-phenyl thiourea and alpha-halogenoacetophenones is described. The chemical structures of the compounds were elucidated. The prepared compounds were tested for antimicrobial activity.

The synthesis and the pharmacological evaluation of benzisothiazole and benzimidazole tetrazolyl- and carboxyl- derivatives 1-6 are described. Structural modification was aimed at investigating the influence of two isosteric substituents (tetrazolyl- and carboxyl-) on the title benzofused heterocycles. The antiphlogistic, antipyretic and analgesic activities have been investigated in in vivo experimental models. Additional investigations have been performed in vitro to study the antiplatelet and spasmolytic activity of the compounds synthetized. All the compounds produced peripheral analgesic effects, but were less effective in hot plate test. The tetrazole and the carboxylic benzisothiazole derivatives 2 and 3 proved to be the most effective drugs within the series, exhibiting maximal inhibition of writhes with a potency 3-fold higher than that of acetaminophen. Only compound 5 provided indication for a central analgesic activity since it was active in hot plate test although with a low potency. The findings obtained in these in vivo and in vitro studies indicate that these compounds do not share the same mechanism of action of acetaminophen. All of the compounds under study present lower acute toxicity than acetaminophen when orally administered in mice.

Recently we reported on 2H-4,6-dimethyl-2-[(4-phenylpiperazin-1-yl)methyl]-3-oxo-2,3-dihydroisothiazolo[5,4-b]pyridine (V), which exhibited high anorectic action in animal models as a result of stimulation of serotoninergic system. This paper describes the synthesis of the series 3-5 of analogues of V prepared from 2-hydroxymethyl-4,6-dimethylisothiazolopyridine (2) and corresponding 4-substituted-piperazines(piperidines) or tetrahydroisoquinoline. The 12 compounds obtained were screened in standard CNS tests in in vivo (mice and rats). In contrast to V, none of its analogues showed serotoninergic activity, whereas several of these compounds were found to be active as weak to moderate analgesic agents. According to X-ray and molecular modeling studies the different pharmacological profile of V and its o-OCH3 analog 3a, taken as an example, should be referred back to the conformational restriction incorporated by the o-substitution rather than effects of different lipophlicity or basicity of these compounds.

New 2-[2-(phenylamino)thiazol-4-yl]ethanamine and 2-(2-benzhydrylthiazol-4-yl)ethanamine derivatives were prepared and tested in vitro as H1 receptor antagonists. The compounds with 2-phenylamino substitution with meta-halide substituents at the phenyl ring, showed weak H1-antagonistic activity (pA2: 4.62-5.04) and this activity was completely lost in the case of meta-methyl substituent (pA2 < 4). When the phenylamino group was replaced by benzhydryl groups of classic antihistamines, the resulting compounds exhibited slightly improved H1-antagonistic activity (at the meta-position pA2: 6.38-6.15; at the para-position pA2: 6.04-5.87).

The key intermediate octahydroquinazoline (1) was obtained in one pot synthesis by a modification of the Biginelli reaction. Compound 1 was allowed to react with phenacyl bromide and bromomalononitrile to furnish thiazolo[2,3-b]quinazoline 3 and 12, respectively. Interaction of compound 12 with formamide, formic acid and phenyl isothiocyanate yielded the corresponding pyrimidino[4',5':4.5]thiazolo[2,3-b] quinazolines 13, 14 and 17, respectively. The structure of the synthesized compounds were elucidated by elemental analyses and spectroscopic analyses. Some of the prepared compounds were tested for their antifungal activity in comparison with tioconazole as a reference fungicide.

The starting materials thiazolo[2,3-b]quinazolines (5a,b) were obtained in one pot synthesis by treating octahydroquinazoline (2) with chloroacetic acid and aromatic aldehydes. Thiazoloquinazoline (5) was reacted with CH2(CN)2/piperidine and CH2(CN)2/NaOH (CH3OH), to furnish pyrano[2',3':4,5]thiazolo[2,3-b]quinazolines (6a,b) and pyrido[2',3':4,5]thiazolo[2,3-b]quinazoline (7), respectively. Refluxing of 5a with NH2CSNH2/KOH and hydrazines in ethanol furnished the corresponding, [1,3]thiazino[4'5':4,5]thiazolo[2,3-b]quinazoline (10) and pyrazolo[3',4':4,5]thiazolo[2,3-b]quinazolines (11a,b), respectively. Antifungal activity was shown for some of the synthesized compounds.

New 2,7-disubstituted 5-amino-6,8-dicyano-2,3-dihydro-3-oxo thiazolo[3,2-a]pyridines have been prepared. Their cyclization with formamide, nitrous acid and triethylorthoformate afforded a series of polycyclic heterocycles containing condensed pyrimidine and triazine rings. Antifungal tests were also performed.

Thirteen 3-substituted benzothiazolone derivatives have been synthesized. Their chemical structures have been elucidated by IR and NMR spectral data and by elemental analyses. Among these compounds, 1-¿3-[2(3H)-benzothiazolon-3-yl[propanoyl]morpholine (5b); 1-¿3-[2(3H)-benzothiazolon-3-yl[propanoyl]-4-benzylpiperidine++ + (5c); 1-¿3-[2(3H)-benzothiazolon-3-yl[-propanoyl]-4-phenylpiperazine (5d); 3-[3-(4-benzylpiperidine-1-yl)propyl]-2(3H)-benzothiazolone (5k); 3-[3-(4-benzylpiperazine-1-yl)propyl]-2(3H)-benzothiazolone (5I); 3-[3-(4-phenylpiperazine-1-yl)propyl]-2(3H)-benzothiazolone (5m) have been found to be significantly more active than the others.

Fifteen new (2/4-substituted)benzaldehyde (2-oxobenzothiazolin-3-yl)acetohydrazones were synthesized and their structures were elucidated by NMR and elemental analysis. Their anticonvulsant activity was tested by a pentylenetetrazole induced seizure test. Compounds 4e and 4h were found to be the most promising among the others.

Some new 2-(1,2-benzisothiazol-3-yl)ethylamine derivatives were synthesised and their putative histaminergic activity was investigated in in vitro gastrointestinal and cardiac preparations. In the isolated guinea pig duodenum, all the compounds induced a tetrodotoxin- and atropine-sensitive contractile activity, which was minimally affected by mepyramine in the case of the compound 2-(1,2-benzisothiazol-3-yl)ethylamine. In the same tissue, all the compounds were devoid of any H3 receptor agonistic or antagonistic activity, but caused a nicotinic and/or 5-HT3 receptor activation. None of these compounds induced any histamine H2 agonistic or antagonistic activity in the isolated guinea pig gastric mucosa or in the isolated papillary muscle. On this latter substrate, the compound N,N,N-trimethyl-2-(1,2-benzisothiazol-3-yl)ethylammonium iodide induced a positive inotropic activity, apparently due to a release of catecholamines. These results demonstrate the substantial inability of 1,2-benzisothiazole derivatives to interact with histamine receptors in functional tests. These compounds, however, possess gangliomimetic properties, related to the activation of 5HT3 and/or nicotinic receptors.

New 2-(1-Piperazinyl)- and 2-(hexahydro-1H-1,4-diazepin-1-yl)benzothiazoles were prepared and tested as H1- and H3-receptor antagonists. A number of compounds showed weak H1-antagonistic activity, with pA2 values ranging from 5.5 to 6.1. The simple alkyl substituted, 2-[1-(4-methyl and 4-ethyl)piperazinyl] analogues show increasing, moderate H3-antagonistic activity (pA2 = 6.0, and pA2 = 7.0). The compounds with 4-phenylalkyl substitution, for both the piperazinyl and the hexahydro-1H-1,4-diazepin-1-yl homologues series, regardless of the different physicochemical properties of the para substituents at the phenyl ring, showed weak H3-antagonistic activity with pA2 values ranging from 4.4 to 5.6.

2-(Substituted-phenyl)-3-[3-(N,N-dimethylamino)propyl]-1,3-thiazolidi n-4- ones (1-15) showed dependence of the potency of the H1-histamine antagonism on the m- and p-substituents suggesting that the aromatic moiety binds the receptor by a strong pi-interaction. Electron-withdrawing substituents decrease the potency while the electron-donating alkyl substituents, enhancing the aryl HOMO energy, increase the antihistamine activity. The m-substituents with the capability to form hydrogen bonds, seems to share an extra-interaction with hydrogen accepting or donating groups of the histamine receptor and exhibits very high potency.

A series of 2-substituted thiazol-4-ylethanamines have been synthesized and tested for their histaminergic H1-receptor activities. The compounds with 2-phenyl substitution, regardless of the different physicochemical properties of the meta-substituents at the phenyl ring, showed weak H1-agonistic activity with pD2 values ranging from 4.35 to 5.36. When the phenyl group was replaced by a benzyl group, the resulting compounds all exhibited weak H1-antagonistic activity (pA2: 4.14-4.82).

Synthesis and in vitro antimicrobial activity of some 3-(substituted phenacyl)-5-[4'(4H-4-oxo-1-benzopyran-2-yl)-benzylidene]-2-4- thiazolidinedione derivatives are described. These products were synthesized by the Knoevenagel reaction from 4'-flavone carboxaldehyde and 3-substituted phenacyl-2,4-thiazolidinediones.

Sixteen (2-benzothiazolone-3-yl and 2-benzoxazolone-3-yl) acetic acid derivatives 5 have been tested for anti-nociceptive and anti-inflammatory activity in this study, 4-[2-(6-Benzoyl-2-benzoxazolone-3-yl)acetyl]morpholine (5c), 4-¿2-[6-(2-chloro-benzoyl)-2-benzoxazolone-3-yl]acetyl¿morpholine (5d), 1-[2-(5-chloro-2-benzoxazolone-3-yl)acetyl]pyrrolidine (5f), methyl (6-methyl-2-benzoxazolone-3-yl)acetate (5k) and N,N-diethyl-2-(2-benzothiazolone-3-yl)acetamide (5m) have shown more potent anti-nociceptive activity than others. Among these compounds, 5c, 5d and 5m have exhibited good anti-inflammatory activity, with 5f, and to a lesser extent, the other molecules displaying some toxic potential.

A series of 1H,3H-naphtho[2',3':4,5]imidazo[1,2-c]thiazoles, TBZ analogues, was prepared in order to explore the influence on anti-HIV activity of the spatial requirements of the hydrophobic moiety fused to imidazothiazole system. In spite of a butterfly-like conformation evidenced by X-ray analysis of compound 4g, the results of in vitro screening suggest that the replacement of the benzene fused ring by the naphthyl moiety negatively influences the activity of analogous thiazolobenzimidazole derivatives, some of which are potent non-nucleoside HIV-1 RT inhibitors.

Derivatives of 4-substituted 1,2-benzisothiazole-1,1-dioxide alkanoic acids were prepared and their in vitro aldose reductase inhibitory activity was tested in rat lens enzyme. The acetic derivatives 10, 12, and 16a-d proved to be much more potent inhibitors than the propionic derivatives 11, 13, and 17a-d. The presence of an acyl moiety on the amino group in position 4 of the acetic derivatives 16a-d led to a significant increase in activity with respect to the parent compound 14. One of the most active compounds in vitro, 10, was also evaluated in vivo as an inhibitor of glutathione lens depletion in galactosemic rats, but it did not show any activity in maintaining the rat lens glutathione level, probably due to problems of ocular bioavailability or metabolism.

N-Hydroxyethyl- and N-hydroxypropyl-1,2-benzisothiazol-3(2H)-one carbamic esters were prepared in order to test their activity against representative bacterial and fungal strains. The obtained results were compared with those reported for parent alcohols and some interesting considerations were drawn. None of the studied derivatives possess genotoxic activity in the Bacillus subtilis rec-assay and Salmonella-microsome test.

A series of aryl-hydroxy-piperidinoalkyl-thiazolidinones was synthesized and evaluated to inhibit castor oil-induced diarrhea in mice. The dose dependent antidiarrheal activity of the most active compound 2-(p-nitrophenyl)-3-¿2-[(4-(p-chlorophenyl)-4-hydroxy)piperidino]ethyl]- 1, 3-thiazolidin-4-one (6) was counteracted by naloxone, resulting comparable with that of loperamide, a mu opiate agonist.

The aldol synthesis of benzimidazole, benzothiazole and benzothiazolium salt derivatives of chromones is described. The structures of the compounds have been proved by elemental analysis and 1H NMR spectra. The antimycobacterial activity of some of the prepared compounds have been tested in vitro against Mycobacterium tuberculosis (H37Rv) and Mycobacterium fortuitum (1021).

To deeply investigate the influence of lipophilicity, phenyl substitution patterns and stereo-chemistry on pharmacological profiles of chiral bisarylthiazolidinones, frequently endowed with stereoselective antiinflammatory, analgesic, antihistaminic activities, we synthesized and explored some 3,3'-(1,2-ethanediyl) analogues 1-4, along with their S-oxidized derivatives 5-8. Each derivative can be isolated as 2R, 2'R/2S, 2'S (a) and 2R, 2'S- or 2S, 2'R- meso (b) diastereomers, which were explored by means of carrageenin edema test, acetic acid writhing and hot plate tests, and also tested for gastrolesive potential and LD50. Independently of lipophilic and electronic features, disulfides 3b, 4b and disulfones 7a, 8a, 8b displayed interesting activity levels which appear to be mainly linked to the disubstitution pattern on benzenic rings.

Several N-(1,2-benzisothiazol-3-yl)amidines were synthesized and examined for their in vitro antimicrobial activity. Some of the compounds studied were effective against bacteria and fungi. Amidines carrying unsaturated alkylic chains showed the highest antimicrobial activity, the propenyl derivative 7 proving to be the most potent with minimum inhibitory concentrations of 25 micrograms/ml against Gram positive bacteria and mould and of 3-12 micrograms/ml against yeasts. The results indicate that an unsaturated moiety is an important function for enhancing the antimicrobial activity in the compounds under investigation.

A series of new 2-aryl-3-[(2-furyl)carbonyl]amino-5-nonsubstituted/methyl-4-thi azolidinones (3) and 2-[(2-furyl)carbonyl]hydrazono-3-alkyl-4-aryl-4-thiazolines (5) was synthesized and evaluated for anticonvulsant activity against pentylenetetrazole induced seizures. Preliminary results indicated that potency was sensitive to substituents at the 2 and 5 positions of the 4-thiazolidinone and 3 and 4 positions of the 4-thiazoline rings. Among 3,2-(phenyl)/ (4-fluorophenyl)-3-[(2-furyl)carbonyl]amino-5-methyl-4-thiazolidinone s (3e and 3f) and among 5, 2-[(2-furyl)carbonyl]hydrazono-3-allyl-4-(4-bromophenyl)-4-thiazol ine (5e), showed the highest protection (40%).

Some (un)substituted imidazo[2,1-b]benzothiazole carboxylic or acetic acids and some related compounds, i.e. imidazo[2,1-b]naphthol[2,1-d]thiazole, 4H-imidazo[2,1-c][1,4]benzothiazine, 4,5-dihydroimidazo[2,1-d][1,5]benzothiazepine carboxylic and acetic acids were synthesized and tested in vivo in order to study the structure-activity relationships (SAR) of their antiinflammatory and analgesic activities. Pharmacological assays confirmed the interest of this class of compounds as potential antiinflammatory and analgesic drugs with low side effects.

N-alkanoic, N-arylalkanoic and N-aryloxyalkanoic acids of 1,2-benzisothiazolin-3-one, esters and amides of N-arylalkanoic and N-aryloxyalkanoic acids and 1,1-dioxide derivatives of N-arylalkanoic acids and esters were investigated in vitro antimicrobial activity. N-arylalkanoic and N-aryloxyalkanoic acids (compounds 4-12) and their esters and amides (compounds 13-26) exhibited a good antimicrobial activity against Gram positive bacteria, with several compounds showing potencies 10-20 times higher than 1,2-benzisothiazolin-3-one. None of the chemicals tested inhibited the growth of E. coli. Yeasts and moulds possess a considerable susceptibility to compounds 12-23. The logP (octanol-water) of esters and amides of N-arylalkanoic and N-aryloxyalkanoic acids were measured by the shake-flask technique and the potencies against Gram positive bacteria of the compounds tested was related to their lipophilicity. QSAR analysis showed a bilinear relation, with a logD0 around 3 for the activity on B. subtilis. The phenoxyacetic and phenoxybutyric acid derivatives are positive outliers, showing a potency higher than that predicted from their lipohilicity. The most active compounds were further tested against different Gram positive bacteria and moulds, including Bacilli, Sarcina lutea, Staphylococcus epidermidis, Candida spp. and dermatophytes. The antibacterial and antifungal activity was specific for 1,2-benzisothiazolin-3-ones, the corresponding 1,1-dioxide derivatives being inactive. The genotoxic properties of the compounds studied were evaluated by the Bacillus subtilis rec-assay and Salmonella-microsome test. None of the compounds showed DNA-damaging or mutagenic activity.

A number of 6-substituted 1, 2-benzisothiazole-1, 1-dioxide alkanoic acids were synthesized and evaluated for crude rat lens aldose reductase inhibitory activity. The inhibitory potency of the acetic (6a, 10a), propionic (6b, 10b, 11b), and isopropionic (6c, 10c, 11c) derivatives was very similar and generally lower than that of the reference compound, Sorbinil. The presence of an acyl moiety on the amino group in position 6, as in the acetic and propionic derivatives 14a-f and 15a, b, respectively, resulted in a significant increase in activity. A good potency was shown by compounds 14g and 15g, in which a second carboxylic function is present on the 6-acylamino group. Also the open products 16, which contain the phenylsulfonyl fragment found in several known inhibitors of aldose reductase, were obtained and tested in the rat lens assay.

The synthesis of new 2-(2-oxobenzothiazole-3-yl)-1-arylethanone derivatives is reported. The structure of these products is supported by their UV, IR and 1H-NMR spectra, as well as by elemental analysis. The new compounds were tested for antimicrobial activity.

In this study, the synthesis and the stereochemical features of novel tricyclic derivatives containing an imidazole nucleus are described. The biological properties of the synthesized compounds as well as some aspects of the structure activity relationship are also discussed.

Owing to the increasing need of drugs for the treatment of a variety of fungal and bacterial opportunistic infections, a study has been started with the aim of synthesizing structures amenable to a number of easily-to-perform structural modifications in order to meet the requirement of bypassing resistance phenomena. This paper reports on the synthesis of several N-(alpha-azaheteroaryl)-substituted 2,5-dimethyl-pyrroles bearing in one beta-position (or in both beta-positions) aminomethyl groups, introduced via a Mannich reaction. Electronic and steric effects by the N-(azaheteroaryl) substituents and the 2- and 5-methyl groups on the course of the Mannich reaction are discussed along with the results of in vitro tests against many Candida species, some bacteria, and several pathogenic plant fungi.

A series of 3-thiosemicarbazono-2-indolinones and 3-(4-thiazolidone-2-hydrazono)-2-indolinones was synthesized by condensation of various isatin derivatives with 4-substituted 3-thiosemicarbazides and cyclization of the products by monochloroacetic acid or ethyl alpha-bromoacetate. In the present work we report on the structure determination and anticonvulsant evaluation of the title compounds.

Several 2-[(2-methylimidazo[1,2-a]pyridine-3-yl)carbonyl]hydrazono- 3-nonsubstituted/substituted-4-phenyl-4-thiazolines (3a-d, 3f-h) and 3-(2-methylimidazo[1,2-a]pyridine-3-yl)-4-nonsubstituted/substitut ed-5- mercapto-4H-1,2,4-triazoles (4a-f, 4i) were synthesized, characterized and evaluated for anticonvulsant activity. Only 3g showed significant activity against MES induced seizures.

Three novel series of 2,6-di-tert-butyl-1,4-benzoquinone derivatives were synthesized: 4-[(3,4-disubstituted-2,3-dihydrothiazol-2-ylidene) hydrazono]-2,6-di-tert-butyl-2,5-cyclohexadien-1-ones, 4-[(3-substituted-5-carbethoxy-4-methyl-2,3-dihydrothiazol-2- ylidene)hydrazono]-2,6-di-tert-butyl-2,5-cyclohexadien-1-one s, and 4-[(3-substituted-4-oxothiazolidin-2-ylidene)hydrazono]-2,6- di-tert- butyl-2,5-cyclohexadien-1-ones. These compounds were prepared by cyclization of the new 4-(N-substituted thiocarbamoylhydrazono)-2,6-di-tert-butyl-2,5-cyclohexadien- 1-ones with phenacyl bromides, ethyl alpha-chloroacetoacetate and ethyl bromoacetate, respectively. Antimicrobial testing of the prepared compounds and of the key intermediate thiosemicarbazones was performed. Some of the compounds revealed higher activity than streptomycin.

A number of 2-(2-furoylhydrazono)-3-substituted 4-thiazolidone and 2-(2-furoylhydrazono)-3,4-disubstituted 4-thiazoline derivatives were synthesized and evaluated for anticonvulsant activity. Most of the tested compounds showed significant activity against MES induced seizures.

The one-pot synthesis of 1H,3H-thiazolo[3,4-a]imidazo[4,5-b]pyridines is described. The antiviral activity against human immunodeficiency virus (HIV) of the compounds obtained was explored: 1-(2',6'-dichlorophenyl) (5g) and 1-(2',6'-difluorophenyl)-1H,3H-thiazolo- [3,4-a]imidazo[4,5-b]pyridine (5h) exhibit reproducible in vitro anti-HIV activity.

A number of 2-(2-furoylhydrazono)-3-substituted 4-thiazolidone and 2-(2-furoylhydrazono)-3,4-disubstituted 4-thiazoline derivatives were synthesized and evaluated for anticonvulsant activity. Most of the tested compounds showed significant activity against MES induced seizures.

The 3,5-diaminoisothiazole derivatives 23-42 were synthesized in excellent yields by oxidative cyclization of 3-amino-3-(dialkylamino)propenethioamide derivatives. These intermediates and the isothiazole derivatives were tested in vitro for their antimicrobial activity.

In pursuing the research on the SARs of chiral 3,3'-Bi-[1,3-thiazolidine-4-one] system derivatives, two new structural modifications were explored, both having on chiral C atoms thienyl or 2/3 pyridyl groups which have been found to improve antiinflammatory and related activities in the previously studied 3,3'-(1,2-ethanediyl)bisthiazolidinones. In particular a trimetylene chain was introduced between N-3 and N-3' thus obtaining the 3,3'-(1,3-propanediyl) derivatives [type Ic compounds], whereas by elimination of a thiazolidinone ring the 2-heteroaryl-3-[2'(heteroarylidenamino) ethyl]-1,3-thiazolidine-4-one derivatives (type II compounds) were prepared. The new compounds were explored in vivo for their antiinflammatory, analgesic, antipyretic activities, as well as for acute toxicity and ulcerogenic effects. The results obtained don't allow us to draw any reliable SAR except that, by increasing the distance between thiazolidinonic rings, in Ic compounds, the pharmacological profile is not improved with respect to (1,2-ethanediyl) inferior homologs. Among compounds II, only the thienyl derivative 5 appears to have antiinflammatory and analgesic activities.

Several 4-oxo-delta 2-thiazolin-2-ylhydrazone derivatives 6 (6-1 - 6-19) derived from the cyclization reaction between the thiosemicarbazones 5 and homologous alpha-chloroacids were prepared. Only compound 6-2 was found to be active against Entamoeba histolytica and Trichomonas vaginalis.

In this study, some thiazolo[3,2-b]-1,2,4-triazole derivatives were synthesized. Their vasodilatory activities were examined in vitro. All examined compounds showed appreciable activity.