Synthesis and Characterization of Pyrazinamide Analogs of Acetylsalicylic Acid and Salicylic Acid
Glenn V. Alea, Faith Marie G. Lagua*, and Michael Dominic M. Ajero
Chemistry Department, De La Salle University, Manila, Philippines
*Corresponding author: This email address is being protected from spambots. You need JavaScript enabled to view it.
ABSTRACT
Pyrazinamide (PZA) is one of the first-line of drugs used to treat tuberculosis. It is an important player in shortening the treatment time of the disease from almost a year to only about six months. The occurrence of resistant strains of the bacteria towards PZA threatens its effectiveness in killing semi-dormant and persistent bacilli in the current and future therapy methods to combat the disease. In this study, PZA analogs of salicylic acid (compounds 5a and 5b) and acetylsalicylic acid (compounds 6a and 6b) were synthesized and characterized. The synthesis involved the preparation of salicylic acid and acetylsalicylic acid derivatives with varying acyl chains via Friedel-Crafts acylation of methyl salicylate, followed by subsequent hydrolysis and acetylation to produce the respective precursor compounds. These were then coupled with 2-pyrazinehydrazide to produce the desired PZA analogs. These analogs may exhibit increased potency against PZA-resistant and susceptible strains of Mycobacterium tuberculosis. Characterizations of the compounds were done by IR spectroscopy, high-resolution mass spectrometry, and 1H-NMR spectroscopy.
INTRODUCTION
Tuberculosis (TB) is now ranked above HIV as a leading cause of death worldwide (WHO 2016). It is caused by Mycobacterium tuberculosis, which may be acquired through the ambient air upon interaction with people that expel the bacteria by coughing (Zhang et al. 2003).
In the previous global TB report of 2015 published by the World Health Organization (WHO), the global prevalence, mortality, and incidence rate of the disease has reached half of its 1990 levels. These improvements were seen specifically in nine of the WHO list of high burden countries, which includes the Philippines. These developments show that effective and timely treatment of the disease could reduce its burden (WHO 2015). . . . read more
REFERENCES
ALEA GV, ABARQUEZ AS, AUSTRIA MB, LIM AS, LAGUA FG, AJERO MM. 2013. Synthesis of 2-Hydroxy-5-(1-(2-(pyrazine-2-carbonyl) hydrazono)hexyl) Benzoic Acid, A Pyrazinamide Analog of Salicylic Acid. Kimika 24(2)18-26.
BYRNE ST, DENKIN SM, ZHANG Y. 2007. Aspirin and ibuprofen enhance pyrazinamide treatment of murine tuberculosis. JAntimicrobChemoth 59:313-316.
CHEN ZF, HUANG Q, LI YY, ZHANG Y, REN Y, LI KS, FU ZJ, XU SQ. 2007. Nutrient starved incubation conditions enhance pyrazinamde activity against Mycobacterium tuberculosis. Zhonghua Jie He He Hu Xi Za Zhi 5:359-362.
IMRAMOVSKY A, POLANC S, VINSOVA J, KOCEVAR M, JAMPILEK J, RECKOVA Z, KAUSTOVA J. 2007. A new modification of anti-tubercular active molecules. BioorganMedChem 15:2551-59.
LU P, HAAGSMA AC, PHAM H, MAASKANT JJ, MOL S, LILL H, BALD D. 2011. Pyrazinoic acid decreases the proton motive force, respiratory ATP synthesis activity and cellular ATP levels. AntimicrobAgentsCh 55 (11):5354-5357.
NJIRE M, TAN Y, MUGWERU J, WANG C, GUO J, YEW W, TAN S, ZHANG T. 2016. Pyrazinamide resistance in Mycobacterium tuberculosis: Review and update. Advances in Medical Sciences 61:63-71.
SAYAHI H, ZIMHONY O, JACOBS JR WR, SHEKHTMAN A, WELCH J. 2011. Pyrazinamide, but not pyrazinoic acid, is a competitive inhibitor of NADPH binding to Mycobacterium tuberculosis fatty acid synthase I. BioorgMedChemLett 21:4804-4807.
SERVUSOVA B, VOBICKOVA J, PATEROVA P, KUBICEK V, KUNES J, DOLEZAL M, ZITKO J. 2013 . Synthesis and antimycobacterial evaluation of N-substituted 5- chloropyrazine-2-carboxamides. BioorgMedChemLett 23:3589-91.
SERVUSOVA B, PATEROVA P, MANDIKOVA J, KUBICEK V, KUCERA R, KUNES J, DOLEZAL M, ZITKO J. 2014. Alkylamino derivatives of pyrazinamide: Synthesis and antimycobacterial evaluation. BioorgMedChemLett 24:450-453.
SHI W, ZHANG X, JIAN X, RUAN H, BARRY 3RD CE, WANG H, ZHANG W, ZHANG Y. 2011. Pyrazinamide inhibits trans-translation for shortening the duration of tuberculosis chemotherapy. Science 333(6049):1630-32.
SRIRAM D, YOGEESWARI P, REDDY SP. 2006. Synthesis of pyrazinamide Mannich bases and its anti-tubercular properties. BioorgMedChemLett 16:2113-16.
VERGARA FMF, DA S. LIMA CH, DE O. HENRIQUES MG, CANDEA ALP, LOURENCO MCS, DE L.FERREIRA M, KAISER CR, DE SOUZA MVN. 2009. Synthesis and antimycobacterial activity of N’-[(E)-(monosubstitutedbenzilidene)]-2-pyrazinecarbohydrazide derivatives. EurJMedChem 44:4954-59.
[WHO] World Health Organization. 2015. WHO Global Tuberculosis Report 2015. Retrieved from http://www.who.int/tb/publications/global_report/en/ on 21 Feb 2016.
[WHO] World Health Organization. 2016. WHO Global Tuberculosis Report 2016. Retrieved from http://www.who.int/tb/publications/global_report/en/ on 6 Jul 2017.
ZHANG Y, WADE MM, SCORPIO A, ZHANG H, SUN Z. 2003. Mode of action of pyrazinamide: disruption of Mycobacterium tuberculosis membrane transport and energetics by pyrazinoic acid. JAntimicrobChemoth 52:790-795.
ZITKO J, DOLEZAL M, SVOBODOVA M, VEJSOVA M, KUNES J, KUCERA R, JILEK P. 2011. Synthesis and antimycobacterial properties of N-substituted 6-amino-5-cyanopyrazine-2-carboxamides. BioorganMedChem 19:1471-76.
ZITKO J, JAMPILEK J, DOBROVOLNY L, SVOBODOVA M, KUNES J, DOLEZAL M. 2012. Synthesis and antimycobacterial evaluation of N-substituted 3-aminopyrazine-2,5-dicarbonitriles. BioorgMedChemLett 22:1598-1601.
