rifampin and pyrazole

One-third of the world's population infected tuberculosis (TB), and more than 1 million deaths annually. The co-infection between the mainly pathogen Mycobacterium tuberculosis (MTB) and HIV, and the incidence of drug-resistant TB, multi-drug resistant TB, extensively drug-resistant TB as well as totally drug-resistant TB have further aggravated the mortality and spread of this disease. Thus, there is an urgent need to develop novel anti-TB agents against both drug-susceptible and drug-resistant TB. The wide spectrum of biological activities and successful utilization of pyrazole-containing drugs in clinic have inspired more and more attention towards this kind of heterocycles. Numerous of pyrazole-containing derivatives have been synthesized for searching new anti-TB agents, and some of them showed promising potency and may have novel mechanism of action. This review aims to outline the recent achievements in pyrazole-containing derivatives as anti-TB agents and their structure-activity relationship.

Topics: Antitubercular Agents; Dose-Response Relationship, Drug; Humans; Molecular Structure; Mycobacterium tuberculosis; Pyrazoles; Structure-Activity Relationship; Tuberculosis

A collection of potent antimicrobials consisting of novel 1,3-bis-benzoic acid and trifluoromethyl phenyl derived pyrazoles has been synthesized and tested for antibacterial activity. The majority of trifluoromethyl phenyl derivatives are highly potent growth inhibitors of Gram-positive bacteria and showed low toxicity to human cultured cells. In particular, two compounds (59 and 74) were selected for additional studies. These compounds are highly effective against Staphylococcus aureus as shown by a low minimum inhibitory concentration (MIC), a bactericidal effect in time-kill assays, moderate inhibition of biofilm formation as well as biofilm destruction, and a bactericidal effect against stationary phase cells representing non-growing persister cells. Multistep resistance assays showed a very low tendency for S. aureus and Enterococcus faecalis to develop resistance through mutation. Additionally, in vivo mouse model studies showed no harmful effects at doses up to 50 mg/kg using 14 blood plasma organ toxicity markers or TUNEL assay in liver and kidney. Investigations into the mode of action by performing macromolecular synthesis inhibition studies showed a broad range of inhibitory effects, suggesting targets that have a global effect on bacterial cell function.

Topics: Aniline Compounds; Anti-Bacterial Agents; Biofilms; Cell Line; Cell Survival; Drug Resistance, Bacterial; Enterococcus faecalis; Gram-Positive Bacteria; Humans; Liver; Microbial Sensitivity Tests; Pyrazoles; Staphylococcus aureus; Structure-Activity Relationship

A library of novel 3-trifluoromethyl pyrazolo-1,2,3-triazole hybrids (5-7) were accomplished starting from 5-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-amine (1) via key intermediate 2-azido-N-(5-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)acetamide (3) through click chemistry approach. Thus obtained compounds in 5-7 series were evaluated for in vitro antimycobacterial activity against Mycobacterium smegmatis (MC(2) 155) and also verified the cytotoxicity. These studies engendered promising lead compounds 5q, 7b and 7c with MIC (μg/mL) values 15.34, 16.18 and 16.60, respectively. Amongst these three compounds, 2-(4-(4-methoxybenzoyl)-1H-1,2,3-triazol-1-yl)-N-(5-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl) acetamide (5q) emerged as the most promising antitubercular agent with lowest cytotoxicity against the A549 cancer cell line. This is the first report to demonstrate the pyrazolo triazole hybrids as potential antimycobacterial agents.

Topics: Anti-Bacterial Agents; Cell Line, Tumor; Click Chemistry; Halogenation; Humans; Microbial Sensitivity Tests; Models, Molecular; Mycobacterium Infections, Nontuberculous; Mycobacterium smegmatis; Pyrazoles; Structure-Activity Relationship; Triazoles

A series of novel pyrazole linked triazolo-pyrimidine hybrids were synthesized and evaluated for their anti-tuberculosis activity against M.tb H37Rv strain. Some of the screened entities rendered promising anti-tb activity (MIC: 0.39μg/mL) and were found non toxic against Vero cells (IC50: ⩾20μg/mL). Further, the docking study against wild type InhA enzyme of Mycobacterium tuberculosis using Glide reproduced the most active inhibitors (J21 and J27) with lowest binding energies and highest Glide XP scores demonstrating efficient binding to the active pocket. Additionally, the enzyme inhibition assay and ADME prediction of the active proved to be an attest to the possibility of developing compound J27 as a potent anti-tubercular lead.

Topics: Animals; Antitubercular Agents; Bacterial Proteins; Chlorocebus aethiops; Humans; Molecular Docking Simulation; Mycobacterium tuberculosis; Oxidoreductases; Pyrazoles; Pyrimidines; Triazoles; Tuberculosis; Vero Cells

As a part of our research to develop novel antitubercular and antimicrobial agents, a series of 3-(4-chlorophenyl)-4-substituted pyrazoles have been synthesised. These compounds were tested for antitubercular activity in vitro against Mycobacterium tuberculosis H37Rv strain using the BACTEC 460 radiometric system, antifungal activity against a pathogenic strain of fungi and antibacterial activity against gram-positive and gram-negative organisms. Among them tested, many compounds showed good to excellent antimicrobial and antitubercular activity. The results suggest that hydrazones, 2-azetidinones and 4-thiazolidinones bearing a core pyrazole scaffold would be potent antimicrobial and antitubercular agents.

Topics: Anti-Infective Agents; Antitubercular Agents; Fungi; Gram-Negative Bacteria; Gram-Positive Bacteria; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pyrazoles; Structure-Activity Relationship

In the present investigation, a series of 3-substituted-N-aryl-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide analogues were synthesized and were evaluated for antitubercular activity by two fold serial dilution technique. All the newly synthesized compounds showed moderate to high inhibitory activities against Mycobacterium tuberculosis H(37)Rv and INH resistant M. tuberculosis. The compound N,3-bis(4-fluorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide (4c) was found to be the most promising compound active against M. tuberculosis H(37)Rv and isoniazid resistant M. tuberculosis with minimum inhibitory concentration 0.78 μM.

Topics: Amides; Antitubercular Agents; Drug Design; Drug Resistance, Bacterial; Indenes; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pyrazoles

The P450 enzymes of the liver are responsible for the metabolism of a wide range of chemical compounds, and hepatocytes are used in pharmacological and toxicological in vitro tests. Thus, it is important to know how stable these enzymes are in culture. We measured the activity of CYP2A and CYP3A in microsomes isolated from both pig liver and primary pig hepatocyte cultures, together with the apoprotein concentration using Western blotting. The CYP2A activity and apoprotein concentration decreased rapidly; only about 5 percent remained after 48 hr incubation, whereas the CYP3A activity and apoprotein concentration was constant. CYP3A was induced 3 times after exposure to rifampicin, whereas neither rifampicin nor pyrazole could induce CYP2A. The hepatocytes were also incubated with varying concentration of FCS and autologous serum, however without effect on the stability of CYP2A, nor did different concentrations of growth hormone and testosterone added to the cultures have any effect.

Topics: Animals; Apoproteins; Aryl Hydrocarbon Hydroxylases; Cells, Cultured; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Enzyme Inhibitors; Female; Hepatocytes; Microsomes, Liver; Oxidoreductases, N-Demethylating; Pyrazoles; Rifampin; Steroid Hydroxylases; Swine