ABSTRACT
Aim: To evaluate the activity, cytotoxicity and efflux pumps inhibition of a series of 12 novels (-)-camphene-based 1,3,4-thiadiazoles (TDZs) against Mycobacterium tuberculosis (Mtb). Materials & methods: The minimum inhibitory concentration (MIC), cytotoxicity for three cell lines, ethidium bromide accumulation and checkerboard methods were carried out. Results: Compounds (6a, 6b, 6c, 6g, 6h and 6j) showed significant anti-Mtb activity (MIC 3.9-7.8 µg/ml) and no antagonism with anti-TB drugs already used in the TB treatment. Selectivity index (SI) was also determined, with values reaching 42.9 for H37Rv strain and 97.1 for clinical isolate. Five compounds also showed bacterial efflux pumps inhibition and one showed modulator effect with three drugs. Conclusion: These six TDZs should be considered as new scaffolds to develop anti-TB drugs.
Subject(s)
Antitubercular Agents/pharmacology , Mycobacterium tuberculosis/drug effects , Thiadiazoles/pharmacology , Animals , Bacterial Outer Membrane Proteins/drug effects , Blood Cells/drug effects , Chlorocebus aethiops , Drug Discovery , Drug Synergism , Humans , Macrophages/drug effects , Microbial Sensitivity Tests , Sheep/blood , Terpenes/pharmacology , Thiadiazoles/chemical synthesis , Thiadiazoles/toxicity , Tuberculosis/drug therapy , Vero Cells/drug effectsABSTRACT
Aim: To evaluate an assay to detect minimum bactericidal concentration (MBC) in Mycobacterium tuberculosis, using as single model rifampicin, isoniazid, levofloxacin (LVX) and linezolid (LNZ) and in combination. Material & methods: MBCs were carried out directly from resazurin microtiter assay plate and 3D checkerboard in M. tuberculosis H37Rv and five resistant clinical isolates. Results: The proposed MBC assay showed similar values to those determined by MGIT™, used as control. LVX and LNZ's MBC values were close to their MIC values. LNZ or LVX combined with isoniazid and rifampicin showed MBC value reduced in 63.7% of the assays. Conclusion: The proposed assay to determine MBCs of drugs can be applied to the study of new compounds with anti-M. tuberculosis activity to detect their bactericidal effect and also in laboratory routine for clinical dose adjustment of drugs according to the patient's profile.
Subject(s)
Antitubercular Agents/pharmacology , Mycobacterium tuberculosis/drug effects , Tuberculosis/drug therapy , Drug Resistance, Multiple, Bacterial , Drug Synergism , Humans , Isoniazid/pharmacology , Levofloxacin/pharmacology , Linezolid/pharmacology , Microbial Sensitivity Tests , Rifampin/pharmacologyABSTRACT
Aim: To evaluate the potential of three benzohydrazones (1-3), four acylhydrazones derived from isoniazid (INH-acylhydrazones) (4-7) and one hydrazone (8) as antituberculosis agents. Materials & methods: Inhibitory and bactericidal activities were determined for the reference Mycobacterium tuberculosis (Mtb) strain and clinical isolates. Cytotoxicity, drug combinations and ethidium bromide accumulation assays were also performed. Results: The tested compounds (1-8) presented excellent antituberculosis activity with surprisingly inhibitory (0.12-250 µg/ml) and bactericidal values, even against multidrug-resistant Mtb clinical isolates. Compounds showed high selectivity index, with values reaching 1833.33, and a limited spectrum of activity. Some of the compounds (2 & 8) are also great inhibitors of bacillus efflux pumps. Conclusion: Benzohydrazones and INH-acylhydrazones may be considered scaffolds for the development of new anti-Mtb drugs.
