Advances in studies on novel agents against Helicobacter pylori

17 3 2005 6 Chinese Bulletin of Life Sciences Vol. 17, No. 3 Jun., 2005 1004-0374(2005)03-0211-07 201203 (Helicobacter pylori) R975.6A Advances in studies on novel agents against Helicobacter pylori LIU Qing, WANG Ming-Wei* (National Center for Drug Screening, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China) Abstract: Helicobacter pylori is a well-recognized cause for gastritis, peptic ulcer and carcinoma of the stomach. With wide use of broad-spectrum antibiotics, drug-resistant strains of Helicobacter pylori have been emerged in a rapid pace. Development of highly efficacious and selective agents against Helicobacter pylori is thus becoming a focal point that attracts global attention. This article reviews a series of new drugs or lead candidates with inhibitory effects on Helicobacter pylori reported in the literature during recent five years, with an aim of providing some useful insights to research and development of novel drugs to treat Helicobacter pylori infection. Key words: research progress; anti-helicobacter pylori drugs (Helicobacter pylori, H. pylori, HP) 1983 Warren Marshall [1] [2~3] ph [4] 2005-04-04 2002AA2Z343AKSCX1-SW-11-2 (1978 ) (1956 ) *

212 (PPI) PPI ( ) ( ) [5~6] ( TAK-083 ) 1 1.1 NE-2001 TG44 NE-2001 TG44 DNA NE-2001 ATCC 43504 12 MIC 0.4~1.6 µg/ml NE-2001 NE-2001 [7~8] 1.2 TAK-083 TAK-083 [9] TAK-083 54 MIC 90 0.031µg/ml (MIC 90 0.125µg/ml 64µg/ml 8µg/ml) TAK-083 -trna ( ) - trna TAK-083 ph (4.5~7.5) 1.3 Tomb [10] Alm [11] () (DHODase) Copeland [12] (R1= R2= N- ) DHODase DHODase( 2 ) Q DHODase 1 Q ( R1= R2=N- )(MIC 2~8µ g/ml) ATCC25238 (-) ATCC25285 (-) ATCC25922 (-) tolc (-) ATCC27853 (-)

213 ATCC49766 (-) ATCC29212 (+) ATCC13709 (+) ATCC12962 (+) MIC 64 µg/ml 1.4 Plaunotol Koga [13] Plau-noi Plaunotol() 5-doxyl- ( ) 16-doxyl ( ) Plaunotol Plaunotol Plaunotol Tago [14] Plaunotol [R 1 = OH NHC(S)NHPh NHC(S)NHCH 2 Ph NHC(S) NHCH 2 CH 2 Ph R 18 = OH NHC(S)NHPh NHC(S) NHCH 2 Ph NHC(S)NHCH 2 CH 2 Ph] R 1 = NHC (S)NHCH 2 CH 2 Ph R 18 = OH Plaunotol ( NCTC11637 ) MIC 0.10 µg/ml, 1.5 ADP- NAD ADP- ADP- (R= 3-4- ) ADP- ADP- [15]

214 1.6 3-( )- N- (R=Ph 3-F-Ph 2-Cl-Ph 3-Cl-Ph 4-Cl-Ph 3-Br-Ph 4-Br-Ph 3-Me-Ph 3-MeO- Ph 3-PhCH 2 O-Ph 3-NO 2 -Ph 3-OH-Ph 1-2- 3-3,4-3- 2-MeO- 2,3-Cl 2-1- 2- ) [16] 3-[2-( - 2-) ]- N- MIC ph 7.0 6.0 5.0 0.063µg/ml, MIC 0.031µg/ml 0.125µg/ml 0.5µg/ml 0.063µg/ml 0.5µg/ml 2.0µg/ml 1.7 2-2-()-4- [R=C1-C4 Me 2 CH (CH 2 ) 2, CF 3 CH 2, CH 3 O(CH 2 ) 2, CH 3 S(CH 2 ) 2, Me 2 N(CH 2 ) 2, AcNH(CH 2 ) 2, Ph(CH 2 ) 2, 2- MeOPh(CH 2 ) 2, 3-MeOPh(CH 2 ) 2, 4-MeOPh(CH 2 ) 2, aryl ] [17~18] (100 µg/ml) 1.8 FR193879 FR193879 [19] β- 1.9 Nitazoxanide Tizoxanide Nitazoxanide (NTZ) [20~21] Nitazoxanide Tizoxanide(TIZ) MIC 90 8µg/ml

215 1.10 (X=O NH R=-NHCOCH2NH2 -NHAc) [22] 3- - 2 6- MIC 0.0125~0.05µg/ml 1.11 KRM-1657 KRM-1648 KRM-1657 KRM- 1648 [23] 44 MIC 90 0.002µg/ml 0.008µg/ml 2 2.1 (Rebamipide) Hayashi [25] MKN-28 MKN-45( ) MKN-28 1.12 β- β- [24] 2.2 (Rabeprazole) [26] (Rabeprazole-TH) ph 7.4 Rabeprazole-TH 50% 0.25~0.5µg/ml 8~32µg/ml 8~16µg/ml 128~256µg/mlRabeprazole- TH MIC 90 0.5µg/ml

216 2.3 TF18 TF18 Spengler [27] Kawase [28] TF18 MIC 50 TF18 3 UreIpH [29~30] [1] Warren J R, Marshall B J. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet, 1983, 1: 1273~1275 [2] Petersen A M, Krogfelt K A. Helicobacter pylori: an invading microorganism? a review. FeMS Immun Med Microb, 2003, 36(3): 117~126 [3] Parsonnet J, Friedman G D, Vandersteed D P, et al. Helicobacter pylori infection and the risk of gastric carcinoma. New Engl J Med, 1991, 325(16): 1127~1231 [4] Ricci V, Zarrilli R, Romano M. Voyage of Helicobacter pylori in human stomach: odyssey of a bacterium. Digest Liver Dis, 2002, 34(1): 2~8 [5] Bazzoli F, Olivieri L, De Luca L, et al. Therapy and drug resistance in Helicobacter pylori infection. Digest Liver Dis, 2000, 32(3): S207~S210 [6] Scarpignato C. Towards the ideal regimen for Helicobacter pylori eradication: the search continues. Digest Liver Dis, 2004, 36(4): 243~247 [7] Cheng N, Xie J S, Zhang M Y, et al. A specific anti- Helicobacter pylori agent NE-2001: synthesis and its effect on the growth of H. pylori. Bioorg Med Chem Lett, 2003, 13 (16): 2703~2707 [8] Kamoda O, Fujiwara H, Yanagi T. Guanidinomethyl cyclohexane carboxylic acid ester derivatives. US Patent: 6284791B1, 2001. [9] Kanamaru T, Nakano Y, Toyoda Y, et al. In vitro and in vivo antibacterial activities of TAK-083, an agent for treatment of Helicobacter pylori infection. Antimicrob Agents Chemother, 2001, 45(9): 2455~2459 [10] Tomb J, White O, Kerlavage A, et al. The complete genome sequence of the gastric pathogen Helicobacter pylori. Nature, 1997, 388(6642): 539~547 [11] Alm R, Ling L, Moir D, et al. Genomic-sequence comparison of two unrelated isolates of the human gastric pathogen Helicobacter pylori. Nature, 1999, 397(6715): 176~180 [12] Copeland R A, Marcinkeviciene J, Haque T S, et al. Helicobacter pylori-selective anti- bacterials based on inhibition of pyrimidine biosynthesis. J Biol Chem, 2000, 275(43): 33373~33378 [13] Koga T, Watanabe H, Kawada H, et al. Interactions of plaunotol with bacterial membranes. J Antimicrob Chemother, 1998, 42(2): 133~140 [14] Tago K, Minami E, Masuda K, et al. Synthesis of plaunotol derivatives and their antibacterial activities against Helicobacter pylori. Bioorg Med Chem, 2001, 9(7): 1781~1791 [15] Masatoshi N, Otsuka Pharma Co Ltd. ADP-ribosyltransferase inhibitor. PCT Patent: 9826769, 1998. [16] Ando R, Kawamura M, Chiba N. 3-(Arylacetylamino)-Nmethylbenzamides: a novel class of selective anti-helicobacter pylori agents. J Med Chem, 2001, 44(25): 4468~4474 [17] Katsura Y, Tomishi T, Inoue Y, et al. Anti-Helicobacter pylori agents. 4. 2-(substituted guanidine)-4-phenylthiazoles and some structurally rigid derivatives. J Med Chem, 2000, 43(17): 3315~3321 [18] Katsura Y, Nishino S, Inoue Y, et al. Anti-Helicobacter pylori agents. 5, 2- (substituted guanidine) -4-arylthiazoles and aryloxazole analogues. J Med Chem, 2002, 45(1): 143~150 [19] Yoshida Y, Matsuda K, Sasaki H, et al. Studies on anti- Helicobacter pylori agents. Part 3: a novel, efficacious cephem derivative, FR 193879. Bioorg Med Chem Lett, 2004, 14(10): 2627~2631 [20] Yamamoto Y, Hakki A, Friedman H, et al. Nitazoxanide, a nitrothiazolide antiparasitic drug, is an anti-helicobacter pylori agent with anti-vacuolating toxin activity. Chemotherapy, 1999, 45(4): 303~312

217 [21] Megraud F, Occhialini A, Rossignol J. Nitazoxanide, a potential drug for eradication of Helicobacter pylori with no cross-resistance to metronidazole. Antimicrobial Agents Chemother, 1998, 42(11): 2836~2840 [22] Yoshida Y, Barrett D, Azami H, et al. Studies on anti- Helicobacter pylori agents. Part 1: benzyloxyisoquinoline derivatives. Bioorg Med Chem, 1999, 7(11): 2647~2666 [23] Akada J K, Shirai M, Fujii K, et al. In vitro anti-helicobacter pylori activities of new rifamycin derivatives, KRM-1648 and KRM-1657. Antimicrob Agents Chemother, 1999, 43 (5): 1072~1076 [24] Horii T, Mase K, Suzuki Y, et al. Antibacterial activities of β-lactamase inhibitors associated with morphological changes of cell wall in Helicobacter pylori. Helicobacter, 2002, 7(1): 39~45 [25] Hayashi S, Sugiyama T, Amano K, et al. Effect of rebamipide, a novel anti- ulcer agent, on Helicobacter pylori adhesion to gastric epithelial cells. Antimicrob Agents Chemother, 1998, 42(8): 1895~1899 [26] Ohara T, Goshi S, Taneike I. Inhibitory action of a novel proton pump inhibitor, rabeprazole, and its thioether derivative against the growth and motility of clarithromycin-resistant Helicobacter pylori. Helicobacter, 2001, 6(2): 125~129 [27] Spengler G, Molnar A, Klausz G, et al. Inhibitory action of a new proton pump inhibitor, trifluoromethyl ketone derivative, against the motility of clarithromycin-susceptible and-resistant Helicobacter pylori. Intern J Antimicrob Agents, 2004, 23(6): 631~633 [28] Kawase M, Harada H, Saito S, et al. In vitro susceptibility of Helicobacter pylori to trifluoromethyl ketones. Bioorg Med Chem Lett, 1999, 9(2): 193~194 [29] Skouloubris S, Thiberge J M, Labigne A, et al. The Helicobacter pylori UreI protein is not involved in urease activity but is essential for bacterial survival in vivo. Infect Immun, 1998, 66(9): 4517~4521 [30] Weeks D L, Eskandari S, Scott D R, et al. A H + -gated urea channel: the link between Helicobacter pylori urease and gastric colonization. Science, 2000, 287(5452): 482~485 2005 5 11 9 (Uk) (r-sk) (rt-pa) ( )30 150 2005 2 GMP http: //www.sibs.ac.cn