Frank P. DiNinno

Dicationic 2-fluorenonylcarbapenems: Potent anti-MRS agents with improved solubility and pharmacokinetic properties

The synthesis and biological evaluation of a series of dicationic-substituted 2-fluorenonylcarbapenems is described. This class of compounds showed enhanced water solubility while maintaining potent activity against MRS. Introduction of a 1-beta-methyl substituent was found to improve pharmacokinetics.

An efficient synthesis of 2-substituted-thio-6-hydroxyethyl-penem-3-carboxylic acids via 2-thioxopenams

Abstract Allyl and p -nitrobenzyl (5R, 6S)-6-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-2-thioxopenam-3-carboxylates ( 19 ) were synthesized by base mediated cyclization of the corresponding 1-carboxylmethyl-4-phenoxy (thiocarbonyl)thio-2-azetidinones ( 16 ). The thioxopenams underwent alkylation and Michael reactions to produce 2-alkylthio- and 2-alkenylthio-penem derivatives 20 and 21 .

A highly efficient method for the preparation of 2-aryl substituted carbapenems exploiting a Pd(0) mediated cross-coupling reaction

Abstract A remarkably mild procedure for the synthesis of 2-aryl substituted carbapenems via a palladium catalyzed coupling reaction of a vinyl triflate with aryl stannanes is described. Employing Pd2(DBA)3.CHCl3 as the catalyst and tris(2,4,6-trimethoxyphenyl)phosphine as the ligand provides generous yields of the desired β-lactams. Reaction times are brief while reaction temperatures never exceed ambient.

Synthesis and activity of 2-(sulfonamido)methyl-carbapenems: Discovery of a novel, anti-MRSA 1,8-naphthosultam pharmacophore

A series of 1beta-methyl carbapenems substituted at the 2-position with lipophilic, acyclic and cyclic (sulfonamido)methyl groups was prepared and evaluated for activity against resistant gram-positive bacteria. From these studies, the 1,8-naphthosultamyl group emerged as a novel, PBP2a-binding, anti-MRSA pharmacophore worthy of further exploration.

4,7-Dichloro benzothien-2-yl sulfonylaminomethyl boronic acid: First boronic acid-derived beta-lactamase inhibitor with class A, C, and D activity

4,7-Dichloro-1-benzothien-2-yl sulfonylaminomethyl boronic acid (DSABA, Compound I) was discovered as the first boronic acid-based class D beta-lactamase inhibitor. It exhibited an IC(50) of 5.6 microM against OXA-40. The compound also inhibited class A and C beta-lactamases with sub to low microM IC(50), and synergized with imipenem against Acinetobacter baumannii.

A facile synthesis of 3-aryl-substituted-benzothiophenes via a lewis acid mediated cyclization of 2-arylthio-acetophenones

Abstract The boron trifluoride-etherate mediated cyclization of 2-arylthio-ketones 1a-h at ambient temperature gave 3-aryl-substituted benzothiophenes 2a-h in excellent yield. None of the rearranged 2-aryl-substituted benzothiophenes were observed.

The synthesis and antibacterial activity of 2-carbolinyl-carbapenems: potent anti-MRSA/MRCNS agents

Abstract A series of 2-carbolinyl-carbapenems was prepared via the Stille stannane coupling reaction. This new class of antibiotics exhibited potent activity in vitro against methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase negative staphylococci (MRCNS) as well as a broad spectrum of antibacterial activity. A high resistance to the mammalian dehydropeptidase, DHP-1, was also observed.

Thiophenyl oxime-derived phosphonates as nano-molar class C beta-lactamase inhibitors reducing MIC of imipenem against Pseudomonas aeruginosa and Acinetobacter baumannii

The preparation and characterization of a series of thiophenyl oxime phosphonate beta-lactamase inhibitors is described. A number of these analogs were potent and selective inhibitors of class C beta-lactamases from Pseudomonas aeruginosa and Enterobacter cloacae. Compounds 3b and 7 reduced the MIC of imipenem against an AmpC expressing strain of imipenem-resistant P. aeruginosa. A number of the title compounds retained micromolar potency against the class D OXA-40 beta-lactamase from Acinetobacter baumannii and at high concentrations compound 3b was shown to reduce the MIC of imipenem against a highly imipenem-resistant strain of A. baumanii expressing the OXA-40 beta-lactamase. In mice compound 3b exhibited phamacokinetics similar to imipenem.

2-Naphthylcarbapenems: Broad spectrum antibiotics with enhanced potency against MRSA

A regioisomeric set of 2-naphthylcarbapenems featuring cationic substituents was synthesized. Optimal placement of the cationic group was found to markedly improve activity against methicillin-resistant staphylococci while maintaining a good spectrum of gram-negative activity.

The discovery and synthesis of 2-biphenylcarbapenems active against methicillin resistant staphylococci

Abstract The discovery and synthesis of the arylcarbapenem 2b possessing potent activity against highly resistant strains of methicillin resistant staphylococci are dislosed.