Hybrid molecules of estrone: new compounds with potential antibacterial, antifungal, and antiproliferative activities.

New hybrid molecules of estrone were synthesized as compounds indicating promising biological activity (antibacterial, antimycobacterial, antifungal, and antiproliferative). The prepared molecules contained various heterocyclic units (pyridine, benzylsulfanyl derivatives of pyridine or derivatives of tetrazole) linked to estrone by n-heptyl bridges. The compounds with charge on molecule (the hybrid pyridinium or benzylsulfanylpyridinium salts) exhibited significant biological activity (antibacterial, antimycobacterial, antifungal, and antiproliferative). On the other hand, the compounds not in the form of salts (omega-(1-phenyl-5-tetrazolylthio)heptylethers of estrone) were inactive. The antimycobacterial activities of three different series of tetrazole derivatives (i.e., the hybrid molecules with estrone, tetrazole-5-thiols, and 5-benzylsulfanyl-1-phenyltetrazoles) with the same substituents on phenyl ring were compared. Amongst them, the 5-benzylsulfanyl-1-phenyltetrazoles were the most potent.

Synthesis and antimycobacterial activity of 2-substituted halogenobenzimidazoles.

A series of substituted 2-polyfluoroalkyl and 2-nitrobenzylsulphanyl benzimidazoles was synthesized. The compounds were evaluated for their activity against four Mycobacterium strains; the activities were expressed as the minimum inhibitory concentration (MIC). The substances tested showed appreciable antimycobacterial activity, particularly 5,6-dichloro-2-nonafluorobutylbenzimidazole (2h), and 5-halogeno- (5a-c) and 4,6-dihalogeno- (5d and 5g) 2-(3,5-dinitrobenzylsulphanyl)benzimidazoles, whose MIC values for Mycobacterium kansasii and Mycobacterium avium exceeded that of isoniazide that was used as a reference compound. Relationships between structure and biological activity of the tested benzimidazole derivatives are discussed.

Antimycobacterial 3-aryl-2H-1,3-benzoxazine-2,4(3H)-diones.

A series of 153 derivatives of 3-phenyl-2H-benzoxazine-2,4(3H)-dione substituted in position 6 or 7 on benzoxazine and on the phenyl ring was synthesized. The compounds were evaluated in vitro for antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii and Mycobacterium avium. The activity of the compounds increases with increasing hydrophobicity and electron-withdrawing properties of the substituents on the phenyl ring, whereas the effect of the substituents on the benzoxazine ring seems to be more complex.

[Advances in the development of new antimycobacterial agents. The alkylsulfanyl group--a pharmacophore for antimycobacterial activity]. / Pokroky ve vývoji nových antimykobakteriálních látek. Alkylsulfanyl skupina--farmakofor antimykobakteriální aktivity.

Tuberculosis ranks among the most widely spread infectious diseases and the need to find new antituberculotics has become more and more urgent. The present review paper aims at the compounds containing an alkylsulfanyl group which can be considered the pharmacophore of antituberculotic activity. The alkylsulfanyl group is bound to various heterocycles, condensed systems, and there is also a bond to the aliphatic structure. The activities of some compounds discussed in the resent paper are comparable with those of the antituberculotics in current use and therefore they could be introduced into practice, or at least suggest further direction of development. The present survey is based on the journal Chemical Abstracts.

Influence of the replacement of the oxo function with the thioxo group on the antimycobacterial activity of 3-aryl-6,8-dichloro-2H-1,3-benzoxazine-2,4(3H)-diones and 3-arylquinazoline-2,4(1H,3H)-diones.

Series of 3-phenyl-6,8-dichloro-2H-1,3-benzoxazine-2,4(3H)-dithiones, 3-arylquinazoline-2,4(1H,3H)-diones and 3-arylquinazoline-2,4(1H,3H)-dithiones were synthesized, and the antimycobacterial activities of the derivatives evaluated in vitro. The compounds were active against Mycobacterium tuberculosis and conditionally pathogenic mycobacteria (Mycobacterium kansasii and Mycobacterium avium). The replacement of oxygen by sulfur in 3-phenyl-6,8-dichloro-2H-1,3-benzoxazine-2.4(3H)-diones and 3-arylquinazoline-2,4(1H,3H)-diones gave rise to an increase of antimycobacterial activity. The most active compound was 3-(3-chlorophenyl)-6,8-dichloro-2H-1,3-benzoxazine-2,4(3H)-dithione.

[Antimicrobial salicylanilides and 3-phenyl-2H-1,3-benzoxazine-2,4(3H)-diones]. / Antimykobakteriální salicylanilidy a 3-fenyl-2H-1,3-benzoxazin-2,4(3H)-diony.

Salicylanilides and 3-phenyl-2H-1,3-benzoxazine-2,4(3H)-diones are strong antimycobacterial substances which can be considered to be potential antituberculotics. In order to be able to verify the prognostics of the relationships between the structure and antimycobacterial activity, the series of previously evaluated substances was extended to include 4'-ethoxycarbonylsalicylanilide, 4'-trifluoromethylsalicylanilide, 4'-cyanidosalicylanilide, 4'-thiocarbamoylsalicylanilide, 3-(4-ethoxycarbonylphenyl)-2H-1,3-benzoxazine-2,4(3H)-dione, 3-(4-trifluoromethylphenyl)-2H-1,3-benzoxazine-2,4(3H)-dione, and 3-(4-cyanidophenyl)-2H-1,3-benzoxazine-2,4-(3H)-dione. The substances were evaluated against Mycobacterium tuberculosis, M. kansasii, and M. avium. In harmony with the previous study (see ref. 1), antimycobacterial activity increased with increasing lipophilicity and electron-acceptor properties of substituents. As the values of regression coefficients were not substantially changed after the complementation of the group, the present authors consider the problem under study to be solved.

Combination of molecular modeling and quantitative structure-activity relationship analysis in the study of antimycobacterial activity of pyridine derivatives.

A set of 4-benzylsulfanyl derivatives of pyridine-2-carbonitriles and pyridine-2-carbothioamides, previously tested for their antimycobacterial activity, were analysed by quantitative structure-activity relationship (QSAR) techniques, using some physicochemical and quantum-chemical parameters. The resulting QSAR revealed that the activity increases with electron withdrawing substituents in the benzyl moiety of studied compounds. HOMO orbitals can play an important role in the description of the mechanism of interactions at the molecular level. Additionally, the results of multiple linear regression indicate the differences between Mycobacterium tuberculosis and M. avium. The hydrophobicity of studied compounds is important for activity against M. avium.

New groups of antimycobacterial agents: 6-chloro-3-phenyl-4-thioxo-2H-1,3-benzoxazine-2(3H)-ones and 6-chloro-3-phenyl-2H-1,3-benzoxazine-2,4(3H)-dithiones.

A series of 6-chloro-3-phenyl-4-thioxo-2H-1,3-benzoxazine-2(3H)-ones 3 and a series of 6-chloro-3-phenyl-2H-1,3-benzoxazine-2, 4(3H)-dithiones 4 were synthesized by melting 6-chloro-3-phenyl-2H-1, 3-benzoxazine-2,4(3H)-dione and its derivatives substituted on the phenyl ring 2 with tetraphosphorus decasulfide. Compounds 2c-e, 3 and 4 exhibited in vitro activity against Mycobacterium tuberculosis, M. kansasii (two strains) and M. avium better than or comparable to that of isoniazid. Replacement of the oxo group by a thioxo group at position 4 led to improvement in activity against M. tuberculosis and M. kansasii. The Free-Wilson method and procedure developed by the authors were used to analyse the structure-activity and structure-antimycobacterial profile relationships, respectively.

New pyridine derivatives as potential antimicrobial agents.

A set of pyridine derivatives bearing a substituted alkylthio chain or a piperidyl ring in position 2 or 4 were synthesized, and their antimycobacterial and antifugal activities were evaluated. Chemical structures were confirmed by IR and NMR data, and by elemental analysis. Minimum inhibitory concentrations (MIC) were used for the evaluation of microbiological activity in vitro. The compounds were moderately active against both Mycobacterium tuberculosis and nontuberculous mycobacteria. The most active compound was 2-cyanomethylthiopyridine-4-carbonitrile (7) with MIC against Mycobacterium kansasii in the range of 8-4 mumol/l. The antifungal activities of the compounds were relatively low.

Relationships between the chemical structure of antimycobacterial substances and their activity against atypical strains. Part 14: 3-Aryl-6,8-dihalogeno-2H-1,3-benzoxazine-2,4(3H)-diones.

A set of eight derivatives of 6,8-dichloro-3-phenyl-2H-benzoxazine-2,4(3H)-dione and nine derivatives of 6,8-dibromo-3-phenyl-2H-1, 3-benzoxazine-2,4(3H)-dione, substituted on the phenyl ring, was prepared by the reaction of the corresponding salicylanilides with ethyl chloroformate. The compounds were evaluated in vitro for antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii, and Mycobacterium avium. Their activity increases with increasing hydrophobicity and electron-withdrawing ability of the substituents on the phenyl ring.

Research on antifungal and antimycobacterial agents. Synthesis and activity of 4-alkylthiopyridine-2-carbothioamides.

A series of 4-alkylthiopyridine-2-carbothioamides have been prepared and evaluated in vitro for antimicrobial activity. Chemical structures have been demonstrated by IR and 1H NMR data and by elemental analysis. The antimycobacterial activity of these compounds against Mycobacterium tuberculosis, Mycobacterium kansasii, Mycobacterium avium, and Mycobacterium fortuitum, and the antifungal activity against Candida albicans, Candida tropicalis, Candida krusei, Candida glabrata, Trichosporon beigelii, Trichophyton mentagrophytes, Aspergillus fumigatus, and Absidia corymbifera were determined by the MIC values. Compounds 3 exhibit good antimycobacterial activity compared to isoniazide. A moderate antifungal activity was observed against T. mentagrophytes. Activity is influenced by hydrophobicity of the alkyl group.