항균제로서 Pteridine이 치환된 Pyridonecarboxylic Acids의 합성 및 항균 작용에 관한 연구

류성렬; 주동준

Journal of the Korean Industrial and Engineering Chemistry, Vol.7, No.6, 1096-1104, December, 1996

Studies on the Synthesis of Pterdine Substituted Pyridonecarboxylic Acids as Potential Antibacterial Agents and their Antimicrobial Activities

류성렬, 주동준

초록

새로운 항균제 및 항종양제를 합성하기 위하여 norfloxacin(8) 또는 ciprofloxacin(9)이 pteroic acid의 C-9위치에 치환되고 C-2 위치에 아미노기 대신 CH₃기가 치환된 새로운 pteroic acid 유도체 13a와 13b를 합성하였다. 이는 출발 물질인 norfloxacin과 ciprofloxacin의 piperazine N-4 위치에 2-amino-3-cyano-5-chloro-methylpyrazine(20)을 결합하여 1-alkyl(ethyl, cyclopropyl) -6-fluoro-1,4-dihydro-4-oxo-7-[[4-N- (2-amino-3-cyanopyrazin-5-yl)methyl]piperazin-1-yl]-3-quinolinecarboxytic acid(12a, 12b)를 합성하였다. 이를 각각 acetamidine. HCI과 고리화시켜 C-2 위치에 아미노기 대신 CH₃기가 치환된 새로운 pteroic acid 유도체 135와 13b를 각각 76.2%와 82.8%의 수율로 합성하였다. 그리고 이들 화합물에 대한 항균활성의 측정은 Pseudomonas aeruginosa ATCC9027을 포함하여 Gram-positive와 Gram-negative bacteria에 대하여 검토한 결과 합성한 화합물 13a와 13b는 일반적으로 norfloxacin보다 낮은 항균활성을 나타냈다.

In order to synthesize a new antibacterial and antitumor agents, we have prepared new analogues pteroic acid(13a, 13b), which means C-9 position of pteroic acid has been replaced by norfloxacin(8) or ciprofloxacin(9) and amino group of C-2 position by CH₃. These derivatives were synthesized coupling at N-4 piperazine of norfloxacin and ciprofloxacin with 2-amino-3-cyano-5-chloromethylpyrazine(20) provided 1-alkyl(ethyl, cyclopropyl)-6-fluoro-1,4-dihydro-4-oxo-7-[[4-N-(2-amino-3-cyanopyrazin-5-yl)methyl]piperazin-1-yl]-3-quinoline-carboxylic acid(12a, 12b). It was then cyclized with acetamidine. HCI to obtain new analogues of C-2 desaminomethylpteroic acid(13a, 13b) in yield of 76.2% and 82.8 % respectively. These compounds were tested in vitro on antibacterial activity against Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa ATCC9027. In general, these synthesized compounds(13a, 13b) showed less potent activities than those of norfloxacin.

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[1] Kovacs JA, Allegra CA, Swan JC, Drake JC, Parrillo JE, Chabner BA, Masur H, Antimicrob. Agents Chemother., 32, 430 (1988)

[2] Allegra CJ, Kovacs JA, Drake JC, Swan JC, Chabner BA, Masur H, J. Exp. Med., 165, 926 (1987)

[3] Broughton MC, Queener SF, Antimicrob. Agents Chemother., 35, 1348 (1991)

[4] Castellano AR, Nittleman MD, J. Am. Med. Assoc., 266, 820 (1991)

[5] Schnitzer RJ, Hawking F, "Experimental Chemistry," Vol. IV, Part I, Academic Press, N.Y. (1966)

[6] Prinder RM, "Medicinal Chemistry," 3rd ed., Part I, A. Burger, Ed., 492-521, Wiley Interscience, New York (1990)

[7] MaryamGhazala MG, Gaumont NY, Kalam TI, Med. Chem., 29, 1263 (1986)

[8] Seeger DR, Smith JM, Hulquist M, J. Am. Chem. Soc., 69, 2567 (1947)

[9] Piper JR, Montgomery JA, J. Het. Chem., 11, 279 (1974)

[10] Taylor EC, "Chemistry and Biology of Pteridine," Proceeding of the forth International Symposium on Pteridine, Toba, 79 (1969)

[11] Taylor EC, International Academic Printing Co., Ltd., Tokyo (1970)

[12] Hughes LR, Marsham PR, Oldfield J, Jackman AL, Proc. Am. Assoc. Cancer. Res., 29, 286 (1988)

[13] Cecchettis V, Dominich S, Fravolini A, Schiaffella F, Eur. J. Med. Chem., 19, 29 (1984)

[14] Fujita T, Drug Design, Fact or Fantasy, G. Jolles, and K.R.H. Wooldridge, eds., 19, Academic Press, London (1984)

[15] Koga H, Itoh A, Murayama S, Suzue S, Irikura T, J. Med. Chem., 23, 1358 (1980)

[16] Wise R, Antimicrob. Ag. Chemother., 23, 559 (1983)

[17] Matsumoto J, Miyamoto T, Minamida A, Nishimura Y, Equwa H, J. Med. Chem., 27, 292 (1984)

[18] Vandamme EJ, Science, 22, 111 (1984)

[19] Ferris JP, Sanchez RA, Mamcuso RW, Org. Syn. Colleet., 5, 32 (1973)

[20] Taylor EC, Rortnoy RC, Hochstetler DC, J. Org. Chem., 40, 2347 (1975)

[21] Jones TR, Calvert AH, Jackman AL, Brown SJ, Jones M, Harrap KR, Eur. J. Cancer, 17, 11 (1981)

[22] Wise R, Andrews JM, Edward I, J. Antimicrob. Agents Chemother., 23, 559 (1983)