Synthesis Characterization and Antibacterial, Antifungal Activity of N-(Benzyl Carbamoyl or Carbamothioyl)-2-hydroxy Substituted Benzamide and 2-Benzyl Amino-Substituted Benzoxazines
New N-(benzyl carbamothioyl)-2-hydroxy substituted benzamides 13, 20, and 21 were synthesized using sodium bicarbonate and benzyl amine with 2-thioxo-substituted-1,3-benzoxazines 6, 10a, b, 11c, and 12a–n. The 2-thioxo-substituted-1,3-oxazines 6, 10a-b, 11d 12a–n, and 26 were converted to the corresponding 2-methylthio-substituted-1,3-oxazines 14a–l and 24 which were then converted to 2-benzyl amino-substituted-benzoxazines 15a–i by refluxing with benzylamine. Products 15a, b, e, f, and g were also synthesized by boiling the corresponding N-(benzyl carbamothioyl)-2-hydroxy substituted benzamides 13a, b, f, l, and m in acetic acid. 2-Oxo-substituted-1,3-benzoxazines 22 and 25 were prepared by treating the corresponding 2-methylthio-substituted-1,3-oxazines 14 and 24 with dilute HCl. The N-(benzyl carbamoyl)-2-hydroxy substituted benzamide 23 was synthesized from the reaction of 2-oxo-substituted-1,3-benzoxazine 22 with benzylamine. The new products were characterized using IR, 1H, and 13C NMR in addition to microanalysis. Selected compounds were tested in vitro for antibacterial and antifungi activity and the most active compounds were found to be the 4-(substituted-benzylamino)-2-hydroxy benzoic acids 9a and d (M. chlorophenolicum, MIC 50 and 25？μgm？L？1, resp.), N1, N3-bis (benzyl carbamothioyl)-4,6-dihydroxy-substituted phthalamides 20a and 20c (B. subtilis MIC 12.5, 50？μgm？L？1, resp.) and 21 (M. chlorophenolicum, MIC 50？μgm？L？1). 1. Introduction The search for new antibacterial compounds is a challenging task as bacteria are continuously developing resistance to antimicrobial compounds; however, infections due to such bacterial strains are infrequent although potentially fatal [1–3]. This ongoing problem has resulted in the search for newer, more effective antibacterial compounds [1–3]. Urea, thiourea 3 (X=O or S), and benzo-1,3-oxazine compounds 5 and 6 (Scheme 1) have been shown to possess antibacterial and antifungal properties [4–11]. The benzyl thiourea analogue 3 has been reported to show activity against Gram-positive bacteria [12]. Scheme 1: Previous synthesis of urea or thiourea 3 (X=O or S) and 2-amino benzo1,3-oxazine 5. The N-benzoyl-2-hydroxybenzamides [13] are important pharmacophores for antibacterial activity in which the 2-hydroxy group (hydrogen bonding donor) contributes to the activity, the imide linker (preferred) or urea linker retains activity and free NH is required for high activity. The Topliss method [14] was used in the optimization of salicylic acid derivatives for potential use as antibacterial agents. The employment and
References
[1]
C. Foucault and P. Brouqui, “How to fight antimicrobial resistance,” FEMS Immunology and Medical Microbiology, vol. 49, no. 2, pp. 173–183, 2007.
[2]
H. C. Neu, “The crisis in antibiotic resistance,” Science, vol. 257, no. 5073, pp. 1064–1073, 1992.
[3]
R. Wise, T. Hart, O. Cars et al., “Antimicrobial resistance,” British Medical Journal, vol. 317, no. 7159, pp. 609–610, 1998.
[4]
J. B. Chylińska, M. Janowiec, and T. Urbański, “Antibacterial activity of dihydro-1,3-oxazine derivatives condensed with aromatic rings in positions 5,6,” British Journal of Pharmacology, vol. 43, no. 3, pp. 649–657, 1971.
[5]
R. E. Stenseth, J. W. Baker, and D. P. Roman, “Substituted 3-phenyl-1,3-benzoxazine-2,4-diones and their bacteriostatic activity,” Journal of Medicinal Chemistry, vol. 6, no. 2, pp. 212–213, 1963.
[6]
R. Selleri, O. Caldini, E. Mura et al., “New derivatives of 2H-1,3-benzoxazine with anti-bacterial activity,” Arzneimittel-Forschung/Drug Research, vol. 15, no. 8, pp. 913–917, 1965.
[7]
K. Waisser, L. Kubicová, V. Buchta et al., “In vitro antifungal activity of 3-phenyl-2H-benzoxazine-2, 4(3H)-diones,” Folia Microbiologica, vol. 47, pp. 488–492, 2002.
[8]
S. C. Sharma, M. P. Swami, and R. C. Sharma, “Nitrogen heterocyclic analogous of cannabinoids. Part-I: synthesis of 6H-indolo[1,2-C][1,3]-benzoxazine systems and evaluation of their biological activities,” Journal of the Indian Chemical Society, vol. 60, no. 10, pp. 1002–1004, 1983.
[9]
S. Sharma and M. Sharma, “Synthesis of 5H-pyrazolo[2, 3-c][1, 3]benzoxazine systems and evaluation of their biological activities,” Acta Ciencia Indica, Series Chemistry, vol. 12, pp. 113–116, 1986.
[10]
T. Haneishi, T. Okazaki, T. Hata, C. Tamura, and M. Nomura, “Oxazinomycin, a new carbon-linked nucleoside antibiotic,” Journal of Antibiotics, vol. 24, no. 11, pp. 797–799, 1971.
[11]
A. Al-Mousawi, J. Al-Rawi, and M. Al-Ajiely M, “Synthesis and antimicrobial activity of 2-substituted-7-chloro-pyrano[3, 4-e][1, 3]oxazine-4, 5-dione,” The Arab Gulf Journal of Scientific Research, vol. 9, pp. 1–8, 1991.
[12]
L. J. Rashan, J. M. A. Al-Rawi, M. T. Nadir, and L. Awni, “Synthesis and biological evaluation of N-salicyloyl-N-benzyl thiourea and 2,2-dimethyl-4-oxo-6-methoxy benzo-1,3-dioxin,” Farmaco, vol. 46, no. 5, pp. 677–683, 1991.
[13]
J. Stec, Q. Huang, M. Pieroni et al., “Synthesis, biological evaluation, and structure-activity relationships of N-benzoyl-2-hydroxybenzamides as agents active against P. falciparum (K1 strain), trypanosomes, and leishmania,” Journal of Medicinal Chemistry, vol. 55, no. 7, pp. 3088–3100, 2012.
[14]
M. D. Silva, C. M. S. Menezes, E. I. Ferreira et al., “Topliss method in the optimization of salicylic acid derivatives as potential antimycobacterial agents,” Chemical Biology and Drug Design, vol. 71, no. 2, pp. 167–172, 2008.
[15]
A. Missir, V. Zota, J. Soare, and I. Chirita, “Investigations on the alcoxybenzoic acid series. 2, 6-dimetoxybenzoid acid thioureids,” Farmacia, vol. 32, no. 1, pp. 53–56, 1984.
[16]
J. Jirman, J. Kavalek, and V. Machacek, “Preparation of substituted 1-benzoylthioureas by transacylation of 1-acetylthioureas,” Sbornik Vedeckych Praci-Vysoka Skola Chemickotechnologicka Pardubice, vol. 50, pp. 101–110, 1987.
[17]
T. Wei, L. Xiong, X. Chen, and Y. Zhang, Preparation of N-phenyl-N′-(2-Acetoxybenzoyl) thiourea derivatives as plant growth regulators, WO, 101735129 A, 20100616, 2010.
[18]
N. Ohi, B. Aoki, and T. Shinozaki, “Semisynthetic β-lactam antibiotics. I. Synthesis and antibacterial activity of new ureidopenicillin derivatives having catechol moieties,” Journal of Antibiotics, vol. 39, no. 2, pp. 230–241, 1986.
[19]
J. Al-Rawi and K. Al-Shahiry, “Synthesis of 4-oxo-2-thioxo-3, 4-dihydro-2H, 1, 3- substituted benzoxazine, their ransformation with water, diazomethane, and amines,” Asian Journal of Chemistry, vol. 2, pp. 343–350, 1990.
[20]
J. M. A. Al-Rawi and K. F. Al-Shahiry, “Carbon-13 chemical shift analysis of 2-thio-3,4-dihydro-2H-1,3-benzoxazine-4-ones and their degradation products with water and amines,” Journal of Environmental Science and Health A, vol. 26, no. 8, pp. 1323–1332, 1991.
[21]
R. Gammill, T. Judge, and J. Morris, “Preparation of 2-morpholino-1-benzopyran-4-ones and-1, 3-benzoxazin-4-ones as antiatherosclerotic and antithrombotic agents,” WO, 9006921, 1990.
[22]
K. M. Pritchard, J. M. Al-Rawi, and A. B. Hughes, “Generalized method for the production of 1,3-benzoxazine, 1,3-benzothiazine, and quinazoline derivatives from 2-(hydroxy, thio, or amino) aromatic acids using triphenylphosphine thiocyanogen,” Synthetic Communications, vol. 35, no. 12, pp. 1601–1611, 2005.
[23]
K. M. Pritchard, J. Al-Rawi, and C. Bradley, “Synthesis, identification and antiplatelet evaluation of 2-morpholino substituted benzoxazines,” European Journal of Medicinal Chemistry, vol. 42, no. 9, pp. 1200–1210, 2007.
[24]
G. D. Lei, L. X. Li, Z. Y. Lu, and M. G. Xie, “Improved one-pot synthesis of 4,6-dihydroxyisophthalic acid and 2,3-dihydroxyterephthalic acid,” Chinese Chemical Letters, vol. 16, no. 8, pp. 1039–1042, 2005.
[25]
R. Hrdina, M. Hrdinová, L. Burgert, V. Bures, H. Lewandowski, and R. Suláková, “Complex compounds of boric acid, salicylic acid or its derivatives and silver, method of their preparation, and a preparation containing these compounds for killing moulds, fungi and ligniperdous insects,” WO, 2008/058490 A1, 2008.
[26]
M. A. Rahim, Y. Matsui, T. Matsuyama, and Y. Kosugi, “Regioselective carboxylation of phenols with carbon dioxide,” Bulletin of the Chemical Society of Japan, vol. 76, no. 11, pp. 2191–2195, 2003.
[27]
Y. Hiroshi, N. Tatsuo, and T. Ikuzo, “Metal salts of aromatic hydroxyl carboxylic acids with substituents,” JP19670330, 1970.
[28]
G. N. Walker and M. A. Klett, “Synthesis of varied heterocyclic and substituted aryl alkyl secondary amines, related schiff bases, and amides,” Journal of Medicinal Chemistry, vol. 9, no. 4, pp. 624–630, 1966.
[29]
J. Patole, D. Shingnapurkar, S. Padhye, and C. Ratledge, “Schiff base conjugates of p-aminosalicylic acid as antimycobacterial agents,” Bioorganic and Medicinal Chemistry Letters, vol. 16, no. 6, pp. 1514–1517, 2006.
[30]
S. J. Wadher, N. A. Karande, S. D. Sonawane, and P. G. Yeole, “Synthesis and biological evaluation of schiff base and 4-thiazolidinones of amino salicylic acid and their derivatives as an antimicrobial agent,” International Journal of ChemTech Research, vol. 1, no. 4, pp. 1303–1307, 2009.
[31]
K. N. Scott, “Carbon-13 nuclear magnetic resonance of biologically important aromatic acids. I. Chemical shifts of benzoic acid and derivatives,” Journal of the American Chemical Society, vol. 94, no. 24, pp. 8564–8568, 1972.
[32]
J. Heppell and j. Al-Rawi, “Functionalisation of quinazolin-4-ones part 1: synthesis of novel 7-substituted-2-thioxoquinazolin-4-ones from 4-substituted-2-aminobenzoic acidsand PPh3(SCN)2,” 2013.
[33]
S. Ihmaid, J. Al-Rawi, and C. Bradley, “Synthesis, structural elucidation and DNA-dependant protein kinase and antiplatelet studies of 2-amino-[5, 6, 7, 8-mono and 7, 8-di-substituted]-1,3- benzoxazines,” European Journal of Medicinal Chemistry, vol. 45, no. 11, pp. 4934–4946, 2010.
[34]
K. M. Pritchard and J. Al-Rawi, “Reaction of Ph3P(SCN)2 with further orthohydroxy carboxylic acid systems, including substituted β-keto acids: synthesis of novel 2-thio-1,3-oxazines and their subsequent transformation with amines,” Synthetic Communications, vol. 38, no. 23, pp. 4076–4096, 2008.
[35]
S. K. Ihmaid, J. M. A. Al-Rawi, C. J. Bradley, M. J. Angove, and M. N. Robertson, “Synthesis, DNA-PK inhibition, anti-platelet activity studies of 2-(N-substituted-3-aminopyridine)-substituted-1, 3-benzoxazines and DNA-PK and PI3K inhibition, homology modeling studies of 2-morpholino-(7, 8-di and 8-substituted)-1, 3-benzoxazines,” European Journal of Medicinal Chemistry, vol. 57, pp. 85–10, 2012.
[36]
J. M. Andrews, “Determination of minimal inhibitory concentration,” Journal of Antimicrobial Chemotherapy, vol. 48, pp. 5–16, 2001.
[37]
R. R. Yocum, J. R. Rasmussen, and J. L. Strominger, “The mechanism of action of penicillin. Penicillin acylates the active site of Bacillus stearothermophilus D-alanine carboxypeptidase,” Journal of Biological Chemistry, vol. 255, no. 9, pp. 3977–3986, 1980.
[38]
S. Petrovski and V. A. Stanisich, “Embedded elements in the IncPβ plasmids R772 and R906 can be mobilized and can serve as a source of diverse and novel elements,” Microbiology, vol. 157, no. 6, pp. 1714–1725, 2011.
[39]
R. C. Schmeltzer, K. E. Schmalenberg, and K. E. Uhrich, “Synthesis and cytotoxicity of salicylate-based poly(anhydride esters),” Biomacromolecules, vol. 6, no. 1, pp. 359–367, 2005.
