Vera Klimesova

Synthesis and preliminary evaluation of benzimidazole derivatives as antimicrobial agents

A series of 2-alkylsulphanylbenzimidazoles was synthesised and the compounds were evaluated for their in vitro antimicrobial activity. The structures of the compounds were confirmed by 1H-NMR and IR data, and their purity by elemental analysis. Antimycobacterial activities against Mycobacterium tuberculosis and non-tuberculous mycobacteria as well as antifungal activities against Candida albicans, Candida tropicalis, Candida krusei, Candida glabrata, Trichosporon beigelii, Trichophyton mentagrophytes and Aspergillus fumigatus were expressed as the corresponding MIC values. The substances exhibited appreciable antimycobacterial activity, in particular, against non-tuberculous mycobacteria. The activity of the most active compound in the set, 3,5-dinitro derivative 4t, exceeded that of the standard isoniazide against M. kansasii and M. avium. The antifungal activities of the compounds were relatively low. A weak antifungal effect was observed against the dermatophyte Trichophyton mentagrophytes. None of the compounds showed significant inhibitory activity against yeasts.

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.

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.

Structure-Activity Relationships of 2-Benzylsulfanylbenzothiazoles: Synthesis and Selective Antimycobacterial Properties

A set of 2-benzylsulfanyl derivatives of benzothiazole was synthesized and evaluated for antimicrobial and cytotoxic activities. The biological screening on antimicrobial activity against a panel of Gram-positive and Gram-negative bacteria, yeasts and fungi identified benzylsulfanyl derivatives of benzothiazole as selective inhibitors of mycobacteria. The lead compounds in the set, dinitro derivatives exhibited significant activity against sensitive and multidrug-resistant strains of M. tuberculosis and low cytotoxicity. The QSAR study indicated that the antituberculotic activity is connected with LUMO and HOMO energies. The lower lipophilicity and the increased size of the molecule contribute to antituberculotic activity. Thus, dinitrobenzylsulfanyl derivatives of benzothiazole represent promising smallmolecule synthetic antimycobacterials.

Preparation and in‐vitro Evaluation of 4‐Benzylsulfanylpyridine‐2‐carbohydrazides as Potential Antituberculosis Agents

A set of 4‐benzylsulfanylpyridine‐2‐carbohydrazides was synthesized and evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, non‐tuberculous mycobacteria, and multidrug‐resistant M. tuberculosis. The activities expressed as the minimum inhibitory concentration (MIC) fall into a range of 2 to 125 μmol/L, most often 4 to 32 μmol/L. The results revealed that the substituents on the benzyl moiety do not influence the antimycobacterial efficacy. The substances exhibited similar activities against sensitive and resistant strains of M. tuberculosis. Furthermore, compounds show low antiproliferative effect and cytotoxicity.

LIPOPHILICITY CHARACTERIZATION BY REVERSED-PHASE HPLC OF POTENTIAL ANTITUBERCULOTICS

ABSTRACT Lipophilicity is one of the properties which influence the partition of a substance in biological media. The reversed-phase high-performance liquid chromatographic (RP-HPLC) capacity factors k of two series of 2-benzylthioderivatives, newly synthesized as potential antituberculous drugs, were determined on a C-18 stationary phase with methanol–water as the mobile phase, using UV detection. The measured log k values were compared with the log P values obtained by means of a mathematical method. High correlation was found between log P and log k values.

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.