Diastereo- and enantioselective synthesis of 1'-C-branched N,O-nucleosides.

A synthetic approach towards 1'-C-branched N,O-nucleosides is reported, based on 1,3-dipolar cycloaddition of ethoxycarbonylnitrone. The asymmetric version of the process exploits the presence of a chiral auxiliary at the carbon atom of nitrone and leads to beta-D and beta-L nucleosides in good yields.

3,3'-Bi(1,3-thiazolidin-4-one) system. VIII. 3,3'-(1,2-Ethanediyl) derivatives and corresponding 1,1'-disulfones: synthesis, stereochemistry and antiinflammatory activity.

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.

3,3'-Bi-[1,3-thiazolidine-4-one] system. VII. Synthesis and SARS of some 2-heteroaryl derivatives with antiinflammatory and related activities.

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.

Fluorocontaining D-cycloserines. Synthesis and in vitro evaluation of antimicrobial and antiviral activities.

Some fluoroacylderivatives at the side chain NH2 of D-cycloserine were synthesized and evaluated in vitro for antimicrobial activity against bacteria and tubercular or non-tubercular mycobacteria. Against the used Gram-positive and Gram-negative strains only trifluoroacetamide 1 exhibited comparable MIC values and lower MBC values than those of parent antibiotic. Other fluoroacycloserines, inactive at all on these bacteria, were found to inhibit the growth of mycobacteria when tested in liquid media. The in vitro anti-Herpex Simplex virus type-2 (HSV-2) activity was also investigated on HEp-2 and Vero cells. The obtained results demonstrated an antiviral activity of the compounds 1 and 3 when tested on Vero cell-lines, whereas the same cycloserine is inactive.

N-trifluoroacetyl derivatives as pharmacological agents. V. Evaluation of antiinflammatory and antimicrobial activities of some N-heterocyclic trifluoroacetamides.

Following the investigation on pharmacological aspects of N-trifluoroacetyl compounds some heterocyclic trifluoroacetamides were prepared and explored as potential antiinflammatory-analgesic and antimicrobial agents. The trifluoroacetamides 3, 4, 5, and 6 reached significant activity in the hot plate analgesic test; the same 4 and 5, along with 7 and 8 showed inhibitory properties in the adjuvant arthritis test; only 7 however, displayed a significant dose-dependent activity in the carrageenin edema test. In addition the parent heterocyclic amines were similarly explored for comparison. Test for antimicrobial activity were carried out in parallel. Among the examined compounds, only 4-aminomorpholine and 2-aminobenzimidazole were found active when assayed against gram+ and gram- bacteria and mycetes.

N-trifluoroacetyl derivatives as pharmacological agents. IV--Antiinflammatory and related properties; antimicrobial activity of some polyaromatic trifluoroacetamides.

Taking into account both the analogy with the antiinflammatory triflamides and our previous observations on a series of trifluoroacetanilides active as acute and chronic antiinflammatory agents, the present series of polyaromatic N-trifluoroacetylderivatives were prepared. Their antiinflammatory and related properties as well as antimicrobial activity were evaluated. Few derivatives were found to display significant analgesic effects (hot plate test) whereas at 50 mg/kg all were devoid of antiinflammatory effects except the benzophenone derivative (III). Instead as regards the antimicrobial screening, a selective antimycoplasmal activity was revealed in six out of ten examined compounds.

3,3'-Di[1,3-thiazolidine-4-one]system. IV. Synthesis and pharmacological properties of 3,3'(1,2-ethanediyl)bis [2-aryl-1,3-thiazolidine-4-one 1,1-dioxide] derivatives.

The 1,1' disulfones obtained by oxidation of the corresponding dl and meso 3,3'(1,2-ethanediyl)bis [2-aryl-4-thiazolidinone] compounds previously investigated, were evaluated as anti-histamine, anti-inflammatory, analgesic and anti-pyretic agents. All 2,2' fluorophenyl compounds were found to be significantly active in inhibiting carrageenin-induced edema, whereas only para-substituted derivatives were active on the histamine-induced bronchospasm in the guinea-pig. They also showed analgesic effects that reached and sometimes exceeded those of indomethacin and phenylbutazone used as reference drugs.

Piperazin-2,5-diones N,N'-substituted. III. Synthesis and pharmacological activities of some 1-aryl-4-arylidene (or heteroarylidene)aminopiperazin-2,5-dione derivatives.

The synthesis, antimicrobial and antitumor activities of new N,N'-substituted-2,5-dioxopiperazine derivatives are reported. The biological investigation showed that only the compounds containing the 5-nitrofurylidene moiety were active against some bacteria. All tested compounds showed no significant antitumor activity against lymphocytic murine leukemia P 388.

[3,3'-bi-1,3-thiazolidine]-4,4'-dione system. III. Evaluation of the antimicrobial and antitumor properties of 2,2'-disubstituted derivatives and their 1,1'-disulfones.

A series of dl and meso 2,2'-disubstituted-[3,3'-bis-1,3-thiazolidine]-4,4'-diones and their 1,1'-disulfone derivatives have been tested for their antimicrobial activity against gram-positive, gram-negative and Candida strains and for antitumor activity against leukemic P.388 tumor system in mice. None of the tested bi-thiazolidinones showed any significant antitumor properties; only few 1,1'-disulfones exhibited some antibacterial activity.

[N-substituted p-fluorobenzencarboxyamides. Evaluation of the in vitro antimicrobial activity]. / p-Fluorobenzencarbossiamide N-sostituite. Valutazione dell'attività antimicrobica in vitro.

As part of our investigations on fluorine containing compounds of potential pharmacological interest, a series of N-substituted p-fluorobenzencarboxyamides, analogs of previously studied p-fluorobenzensolfonamides, was prepared. The in vitro antibacterial and antimycotic properties were also assayed. The replacement of the sulfonamide group with an isosteric carboxyamide one, was found to confer to trifluoromethylsubstituted compounds good activity against some strains of yeasts (Candida) and hyphomycetes (Tricophyton, Aspergillus, Microsporum, Epidermophyton). These compounds however are not very active against the gram-positive and gram-negative bacteria on which the corresponding sulfonanilides showed significant activity.

[3,3'-bi-1,3-thiazolidine]-4,4'-dione system. I. Synthesis, conformational analysis and pharmacological activities of 2,2'-diaryl derivatives.

The two configurational isomers, d1, and meso, of some 2,2'-diaryl-[3,3'-bi-1,3-thiazolidine]-4,4'-dione derivatives have been obtained and characterized. The 1H-N.M.R. spectra of both stereoisomers in DMSO-d6 solution are temperature-dependent and their dynamic behaviour has been related to the hindered rotation of the N--N bond. Evidence for an orthogonal disposition of the two heterocyclic rings, in the ground state, is presented. These new bicyclic compounds possess interesting antiinflammatory, analgesic and antipyretic activities as well as low acute toxicity and ulcerogenicity. The antiinflammatory effect, which in some compounds is higher than that of indomethacin and phenylbutazone, appears to be a function of the relative disposition of the substituents at position 2 and 2': generally the meso isomers are more active than the d1 ones. The lipophilicity of the tested compounds was determined by reversed-phase thin-layer chromatography.

N-Trifluoroacetyl derivatives as pharmacological agents. II. Trifluoroacetanilides: synthesis and antiinflammatory activity.

The analogy with the anti-inflammatory trifluoromethane-sulfonanilides prompted us to the synthesis of a series of trifluoroacetanilides which were found to maintain the pharmacological properties of the analog sulfonanilides. Many of the obtained compounds inhibited either the carrageenin-induced rat paw edema and the adjuvant-induced arthritis; some showed better anti-inflammatory properties than indomethacin and phenylbutazone. Acute toxicity and ulcerogenic effects were significantly lower than those of reference drugs.

Synthesis and pharmacological activity of some 1-alkylamino-3-(2'-methoxy-4'-diethylcarbamoyl-phenoxy)propan-2-ols.

The synthesis and pharmacological properties of some 1-alkylamino-3-(2'-methoxy-4'-diethylcarbamoylphenoxy)propan-2-ols, related to beta-adrenergic drugs, are described. The above compounds were found to possess beta 1 and beta 2-adrenolytic activity associated with local anesthetic and antiarrhythmic activities, which are clearly inferior to those of propranolol.