Development of 1,2,4-triazole-5-thione derivatives as potential inhibitors of enoyl acyl carrier protein reductase (InhA) in tuberculosis.

Document Type : Research article

Authors

Department of Pharmaceutical Chemistry, Bharati Vidyapeeth’s College of Pharmacy, Navi Mumbai-400614, Maharashtra, India.

Abstract

Tuberculosis (TB) ranks second, next to AIDS making it most formidable disease if the present age. One of the crucial enzymes involved in cell wall synthesis of Mycobacterium tuberculosis, InhA (enoyl acyl carrier protein reductase) has been authenticated as an effective target for anti-mycobacterial drug development. In the current work, we have developed novel derivatives of 1,2,4-triazole-5-thione as promising InhA inhibitors. We rationally designed these 1,2,4-triazole-5-thione compounds, synthesized and spectrally characterized them. Anti-mycobacterial potential was determined by resazurin microtiter assay using Mtb H37Rv strain. The mechanism of action of these compounds was confirmed by InhA enzyme inhibition studies. The most active compound of the series displayed MIC of 0.19 µM in resazurin microtiter assay and InhA inhibition with IC50 of 90 nM.

Keywords

Main Subjects


References
Global tuberculosis report 2018. Available from: URL:
https://www.who.int/tb/publicat ions /global_report/
en.
Tunerculosis: Key Facts. Available from: URL: http://
www.who.int /mediacentre/factsheets/fs104/en/index.
html.
Tuberculosis-WHO India. Available from: URL:
http://whoindia.org/EN /Section3/Section123.html.
Udwadia ZF, Amale RA, Ajbani KK and Rodrigues
C. Totally drug-resistant tuberculosis in India. Clin.
Infect. Dis. (2012) 54: 579-81.
Asselineau J and Lederer E. Structure of the Mycolic
Acids of Mycobacteria. Nature (1950) 166: 782-3.
Rozwarski DA Grant GA, Barton DH, Jacobas WR
JR and Sacchettini JC. Modification of the NADH
of the isoniazid target (InhA) from Mycobacterium
tuberculosis. Science (1998) 2.79: 98-102.
Lei B, Wei CJ and Tu SC. Action Mechanism of
Antitubercular Isoniazid Activation by mycobacterium
tuberculosis katG, isolation, and characterization of
inhA inhibitor. J. Biol. Chem. (2000) 275: 2520-6.
Rawat R, Whitty A and Peter JT. The isoniazid-NAD
adduct is a slow, tight-binding inhibitor of InhA, the
Mycobacterium tuberculosis enoyl reductase: Adduct
affinity and drug resistance. Proc. Natl. Acad. Sci. U.
S. A. (2003) 100: 13881-6.
Parikh SL, Xiao G and Tonge PJ. Inhibition of
InhA, the Enoyl Reductase from Mycobacterium
tuberculosis, by Triclosan and Isoniazid. Biochemistry
(2000) 39: 7645-50.
Pan P and Tonge PJ. Targeting InhA, the FASII
enoyl-ACP reductase: SAR studies on novel inhibitor
scaffolds. Curr. Topics Med. Chem. (2012) 12: 672-
693.
Luckner SR, Liu N, Am-Ende CW, Tonge PJ and
Kisker C. A slow, tight-binding inhibitor of InhA,
the enoyl-ACP reductase from Mycobacterium
tuberculosis. J. Biol. Chem. (2010) 285: 14330-7.
Am Ende CW, Knudson SE, Liu N, Childs J, Sullivan
TJ, Boyne M, Xu H, Gegina Y, Knudson DL, Johnson
F, Peloquin CA, Slayden RA and Tonge PJ. Synthesis
and in-vitro antimycobacterial activity of B-ring
modified diaryl ether InhA inhibitors. Bioorg. Med.
Chem. Lett. (2008) 18: 3029-33.
Amir M, Kumar H and Javed SA. Condensed
bridgehead nitrogen heterocyclic system: Synthesis
and pharmacological activities of 1,2,4-triazolo-[3,4-
b]-1,3,4-thiadiazole derivatives of ibuprofen and
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)
(11)
(12)
(13)
biphenyl-4-yloxy acetic acid. J. Med. Chem. (2008)
43: 2056-66.
Amir M and Shikha K. Synthesis and anti-inflammatory,
analgesic, ulcerogenic and lipid peroxidation activities
of some new 2-[(2,6-dichloroanilino) phenyl]acetic
acid derivatives. Eur. J. Med. Chem. (2004) 39: 535-
45.
Reid JR and Heindel ND. Improved syntheses of 5‐
substituted‐4‐amino‐3‐mercapto‐(4H)1,2,4-triazoles.
J. Heterocycl. Chem. (1976) 13: 925-6.
Patil V, Tilekar K, Sonali MM, Mohan R and Ramaa
CS. Synthesis and primary cytotoxicity evaluation of
new 5-benzylidene-2,4-thiazolidinedione derivatives.
Eur. J. Med. Chem. (2010) 45: 4539-44.
Bhanushali U, Saranya R, Keerthana S, Pushkar K,
Kiran C, Chatterjee S and Ramaa CS. 5-benzylidene2,4-thiazolidenedione derivatives: Design, synthesis
and evaluation as inhibitors of angiogenesis targeting
VEGR-2. Bioorg. Chem. (2016) 67: 139-47.
Joshi H, Marulkar K, Gota V and Ramaa CS. Hydroxy
cinnamic acid derivatives as partial PPARγ agonists: In
silico studies, synthesis and biological characterization
against chronic myeloid leukemia cell line (K-562).
Anti-Cancer Agents Med. Chem. (2017) 17: 524-41.
Kabir A, Tilekar K, Upadhyay N and Ramaa CS.
Novel anthraquinone derivatives as dual inhibitors
of topoisomerase 2 and casein kinase 2: In silico
studies, synthesis and biological evaluation on human
leukemic cell lines. Anti-Cancer Agents Med. Chem.
(2018) 18: 1551-62.
Joshi SD, Vagdevi HM, Vaidya VP and Gadaginamath
GS. Synthesis of new 4-pyrrol-1-yl benzoic acid
hydrazide analogs and some derived oxadiazole,
triazole and pyrrole ring systems: A novel class of
potential antibacterial and antitubercular agents. Eur.
J. Med. Chem. (2008) 43: 1989-96.
Zhou CH and Wang Y. Recent researches in triazole
compounds as medicinal drugs. Curr. Med. Chem.
(2012) 19: 239-80.
Daina, A. SwissADME: a free web tool to evaluate
pharmacokinetics, druglikeness and medicinal
chemistry friendliness of small molecules. Sci. Reports
(2016) 7: 42717.
Daina, A and Zoete, V. A BOILED-Egg to Predict
Gastrointestinal Absorption and Brain Penetration of
Small Molecules. ChemMedChem (2016) 11: 1117–21.
Aydogan F, Turgut Z and Ocal N. Synthesis and
electronic structure of new aryl-and alkyl-substituted
1,3,4-oxadiazole-2-thione derivatives. Turk. J. Chem.
(2002) 26: 159-69.