Trifluoromethylcontaining sulfanilamides. I. Synthesis and in vitro antibacterial activity.

In a wider research directed to improve pharmacological profiles of known anti-infective agents by introducing fluorine or trifluoromethyl groups, some sulfanilamides trifluoromethylsubstituted on N1 ring, were synthesized and examined for their in vitro activity against gram-positive and gram-negative bacteria. Two N1-trifluoromethylphenyl-sulfanilamides, 1 and 4, exhibited MIC values, against all tested bacteria, similar or lower than those of the "classical" sulfanilamides, assayed in comparison. The new sulfanilamide 4 appears to be the more interesting: in fact, the presence of p-aminobenzoic acid (PABA) in culture medium did not influence its MIC values and no synergy was observed with trimethoprim, suggesting mechanism of action different from that of known sulfanilamides.

Halogenated isoniazid derivatives as possible antitubercular and antineoplastic agents. Note 1.

Halogenated arylhydrazones, 2-aryl-4-thiazolidinones and their 1,1-dioxides containing isoniazid (INI) moieties were prepared and explored for antimicrobial (against bacteria, Candida and mycobacteria) and antitumor activities. None of the tested compounds showed any marked antimicrobial effect. Furthermore, among the compounds submitted to NCI in vitro primary antitumor screening, those bearing 3-fluoro or -chlorophenyl substituents were found to possess selective inhibitory effects on the growth of non small cell lung cancer, whereas those with para-phenyl substituents displayed selective effects, sometimes statistically significant, against leukemias.

2-(4-Pyridyl)-delta 2-1,3,4-oxadiazolines from isonicotinoylhydrazones and diazomethane as potential antimycobacterial and anti-HIV agents. V.

The 5-aryl-4-methyl-2-(4-pyridyl)-delta 2-1,3,4-oxadiazolines 3, previously synthesized along with isomer 4-aryl-1-methoxy-1-(4-pyridyl)-2,3-diaza-1,3-butadienes 2 from benzaldehyde isonicotinoylhydrazones and diazomethane, were tested for in vitro activity against both M. tuberculosis and some atypical mycobacterial strains as well as against human immunodeficiency virus (HIV-1). Some halophenyl derivatives, 3e, 3g, 3i, 3j, were found to display MIC ranges from 1 to 10 (micrograms/ml against H 37 Rv and a clinical isolate tubercular strain, whereas against M. avium (MAC) the MICs were higher than 20 micrograms/ml. When the combinations of oxadiazolines with ethambutol, acting as inhibitor of cell wall synthesis, were assayed on MAC strain a synergistic effect was demonstrated for 3g and 3h trifluoromethyl derivatives. The antimycobacterial profiles of 2 and 3 analogues are compared and discussed. As shown by compounds 2, no substantial anti-HIV in vitro activity was found in selected delta 2-oxadiazolines; a moderate cytotoxicity, however, appears to be a common property.

Halogenated isoniazid derivatives as possible antimycobacterial and anti-HIV agents--III.

As part of a research directed to the synthesis of novel isoniazid derivatives with potential activity on mycobacteria and HIV virus, the acetophenone-isonicotinoylhydrazones 3 and the 4-aryl-1-methoxy-1-(4-pyridyl)- 2,3-diaza-1,3-butadienes 5, obtained by reaction between isonicotinoylhydrazones and diazomethane, have been prepared and tested for such activities. Both classes of derivatives showed interesting growth inhibitory activity on non-tubercular mycobacteria, including the emerging M. avium. Such activity appears to be linked to fluorine and/or chlorine presence on benzene rings. In contrast, none of the compounds submitted to the anti-AIDS in vitro screening, displayed any protection against HIV-1 virus-induced cytopathic effect in T4-lymphocyte cell lines.

Aminopyrazinyl derivatives: synthesis and evaluation of antiinflammatory and related activities.

Some amides, 1-substituted methylenediamines and 2-substituted thiazolidin-4-ones, all containing the aminopyrazinyl moiety, were synthesized and tested in the experimental models of acute and chronic inflammations and as potential analgesic agents. The first series of compounds are inactive, whereas the N,N'-di-(2-pyrazinyl)-methylene-diamines and the 3-(2'-pyrazinyl)-thiazolidinones 6, 7, 11, 12 and even more 16 and 17 were found to be endowed with antiinflammatory and analgesic properties and low acute toxicity, the two latter being the most interesting.

Halogenated isoniazid derivatives VI. Evaluation of anti-HSV-1 and anti-HIV-1 in vitro activities of fluorinated analogues.

The synthesis and evaluation of antiviral in vitro activity are reported of some 2'-(1-arylethyl)isonicotinohydrazides (5a-d) and N-(1-arylethyl)isonicotinohydrazonic acids (6a-d), obtained by reducing fluorinated acetophenone isonicotinoylhydrazones (2a-d) with sodium cyanoborohydride. These INH analogues, along with other ones previously prepared, i.e. benzaldehyde isonicotinoylhydrazones 1, 4-aryl-1-methoxyl-1-(4-pyridyl)-2,3-diaza-1,3-butadienes 3 and 5-aryl-4-methyl-2-(4-pyridyl)-delta 2-1,3,4-oxadiazolines 4, were assayed for anti-HSV-1 activity on the monoblastoid cell line U937. Only some compounds (1b, 1d, 4d and 4e) displayed a moderate antiherpetic activity. In addition, the reduced compounds 5 and 6, submitted to the anti-HIV-1 screening, did not display significant effects in reducing virus-induced cytopathogenicity. The cytotoxicity of all compounds has been assayed on Vero cells and some considerations in correlation with structure are discussed.

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'-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.

Synthesis and in vitro antimicrobial and antitumoral screening of novel lipophilic isoniazid analogues. VI.

Various kinds of lipophilic analogues of isonicotinic acid hydrazide (Isoniazid) were synthesized and in vitro explored in a search for antimycobacterial agents with extended activity spectrum against pathogens responsible for the AIDS-associated diseases. The primary in vitro screening showed that a) isonicotinoylhydrazones 1a, 1b, 1d, 1e are more active than the parent drug against non-tubercular mycobacteria (MIC ranging between 0.5 and 4 micrograms/ml), b) isonicotinohydrazides 6b and 6e display interesting antibacterial activity on some Gram + and Gram-strains, and c) trifluoromethyl-containing compounds 1a and 2c inhibit the growth of several human tumor cell lines at doses between 10(-5) and 10(-6) M. On the contrary, none of the tested analogues significantly counteracts the cytopathogenicity induced by HIV and HSV viruses.

[N-substituted p-fluorobenzene sulfonamides with antimicrobial activity. I]. / p-Fluorobenzensolfonamidi N-sostituite ad attività antimicrobica. Nota I.

In an extension of the investigations on fluorine derivatives of potential pharmacological interest, some new p-fluorobenzensulfonanilides were synthesized and screened in vitro against many species of Gram-positive and Gram-negative bacteria and against some strains of Candida albicans. Some of these compounds exhibited significant antibacterial activity. The relation between activity and structure revealed that the presence of chloro and trifluoromethyl groups in the aniline ring increases activity against Gram-positive bacteria. The acute toxicity in mice was also determined.

Isoniazid-related copper(II) and nickel(II) complexes with antimycobacterial in vitro activity. Part 9.

Isonicotinoylhydrazones 1, obtained by the primary antituberculous agent Isoniazid, have been used as monoanionic ligands (L) to prepare copper(II) 2 and nickel(II) 3 octahedral complexes of stoichiometry [MeL2(H2O)2]. Their antimycobacterial in vitro activity was evaluated against Mycobacterium tuberculosis H37Rv in comparison with the ligands. Complexes 2a, 2b, 2f, 3b, 3d and 3g displayed MIC values < or = 0.2 microg/mL.

[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.