oxadiazoles and Tuberculosis

With the increasing number of cases of inactive and drug-resistance tuberculosis, there is an urgent need to develop new potent molecules set for fighting this brutal disease. Medicinal chemistry concerns the discovery, the development, the identification, and the interpretation of the mode of action of biologically active compounds at the molecular level. Molecules bearing oxadiazoles are one such class that could be considered to satisfy this need. Oxadiazole regioisomers have been investigated in drug discovery programs for their capacity to go about as powerful linkers and as pharmacophoric highlights. Oxadiazoles can go about as bioisosteric substitutions for the hydrazide moiety which can be found in first-line anti-TB drugs, and some have been likewise answered to cooperate with more current anti-TB targets. This present review summarizes the current innovations of oxadiazole-based derivatives with potential antituberculosis activity and bacteria discussing various aspects of structure-activity relationship (SAR).

Topics: Animals; Antitubercular Agents; Drug Discovery; Humans; Models, Molecular; Mycobacterium tuberculosis; Oxadiazoles; Structure-Activity Relationship; Tuberculosis

Tuberculosis (TB) caused by Mycobacterium tuberculosis is one of the main killers of people all over the world. The major hurdles with existing therapy are the lengthy regimen and appearance of multi drug resistant (MDR) and extensively drug resistant (XDR) strains of M.tuberculosis.. The present work was aimed to synthesize and determine antitubercular and antimicrobial potential of some novel 3-chloro-4-aryl-1-[4-(5-pyrazin-2-yl[1,3,4]oxadiazole-2-ylmethoxy)-phenyl]-azetidin-2-one derivatives 7: (A: -H: ) from pyrazinoic acid as precursor, which is a well-established antitubercular agent. Here we report the synthesis of a new class of heterocyclic molecules in which pyrazine, 1, 3, 4-oxadiazole and azetidinone moieties were present in one frame work.. Pyrazinoic acid (1: ) was esterified first (2: ) followed by amination to produce hydrazide (3: ) which was refluxed with POCl3 to obtain 2-chloromethyl-5pyrazino-1, 3, 4-oxadiazole (4: ). This was then further reacted with 4-amino phenol to obtain 4-[5-pyrazino-1, 3, 4-oxadiazol-2-yl-methoxy]-phenyl amine (5: ) which on condensation with various aromatic aldehydes afforded a series Schiff's bases 6(A-H): . Dehydrative annulations of 6(A-H): in the presence of chloroacetyl chloride and triethylamine yielded 3-chloro-4-aryl-1-[4-(5-pyrazin-2-yl-[1, 3, 4]oxadiazole-2-ylmethoxy)-phenyl]-azetidin-2-one derivatives 7(A-H): . Antibacterial, antifungal and antitubercular potential of all the synthesized compounds were assessed. Docking study was performed using the software VLife Engine tools of Vlifemds 4.6 on the protein lumazine synthase of M. tuberculosis (PDB entry code 2C92).. The present studies demonstrated that synthesized oxadiazole derivatives have good antimicrobial activity against the various microorganisms. Among the synthesized derivative, 7B: and 7G: were found to be prominent compounds which have potential antibacterial, antifungal and antitubercular activity (with MIC 3.12 µg/ml and high dock score ranging from -59.0 to -54.0) against Mycobacterium tuberculosis.. Derivatives 7B: and 7G: would be effective lead candidates for tuberculosis therapy.

Topics: Antifungal Agents; Antitubercular Agents; Aspergillus niger; Azetidines; Candida albicans; Drug Evaluation, Preclinical; Humans; Microbial Sensitivity Tests; Molecular Docking Simulation; Mycobacterium tuberculosis; Mycoses; Oxadiazoles; Pyrazinamide; Tuberculosis

Antibiotic resistance is a major problem of tuberculosis treatment. This provides the stimulus for the search of novel molecular targets and approaches to reduce or forestall resistance emergence in Mycobacterium tuberculosis. Earlier, we discovered a novel small-molecular inhibitor among 3-phenyl-5-(1-phenyl-1H-[1,2,3]triazol-4-yl)-[1,2,4]oxadiazoles targeting simultaneously two enzymes-mycobacterial leucyl-tRNA synthetase (LeuRS) and methionyl-tRNA synthetase (MetRS), which are promising molecular targets for antibiotic development. Unfortunately, the identified inhibitor does not reveal antibacterial activity toward M. tuberculosis. This study aims to develop novel aminoacyl-tRNA synthetase inhibitors among this chemical class with antibacterial activity toward resistant strains of M. tuberculosis. We performed molecular docking of the library of 3-phenyl-5-(1-phenyl-1H-[1,2,3]triazol-4-yl)-[1,2,4]oxadiazole derivatives and selected 41 compounds for investigation of their inhibitory activity toward MetRS and LeuRS in aminoacylation assay and antibacterial activity toward M. tuberculosis strains using microdilution assay. In vitro screening resulted in 10 compounds active against MetRS and 3 compounds active against LeuRS. Structure-related relationships (SAR) were established. The antibacterial screening revealed 4 compounds active toward M. tuberculosis mono-resistant strains in the range of concentrations 2-20 mg/L. Among these compounds, only one compound 27 has significant enzyme inhibitory activity toward mycobacterial MetRS (IC

Topics: Amino Acyl-tRNA Synthetases; Antitubercular Agents; Cell Cycle Proteins; Drug Discovery; Drug Resistance, Bacterial; Fungal Proteins; HEK293 Cells; Hep G2 Cells; Humans; Microbial Sensitivity Tests; Molecular Docking Simulation; Mycobacterium tuberculosis; Oxadiazoles; Tuberculosis; Tumor Suppressor Proteins

Killing more than one million people each year, tuberculosis remains the leading cause of death from a single infectious agent. The growing threat of multidrug-resistant strains of

Topics: Animals; Antitubercular Agents; Crystallography, X-Ray; Drug Design; Drug Discovery; Ethionamide; Female; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Oxadiazoles; Repressor Proteins; Structure-Activity Relationship; Tuberculosis

The rapid and persistent increase of drug-resistant

Topics: Animals; Antitubercular Agents; Benzamides; Blood Donors; Cell Survival; Cells, Cultured; Cytokines; Disease Models, Animal; Histone Deacetylase Inhibitors; Histone Deacetylases; Host-Pathogen Interactions; Humans; Hydroxamic Acids; Macrophages; Mycobacterium marinum; Mycobacterium tuberculosis; Oxadiazoles; Signal Transduction; Transcriptome; Treatment Outcome; Tuberculosis; Zebrafish

The most recent survey conducted by the World Health Organization described Tuberculosis (TB) as one of the top 10 causes of death and the leading cause of death from a single infectious agent. The increasing number of TB-resistant cases has contributed to this scenario. In light of this, new strategies to control and treat the disease are necessary. Our research group has previously described furoxan derivatives as promising scaffolds to be explored as new antitubercular drugs.. Two of these furoxan derivatives, (14b) and (14c), demonstrated a high selectivity against Mycobacterium tuberculosis. The compounds (14b) and (14c) were also active against a latent M. tuberculosis strain, with MIC. Altogether, we have identified two advanced lead compounds, (14b) and (14c), as novel promising candidates for the treatment of TB infection.

Topics: Animals; Antitubercular Agents; Bacteria; Drug Resistance, Bacterial; Female; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Mutagenicity Tests; Mycobacterium tuberculosis; Oxadiazoles; Tuberculosis

In recent times, heterocyclic chemotypes are being explored for the development of new antimycobacterials that target the drug-resistant tuberculosis. Here, we are disclosing the 5-substitued 2-mercapto-1,3,4-oxadiazoles as potent antitubercular agents.. A small library of 2-mercapto-1,3,4-oxadiazoles was synthesized using various acids. The compounds were evaluated for antituberculosis activity against M. tuberculosis H37Rv.. Compound 8j was identified as antitubercular lead with MIC of 0.6 μg/ml against M. tuberculosis H37Rv. This compound was nontoxic to CHO-K1 cells and showed selectivity index of 39. Of note, 8j showed antitubercular activity against pre-extensively drug-resistant clinical isolate of Mycobacterium with MIC of 2 μg/ml.. This study provides potent antitubercular agent which can be further optimized to discover novel antibiotics.

Topics: Antitubercular Agents; Cell Line; Humans; Models, Molecular; Mycobacterium tuberculosis; Oxadiazoles; Tuberculosis; Tuberculosis, Multidrug-Resistant

The development of novel drugs is essential for the treatment of tuberculosis and other mycobacterial infections in future. A series of N-alkyl-2-isonicotinoylhydrazine-1-carboxamides was synthesized from isoniazid (INH) and then cyclized to N-alkyl-5-(pyridin-4-yl)-1,3,4-oxadiazole-2-amines. All derivatives were characterised spectroscopically. The compounds were screened for their in vitro antimycobacterial activity against susceptible and multidrug-resistant Mycobacterium tuberculosis (Mtb.) and nontuberculous mycobacteria (NTM; M. avium, M. kansasii). The most active carboxamides were substituted by a short n-alkyl, their activity was comparable to INH with minimum inhibitory concentrations (MICs) against Mtb. of 0.5-2 μM. Moreover, they are non-toxic for HepG2, and some of them are highly active against INH-resistant NTM (MICs ≥4 μM). Their cyclization to 1,3,4-oxadiazoles did not increase the activity. The experimentally proved mechanism of action of 2-isonicotinoylhydrazine-1-carboxamides consists of the inhibition of enoyl-ACP reductase (InhA) in a way similar to INH, which is blocking the biosynthesis of mycolic acids. N-Dodecyl-5-(pyridin-4-yl)-1,3,4-oxadiazol-2-amine as the most efficacious oxadiazole inhibits growth of both susceptible and drug-resistant Mtb. strains with uniform MIC values of 4-8 μM with no cross-resistance to antitubercular drugs including INH. The mechanism of action is not elucidated but it is different from INH. Obtained results qualify these promising derivatives for further investigation.

Topics: Antitubercular Agents; Drug Resistance, Bacterial; Hep G2 Cells; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Oxadiazoles; Tuberculosis

Topics: Animals; Antitubercular Agents; Drug Design; Humans; Macrophages; Mice; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Oxadiazoles; RAW 264.7 Cells; Tuberculosis

Topics: Antitubercular Agents; Cell Line, Tumor; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Oxadiazoles; Thiones; Triazoles; Tuberculosis

Topics: Antitubercular Agents; Drug Design; Humans; Microbial Sensitivity Tests; Models, Molecular; Mycobacterium tuberculosis; Oxadiazoles; Pyridines; Structure-Activity Relationship; Tuberculosis

A series of novel quinoline-oxadiazole hybrid compounds was designed based on stepwise rational modification of the lead molecules reported previously, in order to enhance bioactivity and improve druglikeness. The hybrid compounds synthesized were screened for biological activity against Mycobacterium tuberculosis H37Rv and for cytotoxicity in HepG2 cell line. Several of the hits exhibited good to excellent anti-tuberculosis activity and selectivity, especially compounds 12m, 12o and 12p, showed minimum inhibitory concentration values<0.5μM and selectivity index>500. The results of this study open up a promising avenue that may lead to the discovery of a new class of anti-tuberculosis agents.

Topics: Animals; Antitubercular Agents; Cell Survival; Hep G2 Cells; Humans; Microbial Sensitivity Tests; Microsomes, Liver; Mycobacterium tuberculosis; Oxadiazoles; Quinolines; Rats; Structure-Activity Relationship; Tuberculosis

A series of indole and pyridine based 1,3,4-oxadiazole derivatives 5a-t were synthesized and evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Ra (MTB) and Mycobacterium bovis BCG both in active and dormant state. Compounds 5b, 5e, 5g and 5q exhibited very good antitubercular activity. All the newly synthesized compounds 5a-t were further evaluated for anti-proliferative activity against HeLa, A549 and PANC-1 cell lines using modified MTT assay and found to be noncytotoxic. On the basis of cytotoxicity and MIC values against Mycobacterium bovis BCG, selectivity index (SI) of most active compounds 5b, 5e, 5g and 5q was calculated (SI=GI50/MIC) in active and dormant state. Compounds 5b, 5e and 5g demonstrated SI values ⩾10 against all three cell lines and were found to safe for advance screening. Compounds 5a-t were further screened for their antibacterial activity against four bacteria strains to assess their selectivity towards MTB. In addition, the molecular docking studies revealed the binding modes of these compounds in active site of enoyl reductase (InhA), which in turn helped to establish a structural basis of inhibition of mycobacteria. The potency, low cytotoxicity and selectivity of these compounds make them valid lead compounds for further optimization.

Topics: Animals; Antitubercular Agents; Cell Line; Humans; Indoles; Microbial Sensitivity Tests; Molecular Docking Simulation; Mycobacterium bovis; Mycobacterium tuberculosis; Oxadiazoles; Pyridines; Structure-Activity Relationship; Tuberculosis

We have previously demonstrated a potent in vitro inhibitory activity for two pentacyano(isoniazid)ferrate(II) compounds, namely IQG-607 and IQG-639, against the Mycobacterium tuberculosis enoyl-acyl carrier protein reductase enzyme. In this study, the activity of these compounds was evaluated using an in vivo murine model of tuberculosis. Swiss mice were infected with M. tuberculosis H37Rv strain and then IQG-607 or IQG-639 (250 mg/kg) was administered for 28 days or 56 days. In addition, a dose-response study was performed with IQG-607 at 5, 10, 25, 50, 100, 200 and 250 mg/kg. The activity of test compounds was compared with that of the positive control drug isoniazid (INH) (25 mg/kg). After 28 days or 56 days of treatment, both IQG-607 and INH significantly reduced M. tuberculosis-induced splenomegaly as well as significantly diminishing the colony-forming units in the spleen and lungs. IQG-607 and INH ameliorated the lung macroscopic aspect, reducing lung lesions to a similar extent. However, IQG-639 did not significantly modify any evaluated parameter. Experiments using early and late controls of infection revealed a bactericidal activity for IQG-607. IQG-607 might well represent a good candidate for clinical development as a new antimycobacterial agent.

Topics: Animals; Antitubercular Agents; Bacterial Load; Disease Models, Animal; Drug Evaluation, Preclinical; Ferrous Compounds; Isoniazid; Lung; Lung Diseases; Male; Mice; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Oxadiazoles; Tuberculosis

The side effects associated with tuberculosis therapy bring with them the risk of noncompliance and subsequent drug resistance. Increasing the therapeutic index of antituberculosis drugs should thus improve treatment effectiveness. Several antituberculosis compounds require in situ metabolic activation to become inhibitory. Various thiocarbamide-containing drugs, including ethionamide, are activated by the mycobacterial monooxygenase EthA, the production of which is controlled by the transcriptional repressor EthR. Here we identify drug-like inhibitors of EthR that boost the bioactivation of ethionamide. Compounds designed and screened for their capacity to inhibit EthR-DNA interaction were co-crystallized with EthR. We exploited the three-dimensional structures of the complexes for the synthesis of improved analogs that boosted the ethionamide potency in culture more than tenfold. In Mycobacterium tuberculosis-infected mice, one of these analogs, BDM31343, enabled a substantially reduced dose of ethionamide to lessen the mycobacterial load as efficiently as the conventional higher-dose treatment. This provides proof of concept that inhibiting EthR improves the therapeutic index of thiocarbamide derivatives, which should prompt reconsideration of their use as first-line drugs.

Topics: Animals; Antitubercular Agents; Binding Sites; DNA-Binding Proteins; Drug Synergism; Ethionamide; Hydrogen Bonding; Ligands; Mice; Models, Molecular; Oxadiazoles; Protein Conformation; Repressor Proteins; Thiophenes; Tuberculosis

3H-1,3,4-Oxadiazol-2-one derivatives were synthesized and tested for their in vitro antimycobacterial activity. Oxadiazolone derivatives showed an interesting antimycobacterial activity against the reference strain of Mycobacterium tuberculosis H(37)Rv. Molecular modeling investigations were performed and showed that the active compounds possess all necessary features to target the protein active site of the mycobacterial cytochrome P450-dependent sterol 14alpha-demethylase in the sterol biosynthesis pathway as the calculated free energy of binding were in agreement with the corresponding MIC values.

Topics: Antitubercular Agents; Bacterial Proteins; Computer Simulation; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Mycobacterium tuberculosis; Oxadiazoles; Protein Binding; Sterol 14-Demethylase; Thermodynamics; Tuberculosis

Topics: Amines; Animals; Antitubercular Agents; Chemical Phenomena; Chemistry; In Vitro Techniques; Mice; Mycobacterium tuberculosis; Oxadiazoles; Pyrazines; Tuberculosis

Topics: Anti-Inflammatory Agents; Antitussive Agents; Humans; Oxadiazoles; Respiratory System; Respiratory Tract Infections; Tuberculosis; Tuberculosis, Pulmonary

Topics: Antitussive Agents; Bronchitis; Humans; Oxadiazoles; Respiratory System; Respiratory Tract Diseases; Tetracycline; Tuberculosis; Tuberculosis, Pulmonary

Topics: Aminosalicylic Acid; Aminosalicylic Acids; Antitubercular Agents; Biomedical Research; Blood; Cycloserine; Drug Resistance; Drug Resistance, Microbial; Ethionamide; Isoniazid; Mice; Oxadiazoles; Pharmacology; Pneumothorax; Pneumothorax, Artificial; Pyrazinamide; Radiography, Thoracic; Sputum; Streptomycin; Toxicology; Tuberculosis; Tuberculosis, Pulmonary; Urine

Topics: Carbonic Anhydrases; Cough; Humans; Oxadiazoles; Prothrombin; Prothrombin Time; Tuberculosis; Tuberculosis, Pulmonary