ethionamide and thiocarlide

One of the first approaches undertaken in the quest for antitubercular compounds was that of understanding the mechanism of action of old drugs and proposing chemical modifications or other strategies to improve their activity, generally lost to the mechanisms of resistance developed by Mycobacterium tuberculosis. A leading case was the work carried out on a set of compounds with proven activity on the essential pathway of the synthesis of mycolic acids. As a result, different solutions were presented, improving the activity of those inhibitors or producing novel compounds acting on the same molecular target(s), but avoiding the most common resistance strategies developed by the tubercle bacilli. This review focuses on the activity of those compounds, developed following the completion of the studies on several of the classic antitubercular drugs.

Topics: Antitubercular Agents; Drug Design; Drug Resistance, Multiple, Bacterial; Ethionamide; Humans; Isoniazid; Mycobacterium tuberculosis; Mycolic Acids; Phenylthiourea; Structure-Activity Relationship; Thioacetazone; Tuberculosis, Pulmonary

Topics: Aminosalicylic Acids; Animals; Bacteria; Drug Resistance, Microbial; Ethionamide; Guinea Pigs; Humans; Isoniazid; Phenylthiourea; Rabbits; Solubility; Streptomycin; Thiosemicarbazones; Tuberculosis; Tuberculosis, Pulmonary; Tuberculosis, Renal

Topics: Animals; Antitubercular Agents; Ethionamide; Guinea Pigs; Humans; In Vitro Techniques; Mice; Phenylthiourea; Rabbits; Rats

Topics: Adrenal Cortex Hormones; Aminosalicylic Acid; Aminosalicylic Acids; Antitubercular Agents; Cycloserine; Ethionamide; Isoniazid; Kanamycin; Mycobacterium tuberculosis; Phenylthiourea; Pyrazinamide; Serologic Tests; Streptomycin; Thiosemicarbazones; Tuberculosis; Tuberculosis, Urogenital; Urine

Topics: Clinical Trials as Topic; Cycloserine; Drug Combinations; Drug Synergism; Ethionamide; Evaluation Studies as Topic; Humans; Isoniazid; Phenylthiourea; Pyrazinamide; Tuberculosis, Pulmonary

A chemical activation study of the thiocarbonyl-type antitubercular prodrugs, ethionamide (ETH), thioacetazone (TAZ), and isoxyl (ISO), was performed. Biomimetic oxidation of ethionamide using H

Topics: Antitubercular Agents; Ethionamide; Hydrogen Peroxide; Models, Molecular; Oxidation-Reduction; Phenylthiourea; Prodrugs; Thioacetazone

Ethionamide (ETH) is a second-line drug for the treatment of tuberculosis. As a prodrug, ETH has to be activated by EthA. ethA is controlled by its repressor EthR. 2-Phenylethyl-butyrate (2-PEB) inhibits EthR binding, enhances expression of EthA, and thereby enhances the growth-inhibitory effects of ethionamide, isoxyl, and thiacetazone in Mycobacterium tuberculosis strains with resistance to ETH due to inhA promoter mutations but not ethA mutations.

Topics: Antitubercular Agents; Bacterial Proteins; Butyrates; Drug Resistance, Multiple, Bacterial; Drug Synergism; Ethionamide; Gene Expression Regulation, Bacterial; Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Oxidoreductases; Oxygenases; Phenylthiourea; Thioacetazone

Isoxyl (ISO), a thiourea (thiocarlide; 4, 4'-diisoamyloxythiocarbanilide), demonstrated potent activity against Mycobacterium tuberculosis H37Rv (MIC, 2.5 micrograms/ml), Mycobacterium bovis BCG (MIC, 0.5 microgram/ml), Mycobacterium avium (MIC, 2.0 microgram/ml), and Mycobacterium aurum A+ (MIC, 2.0 microgram/ml), resulting in complete inhibition of mycobacteria grown on solid media. Importantly, a panel of clinical isolates of M. tuberculosis from different geographical areas with various drug resistance patterns were all sensitive to ISO in the range of 1 to 10 microgram/ml. In a murine macrophage model, ISO exhibited bactericidal killing of viable intracellular M. tuberculosis in a dose-dependent manner (0.05 to 2.50 microgram/ml). The selective action of ISO on mycolic acid synthesis was studied through the use of [1, 2-14C]acetate labeling of M. tuberculosis H37Rv, M. bovis BCG, and M. aurum A+. At its MIC for M. tuberculosis, ISO inhibited the synthesis of both fatty acids and mycolic acids (alpha-mycolates by 91.6%, methoxymycolates by 94.3%, and ketomycolates by 91.1%); at its MIC in M. bovis BCG, ISO inhibited the synthesis of alpha-mycolates by 87.2% and that of ketomycolates by 88.5%; and the corresponding inhibitions for M. aurum A+ were 87.1% for alpha-mycolates, 87.2% for ketomycolates, and 86.5% for the wax-ester mycolates. A comparison with isoniazid (INH) and ethionamide (ETH) demonstrated marked similarity in action, i.e., inhibition of the synthesis of all kinds of mycolic acids. However, unlike INH and ETH, ISO also inhibited the synthesis of shorter-chain fatty acids. ISO showed no acute toxicity against primary macrophage cell cultures as demonstrated by diminution of redox activity. A homologous series of ISO derivatives were synthesized. Most derivatives were as effective or more effective than the parent compound in the agar proportion assay. Thus, these thioureas, like INH and ETH, specifically inhibit mycolic acid synthesis and show promise in counteracting a wide variety of drug-sensitive and -resistant strains of M. tuberculosis.

Topics: Antitubercular Agents; Ethionamide; Isoniazid; Mycobacterium; Mycolic Acids; Phenylthiourea; Thiourea

Topics: Aminosalicylic Acids; Ethambutol; Ethionamide; Fatty Acids; Mycobacterium bovis; Mycobacterium tuberculosis; Phenylthiourea; Streptomycin

Topics: Drug Resistance, Microbial; Ethionamide; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Phenylthiourea; Thioacetazone; Tuberculosis

Topics: Aminosalicylic Acids; Drug Combinations; Drug Synergism; Ethionamide; Female; Humans; Isoniazid; Male; Middle Aged; Phenylthiourea; Streptomycin; Thiosemicarbazones; Tuberculosis; Tuberculosis, Lymph Node; Tuberculosis, Pulmonary

Topics: Adult; Aminosalicylic Acids; Cycloserine; Drug Combinations; Drug Resistance, Microbial; Ethionamide; Female; Humans; Ireland; Isoniazid; Male; Middle Aged; Phenylthiourea; Sputum; Streptomycin; Tuberculosis, Pulmonary

Topics: Administration, Oral; Animals; Body Weight; Drug Combinations; Ethambutol; Ethionamide; Guinea Pigs; Isoniazid; Lung; Mycobacterium; Mycobacterium Infections; Phenylthiourea; Pneumoconiosis; Radiography; Time Factors; Tuberculosis, Pulmonary

Topics: Agar; Aminosalicylic Acids; Animals; Culture Media; Depression, Chemical; Drug Resistance, Microbial; Egg Yolk; Ethionamide; Female; Glycerol; Isoniazid; Mycobacterium tuberculosis; Phenylthiourea; Streptomycin; Surface-Active Agents; Thioacetazone

Topics: Drug Resistance, Microbial; Ethionamide; Humans; Mycobacterium tuberculosis; Phenylthiourea; Thiosemicarbazones; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Capreomycin; Cycloserine; Drug Resistance; Drug Resistance, Microbial; Drug Therapy; Ethambutol; Ethionamide; Kanamycin; Phenylthiourea; Pyrazinamide; Retreatment; Toxicology; Tuberculosis; Tuberculosis, Pulmonary; Viomycin

Topics: Antitubercular Agents; Culture Media; Drug Resistance, Microbial; Ethionamide; Humans; In Vitro Techniques; Phenylthiourea; Thiosemicarbazones; Tuberculosis

Topics: Antitubercular Agents; Cycloserine; Drug Resistance; Drug Resistance, Microbial; Ethionamide; Humans; Phenylthiourea; Tuberculosis; Tuberculosis, Pulmonary

Topics: Aminosalicylic Acid; Aminosalicylic Acids; Anti-Infective Agents; Antitubercular Agents; Bacteriology; Cycloserine; Drug Resistance; Drug Resistance, Microbial; Ethionamide; Isoniazid; Kanamycin; Phenylthiourea; Pyrazinamide; Statistics as Topic; Streptomycin; Toxicology; Tuberculosis; Tuberculosis, Pulmonary; Viomycin

Topics: Adrenal Cortex Hormones; Aminosalicylic Acid; Aminosalicylic Acids; Antitubercular Agents; Cycloserine; Dihydrostreptomycin Sulfate; Ethambutol; Ethionamide; Humans; Isoniazid; Kanamycin; Oxytetracycline; Phenylthiourea; Pyrazinamide; Streptomycin; Thiosemicarbazones; Tuberculosis; Tuberculosis, Renal; Viomycin

Topics: Alcoholism; Alopecia; Aminosalicylic Acid; Aminosalicylic Acids; Antitubercular Agents; Asian People; Chemical and Drug Induced Liver Injury; China; Dermatitis, Exfoliative; Drug Therapy; Ethionamide; Hepatitis A; Hong Kong; Isoniazid; Jaundice; Phenylthiourea; Psychoses, Substance-Induced; Psychotic Disorders; Pyrazinamide; Streptomycin; Toxicology

Topics: Adolescent; Aminosalicylic Acid; Aminosalicylic Acids; Antitubercular Agents; Asian People; Bacteriological Techniques; Biomedical Research; Blood Chemical Analysis; China; Drug Resistance; Drug Resistance, Microbial; Ethionamide; Intestinal Absorption; Isoniazid; Phenylthiourea; Radiography, Thoracic; Sputum; Streptomycin; Thiosemicarbazones; Toxicology; Tuberculosis, Pulmonary

Topics: Anilides; Animals; Antitubercular Agents; Ethionamide; Mice; Phenylthiourea; Tuberculosis

Topics: Antitubercular Agents; Ethionamide; Phenylthiourea; Tuberculosis; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Ethionamide; Humans; Kanamycin; Phenylthiourea; Tuberculosis