Design, Synthesis, and Biological Evaluation of Isothiosemicarbazones with Antimycobacterial Activity.

A series of benzaldehyde and salicylaldehyde-S-benzylisothiosemicarbazones was synthesized and tested against 12 different strains of mycobacteria, Gram-positive and Gram-negative bacteria, and the significant selectivity toward mycobacteria was proved. Twenty-eight derivatives were evaluated for the inhibition of isocitrate lyase, which is a key enzyme of the glyoxylate cycle necessary for latent tuberculosis infection, and their iron-chelating properties were investigated. Two derivatives, 5-bromosalicylaldehyde-S-(4-fluorobenzyl)-isothiosemicarbazone and salicylaldehyde-S-(4-bromobenzyl)-isothiosemicarbazone, influenced the isocitrate lyase activity and caused a better inhibition at 10 µmol/L than 3-nitropropionic acid, a standard inhibitor. The compounds were also found to act as exogenous chelators of iron, which is an obligate cofactor for many mycobacterial enzymes. Due to their low cytotoxicity, together with the activity against isocitrate lyase and the ability to sequester iron ions, the compounds belong to potential antibiotics with the main effect on mycobacteria.

Prediction of retention characteristics of heterocyclic compounds.

The CORAL software ( http://www.insilico.eu/coral ) was used to build up quantitative structure-property relationships (QSPRs) for the retention characteristics of 93 derivatives of three groups of heterocyclic compounds: 2-phenyl-1,3-benzoxazoles, 4-benzylsulfanylpyridines, and benzoxazines. The QSPRs are one-variable models based on the optimal descriptors calculated from the molecular structure represented by simplified molecular input-line entry systems (SMILES). Each symbol (or two undivided symbols) of SMILES is characterized by correlation weight. The optimal descriptor is the sum of the correlation weights. The numerical data on the correlation weights were calculated with the Monte Carlo method by the manner which provides best correlation between endpoint and optimal descriptor for the calibration set. The predictive ability of the model is checked with the validation set (compounds invisible during building up of the model). The approach has been checked with three random splits into the training, calibration, and validation sets: all models have apparent predictive potential. The mechanistic interpretation of the molecular features extracted from SMILES as the promoters of increase or decrease of examined endpoints is suggested.

Structure-activity relationships of N-benzylsalicylamides for inhibition of photosynthetic electron transport.

Inhibition of photosynthetic electron transport (PET) in spinach chloroplasts by sixty-one ring-substituted N-benzylsalicylamides was investigated. The inhibitory potency of the compounds expressed by IC50 value varied from 2.0 to 425.3 µmol/L. Several evaluated compounds can be considered as effective PET inhibitors; these include N-(3,4- dichlorobenzyl)-2-hydroxy-5-nitrobenzamide (IC50 = 2.0 µmol/L), 3,5-dibromo-N-(3,4-dichlorobenzyl)-2-hydroxybenzamide (IC50 = 2.3 µmol/L) and 3,5-dibromo-N-(4-chlorobenzyl)-2-hydroxybenzamide (IC50 = 2.6 µmol/L) with activity comparable with that of the standard Diuron (IC50 = 1.9 µmol/L). The PET inhibiting activity increased approximately linearly with increasing lipophilicity of the compounds as well as with the increasing sum of Hammett σ constants of the substituents on the acyl fragment (R(1) = H, 5-OCH3, 5-CH3, 5-Cl, 5-Br, 5-NO2, 4-OCH3, 4-Cl, 3,5-Cl and 3,5-Br) and the benzylamide fragment (R(2) = H, 4-OCH3, 4-CH3, 4-F, 4-Cl and 3,4-Cl). Based on the evaluated structure-PET inhibiting activity relationships (QSAR) it was confirmed that the inhibitory activity of the compounds depends on lipophilicity (log P or distributive parameters π; (1) and π(2)of individual substituents) and electronic properties of the substituents on the acyl (σ(1)) and the benzylamide fragments (σ(2)), the contribution of σ(1) being more significant than that of σ(2).

Synthesis and biological activity of quaternary ammonium salt-type agents containing cholesterol and terpenes.

New quaternary ammonium salt-type compounds with lipophilic cholesterol and terpene moieties were synthesized. The compounds showed promising antibacterial and antimycobacterial activities. Those compounds containing the cholesterol moiety showed significant activity against Staphylococcus aureus, Staphylococcus epidermidis, and Enterococcus faecium. On the contrary, the antimycobacterial activity increased with the presence of the terpene unit in the molecule.

[Where does the development of new antituberculotics go? Part 2 - in vitro evaluation]. / Kam smeruje vývoj nových antituberkulotik? Cást 2 - hodnocení in vitro.

The present paper is a continuation of a publication of 2012 (Ces. a slov. Farm. 2012; 31, 150-158). It is oriented at the evaluation of potential antituberculotics in vitro, which is the most widely used approach to testing. The paper is based on the information from Chemical Abstracts 2011-2013. It is a selection from nearly three thousand items of information intended to help researchers. The greatest attention is paid to the multiresistant strains of Mycobacterium tuberculosis. In vitro evaluation for the development of new drugs is of great importance, but it is just the first stretch of the road to new medicinal drugs.

SMILES-based quantitative structure-property relationships for half-wave potential of N-benzylsalicylthioamides.

Optimal descriptors calculated with Simplified Molecular Input Line Entry System (SMILES) notation have been used in quantitative structure-property relationships (QSPR) of half-wave potential of N-benzylsalicylthioamides. The QSPR developed is one-variable model based on the optimal descriptors calculated with the Monte Carlo method. The approach has been checked up with three random splits into the training and test sets. Mechanistic interpretations (structural alerts related to the half-wave potential) of the model are discussed.

[Where does the development of new antituberculotics aim at?]. / Kam smeruje vývoj nových antituberkulotik?

Several research teams in the Czech and Slovak Republics are oriented on the development of new antitubeculotics. The present article is based mainly on the information from the Chemical Abstracts from the year 2011 and the beginning of the year 2012. It is a selection from almost three thousand reports aiming to help our scientists. The article presents topical information which may be of interest to several pharmaceutical professions.

[Derivatives of phenylcarbamic acid as potential antituberculotics]. / Deriváty kyseliny fenylkarbamové jako potenciální antituberkulotika.

Basic esters of phenylcarbamic acid were studied by the teams of Prof. Cizmárik and Prof. Waisser as potential antituberculotics. Their antimycobacterial activity increased with lipophilicity. The most active derivatives were substituted with an alkoxy group in position p- on the phenyl. The activity of some of them almost approached that of INH, but they exceeded it only in the evaluation against the INH-resistant strains M. avium and M. kansasii. The carbamates produced by Prof. Vinsová and co-workers published in the last year show that carbamates can be still topical.

Phenyl salicylates - a new group of potential antituberculotics.

Antimycobacterial activity of phenyl salicylates (salols) was studied in connection with antituberculotic activity of salicylic derivatives. Phenyl salicylates are esters. Our attention was previously oriented on amides. Phenyl salicylates (salols) represent a new group of antimycobacterial compounds. They are less active than the corresponding amides. The most active compound in the group under study is substituted on phenyl in the salicyl moiety with a 4-methoxy group. The study reports a new item of information about antimycobacterial salicylic derivatives.

Highly active antimycobacterial derivatives of benzoxazine.

New 3-(4-alkylphenyl)-4-thioxo-2H-1,3-benzoxazine-2(3H)-ones and 3-(4-alkylphenyl)-2H-1,3-benzoxazine-2,4(3H)-dithiones were synthesized. The compounds were tested for in vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium avium and two strains of Mycobacterium kansasii. The antimycobacterial activity increased with the replacement of the carbonyl group by the thiocarbonyl group in the starting 3-(4-alkylphenyl)-2H-1,3-benzoxazine-2,4(3H)-diones. The most active derivatives were more active than isonicotinhydrazide (INH). Free-Wilson analysis was also carried out and the activity contribution was examined.

N-Benzylsalicylthioamides as novel compounds with promising antimycotic activity.

The in vitro biological activity of N-benzylsalicylthioamides was evaluated against eight fungal strains by the broth microdilution method and the results were compared with those obtained with fluconazole. The compounds exhibited an in vitro antifungal activity against the fluconazole-susceptible as well as the fluconazole-resistant fungal strains. The biological activity was analyzed by quantitative structure-activity relationship (QSAR).

A note to the biological activity of benzoxazine derivatives containing the thioxo group.

New 3-benzyl-4-thioxo-2H-1,3-benzoxazine-2(3H)-ones and 3-benzyl-2H-1,3-benzoxazine-2,4(3H)-dithiones were synthesized. The compounds were tested for in vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii and Mycobacterium avium. The replacement of the carbonyl group by the thiocarbonyl group increased the antimycobacterial activity. The most active derivatives were more active than isonicotinhydrazide (INH). The cytotoxicity and the antiproliferative activity were studied as well.

N-benzylsalicylthioamides: highly active potential antituberculotics.

A gseries of 29 new derivatives of N-benzylsalicylthioamides was synthesized and the compounds were tested for in-vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii, and Mycobacterium avium. The activity was analyzed by quantitative structure-activity relationship (QSAR). Activity increased with increasing lipophilicity and electron donating effect of the substituents in the acyl moiety and decreased with the electrophilic superdelocalizability of the molecules. The most active compounds are more active than isoniazid (INH) and are active against INH-resistant potential pathogenic strains of mycobacterium.

Preparation and in vitro evaluation of benzylsulfanyl benzoxazole derivatives as potential antituberculosis agents.

A set of 2-benzylsulfanyl derivatives of benzoxazole was synthesized and evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis, non-tuberculous mycobacteria and multidrug-resistant M. tuberculosis. The activities were expressed as the minimum inhibitory concentration (MIC) in mmol/L. The substances showed similar activity against all tested strains. The lead compounds in the set, dinitro derivatives exhibited significant activity against both sensitive and resistant strains of M. tuberculosis and also against non-tuberculous mycobacteria. To facilitate drug design of benzoxazole as potential antituberculosis agent, we have explored the quantitative structure-activity relationship (QSAR). We demonstrated that lower lipophilicity has significant contribution to activity. Dinitrobenzylsulfanyl derivative of benzoxazole represents the promising small-molecule synthetic antimycobacterials.

Highly active potential antituberculotics: 3-(4-alkylphenyl)-4-thioxo-2H-1,3-benzoxazine-2(3H)-ones and 3-(4-alkylphenyl)-2H-1,3-benzoxazine-2,4(3H)-dihiones substituted in ring-B by halogen.

A series of 6-chloro-3-(4-alkylphenyl)-4-thioxo-2H-1,3-benzoxazine-2(3H)-ones, 7-chloro-3-(4-alkylphenyl)-4-thioxo-2H-1,3-benzoxazine-2(3H)-ones, 6-bromo-3-(4-alkylphenyl)-4-thioxo-2H-1,3-benzoxazine-2(3H)-ones, 6,8-dibromo-3-(4-alkylphenyl)-4-thioxo-2H-1,3-benzoxazine-2(3H)-ones, 6-chloro-3-(4-alkylphenyl)-2H-1,3-benzoxazine-2,4(3H)-dithiones, 7-chloro-3-(4-alkylphenyl)-2H-1,3-benzoxazine-2,4(3H)-dithiones, 6-bromo-3-(4-alkylphenyl)-2H-1,3-benzoxazine-2,4(3H)-dithiones and 6,8-dibromo-3-(4-alkylphenyl)-2H-1,3-benzoxazine-2,4(3H)-dithiones was synthesized. The compounds exhibited in-vitro activity against Mycobacterium tuberculosis, M. kansasii (two strains), and M. avium. 6-bromo-3-(4-propylphenyl)-4-thioxo-2H-1,3-benzoxazin-2(3H)-one and 6-bromo-3-(4-propylphenyl)-2H-1,3-benzoxazin-2,4(3H)-dithione are the most active compounds against M. tuberculosis. The activity is similar to isoniazid (INH). The compounds under study have a broad spectrum of activity against potential pathogenic strains. The replacement of the oxo group by thioxo group of 3-(4-alkylphenyl)-2H-1,3-benzoxazine-2,4(3H)-diones often led to an improvement in the antimycobacterial activity against M. tuberculosis.

The oriented development of antituberculotics (Part II): halogenated 3-(4-alkylphenyl)-1,3-benzoxazine-2,4-(3H)-diones.

Based on our previous studies, 21 new halogenated 3-(4-alkylphenyl)-1,3-benzoxazine-2,4-(3H)-diones were synthesized by the reaction of salicylanilides and methyl-chloroformate. All compounds were screened in vitro against three different strains of mycobacterium, and Free-Wilson method was used to establish structure-activity relationships. 6-Bromo-3-(4-butylphenyl)-1,3-benzoxazine-2,4-(3H)-dione 3b proved to be the most active compound of the series.

QSPR modeling of the half-wave potentials of benzoxazines by optimal descriptors calculated with the SMILES.

Optimal descriptors calculated with Simplified Molecular Input Line Entry System (SMILES) notation have been used in quantitative structure-property relationships (QSPR) modeling electrochemical half-wave potential of benzoxazine derivatives by one-variable correlations.

The oriented development of antituberculotics: salicylanilides.

On the basis of our previous results 22 salicylanilides were synthesized. The compounds were tested for in vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii, and Mycobacterium avium. The Free-Wilson method was used to evaluate structure-antimycobacterial activity relationships. 4-Chloro-N-(4-propylphenyl)salicylamide and 5-chloro-N-(4-propylphenyl)salicylamide were selected for preclinical studies.

A note on the antitubercular activities of 1-aryl-5-benzylsulfanyltetrazoles.

A set of 32 1-phenyl-5-benzylsulfanyltetrazoles substituted on the phenyl ring as well as on the benzyl moiety was synthesized. The compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis. The activity against M. tuberculosis becomes higher with increasing electron-accepting properties of the substituents on the phenyl ring. On the other hand, any substitution on the benzylic moiety decreases the activity.

Heterocyclic isosters of antimycobacterial salicylanilides.

A series of 64 derivatives of substituted heterocyclic analogues of salicylanilides was synthesized. The compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium avium and two strains of Mycobacterium kansasii. For the QSAR study, the combination of Free-Wilson approach with Hansch approach was used. The molecules were separated on the heterocyclic and salicyl moieties and the study of influences of electronic and hydrophobic properties was used as well. The compounds are a new group of potential anti-tuberculotics.