N-HYDROXYAMIDE DERIVATIVES POSSESSING ANTIBACTERIAL ACTIVITYNovel N-hydroxyamide derivatives are disclosed. These N-hydroxyamide derivatives inhibit UPD-3O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase, an enzyme present in gram negative bacteria and are therefore useful as antimicrobials and antibiotics. Methods of synthesis and of use of the compounds are also disclosed.A compound of Formula I, II or III:IIIwhereinAr is an aryl or heteroaryl ring;Xi, X2, X3, and X4 are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, alkenyl, alkenoxy, alkenoxyalkyl, alkynyl, alkynyloxy, nitro, halo, hydroxy, cycloalkyl, cycloalkylalkyl, arylalkoxy, arylalkoxyalkyl, haloalkylthio, haloalkylsulfinyl, haloalkylsulfonyl, haloarylalkyl, haloarylalkynyl, alkylsilylalkynyl, aryl, alkynyloxy, anaminocarbonylalkyl, carboxylate, carboxyl, carboxamide, heterocyele, and substituted heterocyele;R1 and R3 are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, aryl, sustituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxy, alkoxy, and -O-R4 where R4 is a substitated or unsubstituted aryl; with the proviso that R3 in formula III is not hydroxyl;R2 is selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, aryl, sustituted aryl, heteroaryl, substitated heteroaryl, halo, hydroxy, alkoxy, and -O-R4 where R4 is a substituted or unsubstituted aryl; with the proviso that R2 in formula III is not hydroxyl;Z is -CH2- or C(O); and pharmaceutically acceptable salts thereof, any and all tautomers of Formula 1, h or 111, as well as prodrugs thereof; and provided that the compounds of Formula I, II and III have a minimum inhibition concentration of 128 μg/ml or less against at least one ofthe organisms selected from the group consisting of Acinetobacter baumannii, Acinetobacter haemolyticus, Actinobacϊllus actinomycetemcomitans, Aeromonas hydrophila, Bacteroides fragilis, Bacteroides theataioatamicron, Bacteroides distasonis, Bacteroides ovatus, Bacteroides vulgatus, Bordetella pertussis, Brucella melitensis, Burkholderia cepacia, Burkholderia pseudomallei, Burkholderia mallei Fusobacterium, Prevotella corporis, Prevotella intermedia, Prevotella endodontalis, Porphyromonas asaccharolytica, Campylobacter jejuni, Campylobacter fetus, Citrobacter freundii, Citrobacter koseri, Edwarsiella tarda, Eikenella corrodens, Enterobacter cloacae, Enterobacter aerogenes, Enterobacter agglomerans, Escherichia coli, Francisella tularensis, Haemophilus influenzae, Haemophilus ducreyi, Helicobacter pylori, Kingella kingae, Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella rhinoscleromatis, Klebsiella ozaenae, Legionella penumophila, Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Plesiomonas shigelloides, Proteus mirabilis, Proteus vulgaris, Proteus penneri, Proteus myxofaciens, Providencia stuartii, Providencia rettgeri, Providencia άlcalifaciens, Pseudomonas aeruginosa, Pseudomonas fluorescens, Salmonella typhi, Salmonella paratyphi, Serratia marcescens, Shigella flexneri, Shigella boydii, Shigella sonnei, Shigella dysenteriae, Stenotrophomonas maltophilia, Streptobacillus moniliformis, Vibrio cholerae, Vibrio parahaemolyticus, Vibrio vulnificus, Vibrio alginolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Chlamydia pneumoniae, Chlamydia trachomatis, Ricketsia prowazekii, Coxiella burnetii, Ehrlichia chafeensis, and Bartonella hensenae.
항균작용을 갖는 Ｎ-히드록시아미드 유도체신규한 N-히드록시아미드 유도체가 개시된다. 이들 N-히드록시아미드 유도체는 UDP-30-(R-3-히드록시미리스토일)-N-아세틸글루코스아민 디아세틸라아제, 및 그램 음성 박테리아에 존재하는 효소를 억제하고 따라서 항균제와 항생제로서 유용하다. 화합물의 합성 방법과 사용이 또한 개시된다. 화학식 I, II 또는 III의 화합물 및 화학식 I, II 또는 III의 프로드러그는 물론이고, 약학적으로 허용가능한 그들의 염, 어떠한 그리고 모든 호변체.  상기식에서 Ar은 아릴 또는 헤테로아릴 고리이고; X1, X2, X3, 및 X4는 수소, 알킬, 할로알킬, 알킬티오, 알킬술피닐, 알킬술포닐, 히드록시알킬, 알콕시, 알콕시알킬, 할로알콕시, 알케닐, 알케녹시, 알케녹시알킬, 알키닐, 알키닐옥시, 니트로, 할로, 히드록시, 시클로알킬, 시클로알킬알킬, 아릴알콕시, 아릴알콕시알킬, 할로알킬티오, 할로알킬술피닐, 할로알킬술포닐, 할로아릴알킬, 할로아릴알키닐, 알킬실릴알키닐, 아릴, 알키닐옥시, 아나미노카르보닐알킬, 카르복실레이트, 카르복실, 카르복사미드, 헤테로싸이클, 및 치환된 헤테로싸이클로 구성되는 군으로부터 독립적으로 선택되고; R1 및 R3 은 수소, 알킬, 할로알킬, 히드록시알킬, 알케닐, 알키닐, 시클로알킬, 아릴, 치환 아릴, 헤테로아릴, 치환된 헤테로아릴, 할로, 히드록시, 알콕시, 및-O-R4으로 구성되는 군으로부터 독립적으로 선택되고 상기식에서 R4는 치환 또는 치환되지 않은 아릴이고; 단, 화학식 III에서의 R3는 히드록실이 아니고; R2는 수소, 알킬, 할로알킬, 히드록시알킬, 알케닐, 알키닐, 시클로알킬, 아릴, 치환 아릴, 헤테로아릴, 치환된 헤테로아릴, 할로, 히드록시, 알콕시, 및 -0-R4 으로 구성되는 군으로부터 선택되고 상기식에서 R4는 치환 또는 치환되지 않은 아릴 이고; 단, 화학식 III에서 R2 는 히드록실이 아니고; Z는 -CH2- 또는 C(O)이고 ; 단, 화학식 I, II 및 III의 화합물은 Acinetobacter baumannii, Acinetobacter haemolyticus, Actinobacillus actinomycetemcomitans, Aeromonas hydrophila, Bacteroides fragilis, Bacteroides theataioatamicron, Bacteroides distasonis, Bacteroides ovatus, Bacteroides vulgatus, Bordetella pertussis, Brucella melitensis, Burkholderia cepacia, Burkholderiapseudomallei, Burkholderia mallei Fusobacterium, Prevotella corporis, Prevotella intermedia, Prevotella endodontalis, Porphyromonasasaccharolytica, Campylobacterjejuni Campylobacterfetus, Citrobacter freundii, Citrobacter koseri, Edwarsiella tarda, Eikenella corrodens, Enterobacter cloacae, Enterobacter aerogenes, Enterobacter agglomerans, Escherichia coli, Francisella tularensis, Haemophilus influenzae, Haemophilus ducreyi, Helicobacterpylori Kingella kingae, Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella rhinoscleromatis, Klebsiella ozaenae, Legionella penumophila, Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Plesiomonas shigelloides, Proteus mirabilis, Proteus vulgaris, Proteuspenneri, Proteus myxofaciens, Providencia stuartii, Providencia rettgeri, Providencia alcalifaciens, Pseudomonas aeruginosa, Pseudomonasfluorescens, Salmonella typhi, Salmonella paratyphi, Serratia marcescens, Shigellaflexneri, Shigella boydii, Shigella sonnei, Shigella dysenteriae, Stenotrophomonas maltophilia, Streptobacillus moniliformis, Vibrio cholerae, Vibrio parahaemolyticus, Vibrio vulnificus, Vibrio alginolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Chlamydia pneumoniae, Chlamydia trachomatis, Ricketsia prowazekii, Coxiella burnetii, Ehrlichia chafeensis, 및 Bartonella hensenae로 구성되는 군으로부터 선택된 적어도 하나의 유기체에 대해서 128 ㎍/ml 이하의 최소 억제 농도를 가진다. 