Hidenori Azami

Studies on Anti-Helicobacter pylori Agents. Part 1: Benzyloxyisoquinoline Derivatives

The synthesis and optimization of the anti-Helicobacter pylori activity of a novel series of benzyloxyisoquinoline derivatives that was discovered by a random screening process, are described. In the in vitro assay, compound 10c containing a 3-acetamido-2,6-dichlorobenzyl substituent was found to have extremely potent activity against H. pylori and no activity against other common bacteria. The anti-H. pylori activity of 10c was superior to that of amoxicillin (AMPC) (1) and clarithromycin (CAM) (2). However, 10c did not show in vivo efficacy in a mouse infection model; a feature attributed to the lack of strong bactericidal activity at short contact times.

Synthesis and antibacterial activity of novel 4-pyrrolidinylthio carbapenems Part IV. 2-Alkyl substituents containing cationic heteroaromatics linked via a C–C bond

The synthesis and biological activity of a novel series of 2-alkyl-4-pyrrolidinylthio-beta-methylcarbapenems containing a variety of cationic heteroaromatic substituents linked via a C-C bond is described. As a result of these studies, we selected FR21818 (In) as a candidate compound for development. FR21818 exhibited a well balanced spectrum of antibacterial activity, including Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA), excellent urinary recovery, good stability against renal dehydropeptidase-I (DHP-I). no antigenicity and mutagenicity, weak toxicities, and good efficacy and therapeutic effect on mice systemic infections. Affinities to PBPs, permeability of outer membrane, and plasma levels in mice, dog, and cynomolgous monkey of FR21818 are also reported.

Studies on β-lactam antibiotics. Synthesis and antibacterial activity of novel 1β-methylcarbapenems related to FR21818: 5-membered ring analogs

Abstract The synthesis and biological activity of the novel series of 1β-methylcarbapenems 1 are described. Most compounds displayed extremely potent antibacterial activity and high renal DHP-I stability. The best compound in this series, FR21818 (1a) displayed excellent in vivo efficacy against an MRSA infection in mice.

Synthesis and antibacterial activity of novel 4-pyrrolidinylthio carbapenems--I. 2-Alkoxymethyl derivatives.

The synthesis and in vitro antibacterial activity of a novel series of 2-alkoxymethyl-4-pyrrolidinylthio-1 beta-methyl carbapenems are described. As a result of these studies, we discovered that FR27743 (19j) containing a novel 2-fluoroethoxymethyl substituent possesses a broad spectrum of antibacterial activity against both Gram-positive and Gram-negative organisms, including Pseudomonas aeruginosa. Furthermore, FR27743 exhibited excellent stability against renal dehydropeptidase-I (DHP-I), good urinary recovery, and superior in vivo activity compared to that for Meropenem against several systemic infections.

Synthesis and antibacterial activity of novel 4-pyrrolidinylthio carbapenems. Part III:

Abstract The synthesis and biological activity of a novel series of 2-alkyl-4-pyrrolidinylthio-β-methylcarbapenems containing a variety of cationic heteroaromatic substituents is described. As a result of these studies, we uncovered a relationship between in vitro antibacterial activity and the length of the alkyl spacer part, and discovered FR20950 ( 1c ) Download high-res image (74KB) Download full-size image Scheme 3 . Synthetic route to novel carbapenems. Reagents and conditions: (i) NaOMe, MeOH, (or TFA, Et 3 SiH), then 24 , i Pr 2 EtN, DMAC, MeCN; (ii) MeI, Me 2 CO or THF; (iii) ICH 2 CONH 2 , Me 2 CO; (iv) I(CH 2 ) 3 NHAoc, DMF; (v) MeOTf, CH 2 Cl 2 ; (vi) FSO 3 Me, CH 2 Cl 2 ; (vii) Pd(PPh 3 ) 4 , PPh 3 , THF–EtOH, n Bu 3 SnH or morpholine; (viii) Pd(OH) 2 -C, H 2 , THF–phosphate buffer (pH 6.5). , containing a two methylene spacer moiety and an imidazolio group, which possesses a balanced spectrum of antibacterial activity, including Pseudomonas aeruginosa and Methicillin-resistant Staphylococcus aureus (MRSA). Furthermore, FR20950 exhibited excellent urinary recovery, and comparable stability against renal dehydropeptidase-I (DHP-I) to Biapenem. DHP-I stability could be improved by introduction of a substituent on to the imidazole ring.

Discovery of a novel benzyloxyisoquinoline derivative with potent anti-Helicobacter pylori activity.

The synthesis and in vitro optimization of the anti-Helicobacter pylori activity of a novel series of benzyloxyisoquinoline derivatives discovered by a random screening process, are described. FR180102 (7f), having a 3-acetamido-2,6-dichlorobenzyl moiety, was found to have extremely potent activity against H. pylori and no effect against a series of common Gram-positive and Gram-negative bacteria.