benzofurans and Tuberculosis

The study aims at the derivatization of "Phthalides" and synthesizes 3- arylaminophthalides & 3-indolyl-phthalides compounds, and evaluates their anti-tubercular and antioxidant activities. The study has also intended to employ the in silico methods for the identification of possible drug targets in Mycobacterium and evaluate the binding affinities of synthesized compounds.. This report briefly explains the synthesis of phthalide derivatives using ammonium chloride. The synthesized compounds were characterized using spectral analysis. Resazurin Microtiter Assay (REMA) plate method was used to demonstrate the anti-mycobacterial activity of the synthesized compounds. An in-silico pharmacophore probing approach was used for target identification in Mycobacterium. The structural level interaction between the identified putative drug target and synthesized phthalides was studied using Lamarckian genetic algorithm-based software.. In the present study, we report an effective, environmentally benign scheme for the synthesis of phthalide derivatives. Compounds 5c and 5d from the current series appear to possess good anti-mycobacterial activity. dCTP: deaminasedUTPase was identified as a putative drug target in Mycobacterium. The docking results clearly showed the interactive involvement of conserved residues of dCTP with the synthesized phthalide compounds.. On the eve of evolving anti-TB drug resistance, the data on anti-tubercular and allied activities of the compounds in the present study demonstrates the enormous significance of these newly synthesized derivatives as possible candidate leads in the development of novel anti-tubercular agents. The docking results from the current report provide a structural rationale for the promising anti-tubercular activity demonstrated by 3-arylaminophthalides and 3-indolyl-phthalides compounds.

Topics: Algorithms; Ammonium Chloride; Antioxidants; Antitubercular Agents; Benzofurans; Drug Design; Humans; Hydroxyl Radical; Microbial Sensitivity Tests; Molecular Docking Simulation; Mycobacterium tuberculosis; Nucleotide Deaminases; Structure-Activity Relationship; Tuberculosis

Widespread resistance to first-line TB drugs is a major problem that will likely only be resolved through the development of new drugs with novel mechanisms of action. We have used structure-guided methods to develop a lead molecule that targets the thioesterase activity of polyketide synthase Pks13, an essential enzyme that forms mycolic acids, required for the cell wall of Mycobacterium tuberculosis. Our lead, TAM16, is a benzofuran class inhibitor of Pks13 with highly potent in vitro bactericidal activity against drug-susceptible and drug-resistant clinical isolates of M. tuberculosis. In multiple mouse models of TB infection, TAM16 showed in vivo efficacy equal to the first-line TB drug isoniazid, both as a monotherapy and in combination therapy with rifampicin. TAM16 has excellent pharmacological and safety profiles, and the frequency of resistance for TAM16 is ∼100-fold lower than INH, suggesting that it can be developed as a new antitubercular aimed at the acute infection. PAPERCLIP.

Topics: Animals; Antitubercular Agents; Benzofurans; Cell Line; Drug Design; Drug Resistance, Bacterial; Female; Mice; Mice, Inbred BALB C; Models, Molecular; Mycobacterium tuberculosis; Piperidines; Specific Pathogen-Free Organisms; Tuberculosis

We investigated a proteome profile, protein-protein interaction and morphological changes of Mycobacterium tuberculosis after different times of eupomatenoid-5 (EUP-5) induction to evaluate the cellular response to the drug-induced damages.. The bacillus was induced to sub-minimal inhibitory concentration of EUP-5 at 12 h, 24 h and 48 h. The proteins were separated by 2D gel electrophoresis, identified by LC/MS-MS. Scanning electron microscopy and Search Tool for the Retrieval of Interacting Genes/Proteins analyses were performed.. EUP-5 impacts mainly in M. tuberculosis proteins of intermediary metabolism and interactome suggests a multisite disturbance that contributes to bacilli death. Scanning electron microscopy revealed the loss of bacillary form.. Some of the differentially expressed proteins have the potential to be drug targets such as citrate synthase (Rv0896), phosphoglycerate kinase (Rv1437), ketol-acid reductoisomerase (Rv3001c) and ATP synthase alpha chain (Rv1308).

Topics: Bacterial Proteins; Benzofurans; Citrate (si)-Synthase; Electrophoresis, Gel, Two-Dimensional; Genes, Bacterial; Humans; Ketol-Acid Reductoisomerase; Microbial Sensitivity Tests; Microscopy, Electron, Scanning; Mycobacterium tuberculosis; Phenols; Phosphoglycerate Kinase; Protein Interaction Domains and Motifs; Proteome; Proteomics; Tandem Mass Spectrometry; Time Factors; Tuberculosis

A series of novel dibenzo[b,d]furan-1,2,3-triazole conjugates, rationally designed by reorientation of dibenzo[b,d]furan pharmacophore and alkyl/aryl groups appended on 1,2,3-triazole core, were synthesized using click chemistry. The required key intermediate, 2-ethynyl dibenzo[b,d]furan 3 was prepared from dibenzofuran-2-carboxaldehyde using Corey-Fuchs reaction. Further reaction of 3 with various alkyl/aryl azides in the presence of copper catalyst produced 1,2,3-triazole conjugates in excellent yields. Evaluation of all the new compounds for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC27294), resulted 5a (MIC: 1.56 μg/mL), 5d (MIC: 0.78 μg/mL) and 5f (MIC: 0.78 μg/mL) as promising lead analogues. Among these three compounds, 1-(4-bromobenzyl)-4-(dibenzo[b,d]furan-2-yl)-1H-1,2,3-triazole (5f) emerged as the most promising antitubercular agent with lowest cytotoxicity (selectivity index: ≫25) against the HEK-293T cell line.

Topics: Antitubercular Agents; Benzofurans; Click Chemistry; HEK293 Cells; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Structure-Activity Relationship; Triazoles; Tuberculosis

Protein tyrosine phosphatases are often exploited and subverted by pathogenic bacteria to cause human diseases. The tyrosine phosphatase mPTPB from Mycobacterium tuberculosis is an essential virulence factor that is secreted by the bacterium into the cytoplasm of macrophages, where it mediates mycobacterial survival in the host. Consequently, there is considerable interest in understanding the mechanism by which mPTPB evades the host immune responses, and in developing potent and selective mPTPB inhibitors as unique antituberculosis (antiTB) agents. We uncovered that mPTPB subverts the innate immune responses by blocking the ERK1/2 and p38 mediated IL-6 production and promoting host cell survival by activating the Akt pathway. We identified a potent and selective mPTPB inhibitor I-A09 with highly efficacious cellular activity, from a combinatorial library of bidentate benzofuran salicylic acid derivatives assembled by click chemistry. We demonstrated that inhibition of mPTPB with I-A09 in macrophages reverses the altered host immune responses induced by the bacterial phosphatase and prevents TB growth in host cells. The results provide the necessary proof-of-principle data to support the notion that specific inhibitors of the mPTPB may serve as effective antiTB therapeutics.

Topics: Animals; Antitubercular Agents; Apoptosis; Bacterial Proteins; Benzofurans; Cell Line; Cell Survival; Enzyme Inhibitors; Host-Pathogen Interactions; Humans; Interferon-gamma; Kinetics; Macrophages; Mice; Microbial Sensitivity Tests; Mitogen-Activated Protein Kinases; Models, Chemical; Molecular Structure; Mycobacterium tuberculosis; Protein Tyrosine Phosphatases; Triazoles; Tuberculosis

The cellular uptake and antimycobacterial activity of usnic acid (UA) and usnic acid-loaded liposomes (UA-LIPOs) were assessed on J774 macrophages. The minimal inhibitory concentration (MIC) and the minimal bactericidal concentration (MBC) of UA and UA-LIPO against Mycobacterium tuberculosis were determined. Concentrations required to inhibit 50% of cell proliferation (IC(50)) were 22.5 (+/-0.60) and 12.5 (+/-0.26) microg/ml, for UA and UA-LIPO, respectively. The MICs of UA and UA-LIPO were 6.5 and 5.8 microg/mL, respectively. The MBC of UA-LIPO was twice as low (16 microg/mL) as that of UA (32 microg/mL). An improvement in the intracellular uptake of UA-LIPO was found (21.6 x 10(4) +/- 28.3 x 10(2) c.p.s), in comparison with UA (9.5 x 10(4) +/- 11.4 x 10(2) c.p.s). In addition, UA-LIPO remains much longer inside macrophages (30 hours). All data obtained from the encapsulation of usnic acid into liposomes as a drug delivery system (DDS) indicate a strong interaction between UA-liposomes and J774 macrophages, thereby facilitating UA penetration into cells. Considering such a process as ruling the Mycobacterium-transfection by magrophages, we could state that associating UA with this DDS leads to an improvement in its antimycobacterial activity.

Topics: Animals; Antitubercular Agents; Benzofurans; Cell Line; Cell Proliferation; Dose-Response Relationship, Drug; Liposomes; Macrophages; Mice; Mycobacterium tuberculosis; Tuberculosis

Topics: Acids; Benzofurans; Furans; Humans; Lichens; Tuberculosis; Tuberculosis, Pulmonary

Topics: Benzofurans; Tuberculosis; Tuberculosis, Pulmonary

Topics: Acids; Benzofurans; Dihydrostreptomycin Sulfate; Furans; Guinea Pigs; Streptomycin; Tuberculosis

Topics: Benzofurans; Furans; Mycobacterium tuberculosis; Tuberculosis

Topics: Benzofurans; Dermatology; Humans; Tuberculosis

Topics: Benzofurans; Humans; Skin; Tuberculosis; Tuberculosis, Cutaneous

Topics: Benzofurans; Streptomycin; Tuberculosis

Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Benzofurans; Dermatologic Agents; Guinea Pigs; Lichens; Tuberculosis

Topics: Acids; Animals; Benzofurans; Guinea Pigs; Streptomycin; Tuberculosis

Topics: Anti-Bacterial Agents; Bacillus; Benzofurans; Mycobacterium tuberculosis; Tuberculosis