Editorial Board

AstraZeneca Pharmaceuticals 1800 Concord Pike Fairfax Research Center B313 PO Box 15437 Institute of Pharmacy University of Regensburg Universitatsstr. 31 93053 Regensburg Germany University of Minnesota Department of Medical Chemistry 8-101A Weaver Densford Hall Minneapolis, MN 55455 USA Department of Medicinal Chemistry Director

The Medicinal Chemistry of Tuberculosis Chemotherapy

Marriner, Amit Nayyar, Eugene Uh, Sharon Y. Wong, Tathagata Mukherjee, Laura E. Via, Matthew Carroll, Rachel L. Edwards, Todd D. Gruber, Inhee Choi, Jinwoo Lee, Kriti Arora, Kathleen D. England, Helena I.M. Boshoff, and Clifton E. Barry III Abstract The development of effective chemotherapy for the treatment of tuberculosis (TB) began in the 1940s and has been reinvigorated recently due to concern regarding the emergence of highly drug-resistant TB strains. This chapter explores...

Structure Activity Relationship

Initial studies of structural modifications of EMB concluded that the size and nature of the alkyl group on the ethylenediamine nitrogens were critical for activity. These studies confirmed that small a-branched alkyl groups were more effective than alkyl chains branched at positions other than a and that a longer alkyl chain was detrimental to activity 264 . Alterations in the linker region of the molecule were deleterious since any lengthening, incorporation of heteroatoms, or branching of...

Classes of Compounds in Clinical Development 31 Nitroimidazoles 311 History

Nitroimidazoles are a class of compounds with growing importance in the field of tuberculosis chemotherapy. Nitroimidazoles show better activity against obligate anaerobes than aerobic organisms because their bactericidal activity requires a bioreduction of the aromatic nitro group whose reduction potential lies beyond the reach of eukaryotic aerobic redox systems 135, 136 . 2-Nitroimidazole derivatives modified at the 1- and 5-positions were among the first series (Fig. 11) of this class...

Potential Synergy Across Targets Diseases

Disease-specific targets relevant to the drug discovery of DDW are discussed in the following chapters of this book. Some targets and leads, which may be broadly applicable across multiple diseases, are briefly discussed here. Certain metabolic pathways and potential drug targets may be similar across a number of parasites, particularly those performing the same biochemical function such as proteases, kinases, and enzymes involved in the oxidative and reductive metabolism. The biological...

Pharmacological Models for Antitubercular Drugs

An evaluation of the pharmacological properties of new TB drugs is essential for effective treatment and overall cure of disease. Currently, most TB drugs are evaluated through preclinical animal models to establish appropriate dosing levels that promote optimal bacterial killing with limited toxicity. In vivo efficacy for TB drugs is not solely dependent on plasma concentration but more significantly dependent on tissue concentrations near and within lesions 78 . These concentrations must...