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Novel 1,3,4-oxadiazoles as antitubercular agents with limited activity against drug-resistant tuberculosis

    Vitthal B Makane

    Department of Organic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India

    Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh 201002, India

    ,
    Vagolu Siva Krishna

    Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet Mandal, RR District, Hyderabad 500 078, India

    ,
    Eruva Vamshi Krishna

    Department of Biology, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India

    Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh 201002, India

    ,
    Manjulika Shukla

    Department of Microbiology, CSIR-Central Drug Research Institute, Lucknow 226021, Uttar Pradesh, India

    ,
    Balakrishnan Mahizhaveni

    Department of Bacteriology, National Institute for Research in Tuberculosis, Chennai, India

    ,
    Sunil Misra

    Department of Biology, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India

    Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh 201002, India

    ,
    Sidharth Chopra

    Department of Microbiology, CSIR-Central Drug Research Institute, Lucknow 226021, Uttar Pradesh, India

    ,
    Dharmarajan Sriram

    Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet Mandal, RR District, Hyderabad 500 078, India

    ,
    Vijayan N Azger Dusthackeer

    Department of Bacteriology, National Institute for Research in Tuberculosis, Chennai, India

    &
    Haridas B Rode

    *Author for correspondence:

    E-mail Address: haridas.rode@iict.res.in

    Department of Organic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India

    Academy of Scientific & Innovative Research, Ghaziabad, Uttar Pradesh 201002, India

    Published Online:https://doi.org/10.4155/fmc-2018-0378

    Aim: 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. Methodology: 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. Results: 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. Conclusion: This study provides potent antitubercular agent which can be further optimized to discover novel antibiotics.

    Graphical abstract

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1 WHO. WHO Global Tuberculosis Report 2018 (2018). www.who.int/tb/publications/global report/gtbr2018 main text.pdf.
    • 2 Pym AS, Diacon AH, Tang SJ et al. Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis. Eur. Respir. J. 47(2), 564–574 (2016).
    • 3 Pethe K, Bifani P, Jang JC et al. Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. Nat. Med. 19(9), 1157–1160 (2013). • A discovery of Q203 is reported.
    • 4 Kang S, Kim RY, Seo MJ et al. Lead optimization of a novel series of imidazo[1,2-a]pyridine amides leading to a clinical candidate (Q203) as a multi- and extensively-drug-resistant anti-tuberculosis agent. J. Med. Chem. 57(12), 5293–5305 (2014).
    • 5 Jang J, Kim R, Woo M et al. Efflux attenuates the antibacterial activity of Q203 in Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 61(7), e02637–e02716 (2017).
    • 6 Gao C, Peng C, Shi Y et al. Benzothiazinethione is a potent preclinical candidate for the treatment of drug-resistant tuberculosis. Sci. Rep. 6, 29717 (2016).
    • 7 Makarov V, Manina G, Mikusova K et al. Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science 324(5928), 801–804 (2009). • Compound BTZ043 for drug-sensitive and extensively drug-resistant TB is disclosed.
    • 8 Lade DM, Vagolu SK, Sriram D et al. A facile synthesis and antituberculosis properties of almazole D and its enantiomer. ChemistrySelect 2(3), 1250–1252 (2017).
    • 9 Desai NC, Somani H, Trivedi A et al. Synthesis, biological evaluation and molecular docking study of some novel indole and pyridine based 1,3,4-oxadiazole derivatives as potential antitubercular agents. Bioorg. Med. Chem. Lett. 26(7), 1776–1783 (2016).
    • 10 Navarrete-Vázquez G, Molina-Salinas GM, Duarte-Fajardo ZV et al. Synthesis and antimycobacterial activity of 4-(5-substituted-1,3,4-oxadiazol-2-yl)pyridines. Bioorg. Med. Chem. 15(16), 5502–5508 (2007).
    • 11 Karabanovich G, Zemanová J, Smutný T et al. Development of 3,5-dinitrobenzylsulfanyl-1,3,4-oxadiazoles and thiadiazoles as selective antitubercular agents active against replicating and nonreplicating Mycobacterium tuberculosis. J. Med. Chem. 59(6), 2362–80 (2016). •• Antimycobacterial activity of 5-pyridyl-1,3,4-oxadiazole is described.
    • 12 Ahsan MJ, Samy JG, Khalilullah H et al. Molecular properties prediction and synthesis of novel 1,3,4-oxadiazole analogues as potent antimicrobial and antitubercular agents. Bioorg. Med. Chem. Lett. 21(24), 7246–7250 (2011).
    • 13 Subramanian R, Aidasani D, Bailey K et al. P450-mediated O-demethylated metabolite is responsible for rat hepatobiliary toxicity of pyridyltriazine-containing PI3K inhibitors. Toxicol. Sci. 142(1), 298–310 (2014). • Pyridine mediated hepatotoxicity in rat is described.
    • 14 Wang P, Pradhan K, Zhong XB et al. Isoniazid metabolism and hepatotoxicity. Acta Pharm. Sin B. 6(5), 384–392 (2016). •• Highlights the metabolic pathways of isoniazid and discusses their associations with isoniazid-induced liver injury.
    • 15 Carlson GP. Comparison of the effects of pyridine and its metabolites on rat liver and kidney. Toxicol. Lett. 85(3), 173–178 (1996). • Effects of pyridine and its metabolites on rat kidney and liver were studied.
    • 16 Malapati P, Krishna VS, Nallangi R et al. Identification and development of benzoxazole derivatives as novel bacterial glutamate racemase inhibitors. Eur. J. Med. Chem. 145, 23–34 (2018).
    • 17 Collins L, Franzblau SG. Microplate alamar blue assay versus BACTEC 460 system for high-throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium. Antimicrob. Agents Chemother. 41(5), 1004–1009 (1997).
    • 18 Singireesu S, Misra S, Mondal SK et al. Costunolide induces micronuclei formation, chromosomal aberrations, cytostasis, and mitochondrial-mediated apoptosis in Chinese hamster ovary cells. Cell. Biol. Toxicol. 34(2), 125–142 (2018).
    • 19 Weinstein MP.Methods For Dilution Antimicrobial Susceptibility Tests For Bacteria That Grow Aerobically. 8th EditionWayne PA, Clinical and Laboratory Standards Institute, PA, USA (2012).
    • 20 Lee J, Armstrong DT, Ssengooba W et al. Sensititre MYCOTB MIC plate for testing Mycobacterium tuberculosis susceptibility to first- and second-line drugs. Antimicrob. Agents Chemother. 58(1), 11–8 (2014).
    • 21 Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 7, 42717 (2017).
    • 22 Lipinski CA, Lombardo F, Dominy BW et al. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 46(1–3), 3–26 (2001).
    • 23 Lipinski CA. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov. Today Technol. 1(4), 337–341 (2004).
    • 24 Lei BF, Wei CJ, Tu SC. Action mechanism of antitubercular isoniazid. Activation by Mycobacterium tuberculosis KatG, isolation, and characterization of inha inhibitor. J. Biol. Chem. 275(4), 2520–2526 (2000).
    • 25 Singhal P, Dixit P, Singh P et al. A study on pre-XDR & XDR tuberculosis & their prevalent genotypes in clinical isolates of Mycobacterium tuberculosis in north India. Indian J. Med. Res. 143(3), 341–347 (2016).