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Infections caused by hard-to-treat methicillin-resistant Staphylococcus aureus (MRSA) are a serious global public-health concern, as MRSA has become broadly resistant to many classes of antibiotics. We disclose herein the discovery of a new class of non-β-lactam antibiotics, the oxadiazoles, which inhibit penicillin-binding protein 2a (PBP2a) of MRSA. The oxadiazoles show bactericidal activity against vancomycin- and linezolid-resistant MRSA and other Gram-positive bacterial strains, in vivo efficacy in a mouse model of infection, and have 100% oral bioavailability.

A straightforward solid phase-based strategy for the rapid generation of two small libraries of trans 3-alkyl-substituted β-lactams is described. For the glycine-derived library, a controlled excess of nonactivated acid chlorides was used to prevent oxazinone formation. The second library involved the attachment of Fmoc-protected p -aminophenol to Wang resin for the preparation of structurally-closed analogues of known cholesterol absorption inhibitors. This strategy allowed us to introduce diversity in the three variable positions of the β-lactam ring.

The copper-mediated and non-basic oxidative cross-coupling of organotrifluoroborates with phenols was applied to elaboration of the structures of thiirane-based inhibitors of matrix metalloproteinases. By revision of the synthetic sequence to allow this cross-coupling as the final step, and taking advantage of the neutral nature of organotrifluoroborate cross-coupling, a focussed series of inhibitors showing aryloxy and alkenyloxy replacement of the phenoxy substitutent was prepared. This reaction shows exceptional promise as an alternative to the classic copper-mediated but strongly basic Ullmann reaction, for the diversification of ether segments within base-labile lead structures.

A series of 4-[(triazolyl)methoxy]phenyl analogs of the phenoxyphenyl-substituted thiirane SB-3CT 1 was evaluated for its ability to inhibit gelatinases, members of the matrix metalloproteinase family of enzymes. The triazole segment of these inhibitors was assembled using the Meldal-Sharpless copper-catalyzed Huisgen dipolar cycloaddition of an azide and a terminal alkyne. While these triazole derivatives possessed fair activity as gelatinase inhibitors, an intermediate used in the dipolar cycloaddition, 4-(propargyloxy)phenyl derivative 2, showed very good activity (

In the 80 years since their discovery the β-lactam antibiotics have progressed through structural generations, each in response to the progressive evolution of bacterial resistance mechanisms. The generational progression was driven by the ingenious, but largely empirical, manipulation of structure by medicinal chemists. Nonetheless, the true creative force in these efforts was Nature, and as the discovery of new β-lactams from Nature has atrophied while at the same time multi-resistant and opportunistic bacterial pathogens have burgeoned, the time for empirical drug discovery has passed. We concisely summarize recent developments with respect to bacterial resistance, the identity of the new β-lactams, and the emerging non-empirical strategies that will ensure that this incredible class of antibiotics has a future.

The ozonolysis of carbohydrate derived norbornene systems in participating solvents demonstrated that different remote controlling factors could induce the regioselective fragmentation of the primary ozonide. The exo norbornene series afforded a complete regioselective process.

An efficient and selective procedure for a rapid access to polymer-supported carboxylic acids from their corresponding methyl esters using trimethyltin hydroxide is described. Silyl and benzyl ether, and Rink amide linkers are stable to the reaction conditions.

Ozonolysis of a carbohydrate derived norbornene system afforded a stable intramolecular cross-ozonide through a stereocontrolled pathway involving a regioselective fragmentation of the primary ozonide.