Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

Design, Synthesis and Anti-tuberculosis Activity of Hydrazones and N-acylhydrazones Containing Vitamin B6 and Different Heteroaromatic Nucleus

Author(s): Thais Cristina Mendonça Nogueira, Lucas dos Santos Cruz, Maria Cristina Lourenço and Marcus Vinicius Nora de Souza*

Volume 16, Issue 7, 2019

Page: [792 - 798] Pages: 7

DOI: 10.2174/1570180815666180627122055

Price: $65

Abstract

Background: The term vitamin B6 refers to a set of six compounds, pyridoxine,pyridoxal ,and pyridoxamine and their phosphorylated forms, among which pyridoxal 5´-phosphate (PLP) is the most important and active form acting as a critical cofactor. These compounds are very useful in medicinal chemistry because of their structure and functionalities and are also used in bioinorganic chemistry as ligands for complexation with metals.

Methods: In this study, a series of hydrazones 1a-g and N-acylhydrazones 2a-f containing vitamin B6 have been synthesized from commercial pyridoxal hydrochloride and the appropriate aromatic or heteroaromatic hydrazine or N-acylhydrazine. All synthesized compounds have been fully characterized and tested against Mycobacterium tuberculosis.

Results: Among the N-acylhydrazones derivatives 2a-f, 2d (para- pyridine substituted Nacylhydrazone; MIC = 10.90 µM) exhibited the best activity. The ortho-pyridine derivative 2b exhibited intermediate activity (MIC = 87.32 µM), and the meta-pyridine derivative 2c was inactive. In case of the hydrazone series 1a-g, 7-chloroquinoxaline derivative 1f (MIC = 72.72 µM) showed the best result, indicating that the number of nitrogen and chlorine atoms in the radical moiety play an important role in the anti-tuberculosis activity of the quinoxaline derivatives (1f and 1g).

Conclusion: The data reported herein indicates that the isoniazid derivative 2d (MIC = 10.90 µM) exhibited the best activity in the N-acylhydrazone series and; the quinoxaline nucleus derivative 1f (MIC = 72.72 µM) was the most active compound in the hydrazone series.

Keywords: Vitamin B6, pyridoxal, tuberculosis, drugs, hydrazone, N-acylhydrazone.

Graphical Abstract
[1]
Definitive Nomenclature for Vitamins B-6 and Related Compounds. Pure Appl. Chem., 2009, 33(2-3), 445-452.
[2]
McCormick, D. In: Vitamin B6; Bowman, B.; Russell, R., Eds., In: Present Knowledge in Nutrition; 9th ed; International Life Sciences Institute: Washington DC, 2006, p. 269-277.
[3]
Eliot, A.C.; Kirsch, J. Pyridoxal phosphate enzymes: Mechanistic, structural and evolutionary considerations. Annu. Rev. Biochem., 2004, 73, 383-415.
[4]
Jansonius, J.N. Structure, evolution and action of vitamin B6- dependent enzymes. Curr. Opin. Struct. Biol., 1998, 8, 759-769.
[5]
Hayashi, H. Pyridoxal enzymes: Mechanistic diversity and uniformity. J. Biochem., 1995, 118, 463-473.
[6]
Brattnshtbin, A.E.; Shemyakin, M.M. Theory of the process of amino-acid metabolism, catalysed by pyridoxal enzymes. Biokhimiya, 1953, 18, 393-411.
[7]
Metzler, D.E.; Ikawa, M.; Snell, E.E. A general mechanism for vitamin B6-catalyzed reactions. J. Am. Chem. Soc., 1954, 76(3), 648-652.
[8]
Percudani, R.; Peracchi, A. The B6 database: A tool for the description and classification of vitamin b6-dependent enzymatic activities and of the corresponding protein families. BMC Bioinformatics, 2009, 10, 273.
[9]
John, R.A. Pyridoxal phosphate-dependent enzymes. Biochim. Biophys. Acta, 1995, 1248, 81-96.
[10]
Mehta, P.K.; Christen, P. The molecular evolution of pyridoxal-5′- phosphate-dependent enzymes. Adv. Enzymol, 2000, 74, 129-184.
[11]
Schneider, G.; Kack, H.; Lindqvist, Y. The manifold of vitamin B6 dependent enzymes. Structure Fold Des., 2000, 8, R1-R6.
[12]
Christen, P.; Mehta, P.K. From cofactor to enzymes. The molecular evolution of pyridoxal-5′-phosphate-dependent enzymes. Chem. Rec., 2001, 1, 436-447.
[13]
Percudani, R.; Peracchi, A. A genomic overview of pyridoxal-phosphate-dependent enzymes. EMBO Rep., 2003, 4, 850-854.
[14]
Toney, M.D. Reaction specificity in pyridoxal phosphate enzymes. Arch. Biochem. Biophys., 2005, 433, 279-287.
[15]
Galluzzi, L.; Vacchelli, E.; Michels, J.; Garcia, P.; Kepp, O.; Senovilla, L.; Vitale, I.; Kroemer, G. Effects of vitamin B6 metabolism on oncogenesis, tumor progression and therapeutic responses. Oncogene, 2013, 32(42), 4995-5004.
[16]
He, X.M.; Liu, H.W. Formation of unusual sugars: Mechanistic studies and biosynthetic applications. Annu. Rev. Biochem., 2002, 71, 701-754.
[17]
Selhub, J. Folate, vitamin B12 and vitamin B6 and one carbon metabolism. J. Nutr. Health Aging, 2002, 6(1), 39-42.
[18]
Drewke, C.; Leistner, E. In: Biosynthesis of vitamin B6 and structurally related derivatives; Litwack, G., Ed.; In: Vitamins and Hormones; Academic Press: San Diego, 2001, Vol. 63, p. 121- 155.
[19]
Martell, A.E. Reaction pathways and mechanisms of pyridoxal catalysis. Adv. Enzymol. Relat. Areas Mol. Biol., 1982, 53, 163-199.
[20]
Metzler, D.E.; Ikawa, M.; Snell, E.E. A general mechanism for vitamin B6-catalyzed reactions. J. Am. Chem. Soc., 1954, 76, 648-652.
[21]
Kern, A.D.; Oliveira, M.A.; Coffino, P.; Hackert, M.L. Structure of mammalian ornithine decarboxylase at 1.6 Å resolution: Stereochemical implications of PLP-dependent amino acid decarboxylases. Struct. Fold. Des., 1999, 7, 567-581.
[22]
He, X.M.; Liu, H.W. Formation of unusual sugars: Mechanistic studies and biosynthetic applications. Annu. Rev. Biochem., 2012, 71, 701-754.
[23]
Jansonius, J.N. Structure, evolution and action of vitamin Bs-dependent enzymes. Curr. Opin. Struct. Biol., 1998, 8(6), 759-769.
[24]
Eliot, A.C.; Kirsch, J.F. Pyridoxal phosphate enzymes: Mechanistic, structural, and evolutionary considerations. Annu. Rev. Biochem., 2004, 73, 383-415.
[25]
Percudani, R.; Peracchi, A. The B6 database: A tool for the description and classification of vitamin b6-dependent enzymatic activities and of the corresponding protein families. BMC Bioinformatics, 2009, 10, 273-281.
[26]
Stover, P.J.; Field, M.S. Vitamin B-6. Adv. Nutr., 2015, 1, 132-133.
[27]
Mackey, A.; Davis, S.; Gregory, J. In: Vitamin B6; Shils, M.; Shike, M.; Ross, A.; Caballero, B.; Cousins, R., Eds.; In: Modern Nutrition in Health and Disease. 10th ed; Lippincott Williams & Wilkins: Philadelphia, 2006; pp.452-461.
[28]
Institute of Medicine. In: Vitamin B6; In: Food and Nutrition Board. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline; National Academy Press: Washington DC, 1998, p. 150- 195.
[29]
Reynolds, R.D. Bioavailability of vitamin B6 from plant foods. Am. J. Clin. Nutr., 1988, 48, 863-867.
[30]
Kabir, H.; Leklem, J.; Miller, L.T. Measurement of glycosylated vitamin B6 in foods. J. Food Sci., 1983, 48, 1422-1425.
[31]
Tomarelli, R.M.; Spence, E.R.; Berhnart, F.W. Biological availability of vitamin B6 of heated milk. J. Agric. Food Chem., 1955, 3(4), 338-341.
[32]
Mackey, A.; Davis, S.; Gregory, J. Vitamin B6. In: Shils M, Shike M, Ross A, Caballero B, Cousins R, eds. Modern Nutrition in Health and Disease. 10th ed; Baltimore, MD: Lippincott Williams & Wilkins; 2005.
[33]
Woodring, M.J.; Storvick, C.A. Vitamin B6 in milk: Review of literature. J. Assoc. Off. Agric. Chem., 1960, 43, 63-79.
[34]
Kabir, H.; Leklem, J.; Miller, L.T. Measurement of glycosylated vitamin B6 in foods. J. Food Sci., 1983, 48, 1422-1425.
[35]
National Institutes of Health (NIT). Vitamin B6 Dietary Supplement Fact Sheet. National Institutes of Health (NIT). Available from: http://ods.od.nih.gov/factsheets/VitaminB6-HealthProfessional/ Accessed 2nd January 2018.
[36]
Bender, D.A. Non-nutritional uses of vitamin B6. Br. J. Nutr., 1999, 81, 7-20.
[37]
Hansson, O.; Sillanpaa, M. Letter: Pyridoxine and serum concentration of phenytoin and phenobarbitone. Lancet, 1976, 1, 256.
[38]
Leklem, J.E. Vitamin B-6. In: Shils M, Olson JA, Shike M, Ross AC, eds. Modern Nutrition in Health and Disease. 9th ed. Baltimore: Williams & Wilkins; , 1999; pp. 413-422.
[39]
Clayton, P.T. B6-responsive disorders: A model of vitamin dependency. J. Inherit. Metab. Dis., 2006, 29(2-3), 317-326.
[40]
Morris, M.S.; Picciano, M.F.; Jacques, P.F.; Selhub, J. Plasma pyridoxal 5′-phosphate in the US population: The National Health and Nutrition Examination Survey, 2003-2004. Am. J. Clin. Nutr., 2008, 87(5), 1446-1454.
[41]
Chang, H.Y.; Tang, F.Y.; Chen, D.Y.; Chih, H.M.; Huang, S.T.; Cheng, H.D.; Lan, J.L.; Chiang, E.P. Clinical use of cyclooxygenase inhibitors impairs vitamin B-6 metabolism. Am. J. Clin. Nutr., 2013, 98(6), 1440-1449.
[42]
Leklem, J.E. In: Vitamin B6; Coates, P.M; Betz, J.M.; Blackman. M.R.; et al., Eds; In: Encyclopedia of Dietary Supplements; 2nd ed.; Informa Healthcare: London and New York, 2010; pp 792-811.
[43]
Voziyan, P.A.; Hudson, B.G. Pyridoxamine as a multifunctional pharmaceutical: Targeting pathogenic glycation and oxidative damage. Cell. Mol. Life Sci., 2005, 62(15), 1671-1681.
[44]
Rios, A.; Amyes, T.L.; Richard, J.P. Formation and stability of organic zwitterions in aqueous solution: Enolates of the amino acid glycine and its derivatives. J. Am. Chem. Soc., 2000, 122, 9373-9385.
[45]
Patel, V.; Trivedi, P.; Gohel, H.; Khetani, D. Synthesis and characterization of schiff base of p-chloro aniline and their metal complexes and their evaluation for antibacterial activity. Int. J. Adv. Pharm. Biol. Chem., 2014, 3(4), 999-1003.
[46]
Wondrak, G.T.; Jacobson, E.L. Vitamin B6: Beyond coenzyme functions. Subcell. Biochem., 2012, 56, 291-300.
[47]
Reddy, K.H. Coordination compounds in biology - The chemistry of vitamin B12 and model compounds. Resonance, 2011, 16(12), 1273-1283.
[48]
Romo, A.J.; Liu, H. Mechanisms and structures of vitamin B6-dependent enzymes involved in deoxy sugar biosynthesis. Biochim. Biophys. Acta, 2011, 1814(11), 1534-1547.
[49]
Arulmurugan, S.; Kavitha, A.P.; Venkatraman, B.R. Biological activities of Schiff base and its complexes: A Review. Rasayan J. Chem., 2010, 3(3), 385-410.
[50]
Rollas, S.; Küçükgüzel, Ş.G. Biological activities of hydrazones derivatives. Molecules, 2007, 12, 1910-1939.
[51]
Ponka, P.; Borova, J.; Neuwirt, J.; Fuchs, O. Mobilization of iron from reticulocytes, identification of pyridoxal isonicotinoyl hydrazone as a new iron chelating agent. FEBS Lett., 1979, 97(2), 317-321.
[52]
Ponka, P.; Borova, J.; Neuwirt, J.; Fuchs, O.; Necas, E. A study of intracellular iron metabolism using pyridoxal isonicotinoyl hydrazone and other synthetic chelating agents. Biochim. Biophys. Acta, Gen. Subj., 1979, 586(2), 278-297.
[53]
Richardson, D.R.; Ponka, P. Orally effective iron chelators for the treatment of iron overload disease: The case for a further look at Pyridoxal Isonicotinoyl Hydrazone (PIH) and its analogs. J. Lab. Clin. Med., 1998, 132(4), 351-352.
[54]
Altaf, A.A.; Shahzad, A.; Gul, Z.; Rasool, N.; Badshah, A.; Lal, B.; Khan, E. A review on the medicinal importance of pyridine derivatives. J. Drug Des. Med. Chem., 2015, 1(1), 1-11.
[55]
Sarel, S.; Iheanacho, E.N.; Avramovici-Grisaru, S. Growth inhibition of drug-resistant species of Plasmodium falciparum by domain structured N1,N2-derivatized hydrazines: Denticity effects, redox switches, and reductant-driven redox-cycling. Med. Chem., 2005, 1(2), 159-171.
[56]
Sah, P.P.T. Nicotinyl and isonicotinyl hydrazones of pyridoxal. J. Am. Chem. Soc., 1954, 76, 300.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy