Beena Bhatia

Structure-Activity Relationship of the Aminomethylcyclines and the Discovery of Omadacycline

ABSTRACT A series of novel tetracycline derivatives were synthesized with the goal of creating new antibiotics that would be unaffected by the known tetracycline resistance mechanisms. New C-9-position derivatives of minocycline (the aminomethylcyclines [AMCs]) were tested for in vitro activity against Gram-positive strains containing known tetracycline resistance mechanisms of ribosomal protection (Tet M in Staphylococcus aureus, Enterococcus faecalis, and Streptococcus pneumoniae) and efflux (Tet K in S. aureus and Tet L in E. faecalis). A number of aminomethylcyclines with potent in vitro activity (MIC range of ≤0.06 to 2.0 μg/ml) were identified. These novel tetracyclines were more active against one or more of the resistant strains than the reference antibiotics tested (MIC range, 16 to 64 μg/ml). The AMC derivatives were active against bacteria resistant to tetracycline by both efflux and ribosomal protection mechanisms. This study identified the AMCs as a novel class of antibiotics evolved from tetracycline that exhibit potent activity in vitro against tetracycline-resistant Gram-positive bacteria, including pathogenic strains of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci (VRE). One derivative, 9-neopentylaminomethylminocycline (generic name omadacycline), was identified and is currently in human trials for acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP).

In Vitro and In Vivo Antimalarial Efficacies of Optimized Tetracyclines

ABSTRACT With increasing resistance to existing antimalarials, there is an urgent need to discover new drugs at affordable prices for countries in which malaria is endemic. One approach to the development of new antimalarial drugs is to improve upon existing antimalarial agents, such as the tetracyclines. Tetracyclines exhibit potent, albeit relatively slow, action against malaria parasites, and doxycycline is used for both treatment (with other agents) and prevention of malaria. We synthesized 18 novel 7-position modified tetracycline derivatives and screened them for activity against cultured malaria parasites. Compounds with potent in vitro activity and other favorable drug properties were further tested in a rodent malaria model. Ten compounds inhibited the development of cultured Plasmodium falciparum with a 50% inhibitory concentration (IC50) after 96 h of incubation of <30 nM, demonstrating activity markedly superior to that of doxycycline (IC50 at 96 h of 320 nM). Most compounds showed little mammalian cell cytotoxicity and no evidence of in vitro phototoxicity. In a murine Plasmodium berghei model, 13 compounds demonstrated improved activity relative to that of doxycycline. In summary, 7-position modified tetracyclines offer improved activity against malaria parasites compared to doxycycline. Optimized compounds may allow lower doses for treatment and chemoprophylaxis. If safety margins are adequate, dosing in children, the group at greatest risk for malaria in countries in which it is endemic, may be feasible.

Unexpected and facile bridgehead substitution in 5,6,7,8,9,10-hexahydro-5,9-methano-pyrimido[4,5-b]azocin-4(3H)-ones

Abstract Condensation of 2,6-diamino-4(3 H )-pyrimidinone with 2-cyclohexen-1-one gives a tricyclic product resulting from Michael addition followed by intramolecular hemiaminal formation. A methodology has been developed for reductive removal of the bridgehead hydroxyl group.

Antibiotic and non-antibiotic tetracycline patents: 2002 - 2007

Background: Infectious diseases in all populations are increasing in frequency and severity as the problem of antibiotic resistance continues to emerge. As other antibiotics become ineffective, it is up to researchers worldwide to create new and more potent compounds to thwart such diseases. Objective: This review presents the recent efforts and patent portfolios of those groups actively engaged in tetracycline research. Methods: The tetracyclines, once studied thoroughly shortly after their discovery > 50 years ago, have been neglected as new sources of scaffolds suitable for producing more potent compounds until recently, where several companies and research institutions have described newer and more potent analogs via semisynthesis or by total synthesis. Furthermore, other useful therapeutic properties of the tetracyclines have also been discovered, primarily as observations from their use as clinical antibiotic agents, in the areas of inflammation, neurodegeneration and diseases characterized by tissue degradation. Results and conclusions: The recent patents pertaining to the synthesis and biological properties indicate that the tetracyclines are undergoing a renaissance as their activities are being revised against prokaryotic organisms and against mammalian disease states related to inflammation.