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The synthesis and the pharmacological activity of a series of 1-aroyl derivatives of kynurenic acid methyl ester (4-oxo-quinolin-2-carboxy methyl (KYNA) esters), structurally related to NSAID indomethacin are described. The derivatives were screened in vivo for anti-inflammatory and analgesic activities. Most of the compounds exhibited good anti-inflammatory and analgesic activities. An automatic docking of the synthesized compounds was performed using X-ray structures of COX-1 and COX-2. Docking results are in good accordance with the experimental biological data.

Aminoalkylindoles (AAIs), although structurally dissimilar from the classical cannabinoids, are known to be capable of binding to cannabinoid receptors and of evoking cannabinomimetic responses. With the aim of investigating the structure-activity relationships (SAR) for the binding of non-classical agonists to CB1 and CB2 cannabinoid receptors, we designed and synthesized a series of indole derivatives. The compounds were tested for their analgesic action by formalin test and compared to WIN 55212-2, an AAI acting to the cannabinoid receptors. In receptor binding assay, compound 5 showed affinity for the CB1 receptor comparable to WIN 55212-2.

Loperamide is a piperidine analogue, acting as agonist on peripheral opioid receptors, exhibiting affinity and selectivity for the cloned mu human opioid receptor compared with the delta human opioid receptor. Automatic docking studies of loperamide, using AutoDock, on human mu- and delta-opioid receptors is described. Whilst no meaningful difference was detected concerning the docking of the arylpiperidine moiety, mu/delta selectivity could be explained as a different accommodation of the two phenyl groups in two lipophylic pockets of receptors.

Loperamide is a well-known peripherally acting opiate used for the treatment of diarrhoea. To gain more knowledge on the structure-activity relationships of antidiarrhoeal drugs and to develop new active molecules, a series of aryl-cyano-piperidinoalkyl-thiazolidinones related to Loperamide was synthesized and screened for antidiarrhoeal activity in mice by castor oil test. To characterize the potency and toxicity of the synthesized compounds ED50 and LD50 values were also determined. The thiazolidinones 2-6 displayed antidiarrhoeal activity at doses ranging between 15 and 82 mg/kg. Although the results show that the synthesized compounds are 15- to 80-fold less active respect to the reference compound, Loperamide, they are much less toxic (> or = 1000 mg/kg and 108.9 mg/kg, respectively). Besides, to evaluate the involvement of opioid receptors in antidiarrhoeal activity, Naloxone was administered prior to test the 2-phenyl-3-{2-[(4-phenyl-4-cyano)piperidino]ethyl}-1,3-thiazolidin-4-one (2), the more active compound of this series. The results obtained by this study, suggest that the antidiarrhoeal activity of this series of thiazolidinone derivatives could involve the opioid receptors.

Novel antitumoral agents with quinonic structure were synthesized and evaluated for their in vitro cytotoxic activities. This study examines the cytotoxic activities of several aryl benzo[g]isoquinoline-5,10-dione derivatives and a number of aminoacyl dihydrothieno[2,3-b]naphtho-4,9-dione (DTNQ) derivatives containing amino acids in position 3 of the ring system. Compound 6 showed remarkable cytotoxic activity at submicromolar concentration not only against several human leukaemia and solid tumour cell lines, but also toward sensitive and resistant human cell lines.

We report evidence of an unusual C-H--O interaction between an alpha-methylene hydrogen of the alkylamine chain of substituted (N,N-dimethylamino)propyl-azetidinones, substituted (N,N-dimethylamino)propyl-thiazolidinones and substituted (N,N-dimethylamino)propyl-thiazinone and the lactam carbonyl oxygen. NMR analysis results, supported by molecular mechanic predictions, were in agreement with ab initio calculations. The observed interaction shorting the nitrogen-nitrogen distance in the H1-histamine antagonist, 2-(4-methylphenyl)-3-[3-(N,N-dimethylamino)propyl]-1,3-thiazolidin-4-one (1) could explain its fitting with the H1-antihistaminic pharmacophoric model and the high antihistaminic activity.

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 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.

A series of 1-(p-substituted)phenyl-3-(p-alkoxy)phenyl-4-phenyl-azetidin-2-one s 1a-20a, was synthesized and characterized. Their antimicrobial activity, against Gram+ and Gram- bacteria and Fungi, was tested. The compounds 8a, 13a, 14a, 18a and 6a, 9a, 10a showed remarkable activity respectively against Pseudomonas aeruginosa and against Fungi.

A series of 2-(3- and 4-substituted phenyl)-3-[3-(N, N-dimethyl-amino)propyl]-1,3-thiazolidin-4-ones acting as H1-antihistaminics was investigated with a combined Hansch-CoMFA approach. The substituents at the 3- and 4-positions of the phenyl ring have been described through steric, electronic and hydrophobic parameters and correlated with pA2 values. The obtained quantitative models suggest that affinity to the receptor is promoted by hydrophobic and small 4-substituents and by 3- and 4-substituents generating a positive electrostatic potential towards a complementary receptor region.

Intraperitoneal administration of some flavonoids (apigenin, flavone, kaempferol, morin, myricetin, naringin and rutin; 12.5-50 mg kg-1) significantly (P < 0.05-0.01) reduced small (28-69%) and large (83-134%) intestinal transit in mice. Other flavonoids (naringenin, silibinin, silymarin and taxifolin, 100-200 mg kg-1) reduced (23-41%; P < 0.05-0.01) intestinal transit at doses of 100-200 mg kg-1 while hesperitin, catechin and phloridzin (up to 200 mg kg-1) had no effect. This effect was antagonized by yohimbine (87-96%) and phentolamine (87-91%) but not by prazosin, propranolol, atropine, hexamethonium, mepyramine, cyproheptadine and naloxone. Yohimbine (92-96%) also antagonized the inhibitory effect of flavonols (12.5-50 mg kg-1) (P < 0.05-0.01) on intraluminal accumulation of fluid and diarrhoea induced by castor oil. By contrast, verapamil potentiated the flavonol effect. It is suggested that these effects, influenced by the structure of the molecules, are mediated by alpha 2-adrenergic receptors and calcium.

The N-(2-hydroxy-5-carboxy-benzyliden)-4-substituted anilines (1-6) and the corresponding 5-carbomethoxy derivatives (7-12) were synthesized and characterized. Antimicrobial and antifungal activity was tested against Gram+ and Gram- bacteria and Fungi.

A new series of 2-(4- and 3-substituted phenyl)-3-[3-(N,N-dimethylamino) propyl]-1,3-thiazolidin-4-ones were synthesized, characterized, and evaluated for their ability to inhibit the contractions induced by histamine on guinea pig ileum. The measurement of pA2 values suggested that the reported compounds showed H1-antagonism. The more active compounds 5, 9, and 13 exhibited activity close to that of mepyramine.

A set of substituted 1,3,4-triaryl-2-azetidinones were synthesized and characterized. Their antimicrobial activity, against Gram+ and Gram- bacteria and Fungi, was tested. The compounds 23 and 30 showed remarkable activity against Pseudomonas aeruginosa.

The following 2-substituted phenyl-3-(N,N-dimethylaminopropyl)-1,3-thiazolidin-4-one of general formula (A): [formula: see text] where: X = H (I), 3-F (II), 3-Cl (III), 3-Br (IV), 3-CH3 (V), 3-OCH3 (VI), 3-NO2 (VII), 4-F (VIII), 4-Cl (IX), 4-Br (X), 4-CH3 (XI), 4-OCH3 (XII), 4-NO2 (XIII) were prepared and tested for antihistamine activity. The synthetic procedure involves the cyclocondensation of the appropriate Schiff base with thioglycolic acid in refluxing dry benzene. The compounds herein presented were tested for their ability to inhibit the contraction inducted by histamine 5.10(-7) M "in vitro", on guinea pig ileum. The results are reported as contraction of test compound causing 50% of submaximal contraction induced by histamine (IC50), and related to mepyramine as control. The results of the antihistamine tests showed an interesting degree of activity of some of the new thiazolidinone-derivatives. Compounds II, III, V, X, and XI showed IC50 values near the value of the control, compound XI being the most active. These compounds seem to be worthy of further investigation.

4-hydroxy-isophthalaldehyde acid (1), its alkyl esters (methyl, ethyl, propyl and butyl) and alkyl ethers (propyl, butyl, pentyl and esyl), as well as 6-hydroxy-isophthalaldehyde acid (2) ita alkyl esters (methyl and ethyl), 4-hydroxy-5-iodo-isophthalaldehyde acid (3) and its methyl ester were synthesized and characterized. Antimicrobial and antifungal activity was tested and the LD50 of the most active compound 4 was determined.

The following halogenated 3'-phenyl [3H-indole-3,2'-thiazolidine]-2,4'(1H)-dione of general formula (A) were synthesized and screened for antimicrobial activity. (formula: see text) where: X = H (I, III, V, VII, IX, XI, XIII, XV), CH3 (II, IV, VI, VIII, X, XII, XIV, XVI); Y = H (I, II), 3-F (III, IV), 2-Cl (V, VI), 3-Cl (VII, VIII), 4-Cl (IX, X), 2-Br (XI, XII), 3-Br (XIII, XIV), 4-Br (XV, XVI). The synthetic approach involves the preparation of variously substituted Schiff-bases of indol-2,3-dione, which then are subjected to cyclocondensation with alpha-mercaptoalkanoic acids, to give spirothiazolidinones of type (A). The prepared compounds were screened against S. aureus, B. cereus, M. paratuberculosis, E. coli, S. typhi, Pr. mirabilis, Ps. aeruginosa, C. albicans, S. cerevisiae, A. niger by a disk-diffusion assay (Kirby-Bauer modified. The results of the antimicrobial screening showed that the prepared compounds exhibited varying degrees of activity against Gram-positive, Gram-negative bacteria, and fungi. 3-Fluoro-derivative (III) showed inhibitory activity especially toward S. aureus and C. albicans. Chloroderivatives (VII) and (VIII) showed broad-spectrum "in vitro" antimicrobial activity, and were especially inhibitory toward S. aureus, E. coli, and S. Typhi. Fluoro-derivative (IV) and bromo-derivatives (XIII) and (XIV) possessed marked antimicrobial activity against M. paratuberculosis.

The following polyhalogenated 3'-phenyl 3H-indole-3,2'-thiazolidine -2,4' (1H)-dione of general formula (A) were synthesized and screened for antimicrobial activity. (formula: see text) where: X = H (I, III, V, VII, IX, XI), CH3 (II, IV, VI, VIII, X, XII); Y = H (I, II), 2,4-F2 (III, IV), 2,4-Cl2 (V, VI), 3,4-Cl2 (VII, VIII), 2,6-Cl2 (IX, X), 2,4,6-Cl3 (XI, XII). The general synthetic route involves the preparation of variously substituted isatin-3-imines, which are subjected to cyclocondensation with thioglycolic acid to give compounds I, III, V, VII, IX, XI, or thiolactic acid to give compounds II, IV, VI, VII, X, XII. The prepared compounds were screened against S. aureus, B. cereus, M. paratuberculosis, E. coli, Pr. mirabilis, Ps. aeruginosa, C. albicans, S. cerevisiae, A. niger by a disk-diffusion assay (Kirby-Bauer modified). The results of the antimicrobial screening showed that the polyhalogenated derivatives of type (A) exhibited varying degrees of activity against Gram-positive, Gram-negative bacteria, and fungi. Compound (III) showed a significant activity toward A. niger, moreover compound (IV) was active toward C. albicans. Compound (IX) was very active toward S. typhi and Ps. aeruginosa. Compounds (VII), (IX) and (XII) were very active toward M. paratuberculosis.

The following 2,3-diaryl-1,3-thiazolidin-4-ones of general formula (A) were synthesized and screened for antimicrobial activity. (formula; see text) where: X = H (I, III, V, VII, IX, XI, XIII, XV, XVII, XIX, XXI, XXIII), CH3 (II, IV, VI, VIII, X, XII, XIV, XVI, XVIII, XX, XXII, XXIV); R = H (I, II, V, VI, VII, VIII, XI, XIII), 4-CH3 (XXI, XXII, XXIII, XXIV), 4-Br (III, IV, IX, X), 2-NO2 (XIII, XIV), 3-NO2 (XV, XVI), 4-NO2 (XVII, XVIII), 4-OCH3 (XIX, XX); R' = H (I, II, III, IV, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII), 4-CH3 (XXIII, XXIV), 3-Br (V, VI), 4-Br (VII, VIII, IX, X), 4-J (XI, XII). These compounds were prepared by the general synthetic procedure previously reported for the 1,3-thiazolidin-4-one derivatives already prepared and screened in this SARs program. The synthetic approach involves the cyclocondensation of the appropriate Schiff bases with alpha-mercaptoalkanoic acids. The prepared compounds were screened against S. aureus, S. beta-haemolititicus, B. subtilis, M. paratuberculosis 607, S. typhi, Kl. pneumoniae, E. coli Bb, Ps, aeruginosa, C. albicans, A. niger, S. cerevisiae by a disk-diffusion assay (Kirby-Bauer modified). The results obtained in this investigation showed that the prepared compounds exhibited varying degrees of antimicrobial activity. They were especially inhibitory toward Gram-positive bacteria, and fungi. 4-Nitroderivatives (XVII), (XVIII), and 2-nitroderivatives (XIV) and (XIII) possessed marked antimicrobial activity against S. aureus, S. beta-haemoliticus, and B. subtilis.(ABSTRACT TRUNCATED AT 250 WORDS)

A series of 1,3-bis-anilides of 4-hydroxyisophthalic acid was prepared and investigated for antibacterial and antifungal activities. The prepared compounds (I-XIV), of the general formula (A), where Xn = 2-NO2 (I); 2,4-(NO2)2 (II); 2,4-NO2, Cl (III); 2,4-NO2,CF3 (IV); 3,4-NO2,Cl (V); 2,4-Cl,NO2 (VI); 2,5-Cl,NO2 (VII); 2,4,6-Cl,NO2,Cl (VIII); 2,4-Br, NO2 (IX); 2-CF3 (X); 3-CF3 (XI); 2,5-Cl,CF3 (XII); 2,5-CH3,Cl (XIII); 3,4-Cl,CH3 (XIV), were obtained in satisfactory yield by reacting 4-hydroxyisophthalic acid with the appropriate substituted aniline. (Formula: see text). The prepared compounds were tested for antimicrobial activity by a disk-diffusion assay (Kirby-Bauer modified). The organisms used were the following: S. aureus, B. subtilis, B. anthracis, M. paratuberculosis 607, E. coli Bb, S. typhi, S. typhimurium, S. paratyphi B, Pr. vulgaris, K1. pneumoniae, Ps. aeruginosa, C. albicans, and A. niger. The results of the antimicrobial screening showed that a number of substituted anilides exhibited varying degrees of activity against Gram-positive and Gram-negative bacteria, and fungi, nitro-halogen-derivatives being the most interesting members of the series.

The following hydrazono derivatives (I-XIX) of type (A) (sequence in text) where Rn = (sequence in text ) (I-XVII); (sequence in text) (XVIII); -CCl3 (XIX); and Xn = H (I); 2-Cl (II); 3-Cl (III); 4-Cl (IV); 2-NO2 (V); 3-NO2 (VI); 4-NO2 (VII); 2-OH (VIII); 3-OH (IX); 4-OH (X); 4-F (XI); 3,4-OCH3,OH (XII); 3,4,5-OCH3,OH,J (XIII); 3,4-OCH3,OCH3 (XIV); 2,4-Cl2 (XV); 3,4-Cl2 (XVI); 2,6-Cl2 (XVII); were prepared and characterized in an attempt to make available for testing a representative selection of hitherto unreported 4-hydroxyisophthalic acid derivatives. The new compounds in question were obtained in satisfactory yield by condensation of 4-hydroxyisophthalic acid hydrazide with the appropriate aldehydes. The prepared compounds were tested for their possible activity against Gram-positive (S. epidermidis, B. subtilis, B. anthracis) and Gram-negative bacteria (P. aeruginosa, B. melitensis, S. typhi O, S. typhi H, S. infantis, S. paratyphi B, E. coli Bb, E. coli 7075), and fungi (C. albicans, A. niger, S. cerevisiae). The "in vitro" antimicrobial assays were carried out using the paper disk technique (Kirby-Bauer modified). The influence of certain structural modifications on the antimicrobial activity was evaluated.

A number of hitherto undescribed 4-hydroxy-5-formylbenzoic acid derivatives (A), have been prepared and characterized. (formula; see text) Esters (X = CH3) and Schiff's bases (Z = N-aryl) were prepared by conventional methods and were obtained in satisfactory yield and in a good state of purity. The prepared compounds have been tested for "in vitro" activity against Gram+ bacteria (S.epidermidis, B.subtilis, B.anthracis, M.paratuberculosis), Gram- bacteria (P.aeruginosa, S.typhi murium, E.coli Bb, S.typhi O, S.typhi infantis, S.paratyphi A, S.paratyphi B) and fungi (C.albicans, A.niger, S.cerevisiae) by agar-diffusion method (Kirby-Bauer modified). The prepared compounds, generally, showed inhibitory activity against Gram+ bacteria. Esters (A: X = CH3) showed antibacteric and antimycotic activity. The greatest activity was observed in the methyl ester (XV) of 4-hydroxy-5-formylbenzoic acid (I).

A study has been made on the iodination of phenols by elemental iodine in Na2CO3 solution. The results attained by applying the suggested procedure to a number of practical cases have been very encouraging. This method gives rise to the iodine derivatives of aldehydes (2-hydroxy- and 4-hydroxy-3,5-diiodobenzaldehyd), ketones (2-hydroxy-5-iodo-, 2-hydroxy-3,5-diiodo- and 4-hydroxy-3,5-diiodo-acetophenone, 4-hydroxy-3,5-diiodo-propiophenone), acids (3,5-diiodo-4-hydroxybenzoic acid, 3-formyl-4-hydroxy-5-iodobenzoic acid), aminoacids (3-iodo- and 3,5-diiodo-tyrosine), esters (methyl ester of 2-hydroxy- and 4-hydroxy-3,5-diiodobenzoic acid, methyl ester of 3-iodo-5-chloro-, 3-iodo-5-bromo- and 3,4,5-triiodosalicylic acid, dimethyl- and diethyl-ester of 4-hydroxy-5-iodo-isophthalic acid), amides (2-hydroxy-3,5-diiodobenzamide) and benzoxazole derivatives (2-(2'-hydroxy-3',5'-diiodophenyl)benzoxazole).