Combinatorial Chemistry & High Throughput Screening - Volume 8, Issue 1, 2005

Combinatorial Chemistry & High Throughput Screening begins its eighth year of publication with this issue. Given this perspective, it is interesting how rapidly this field is changing and yet still remains relevant to the discovery and development of new drugs, catalysts, and other materials. For example, in just eight years we have witnessed a trend away from the practice of assembling enormous random libraries of compounds Read More

X-ray crystallography is a technique which is finding increasing utility in the effort to find new antimalarial drugs. This is in spite of the serious difficulties often encountered in obtaining sufficient quantities of protein to crystallize. This review provides an overview of the Plasmodium falciparum proteins which have been crystallized with bound inhibitors and the methodology employed in the heterologous expression of Read More

In biological systems, fatty acids can be synthesized by two related, but distinct de novo fatty acid synthase (FAS) pathways. Human cells rely on a type I FAS whereas plants, bacteria and other microorganisms contain type II FAS pathways. This difference exposes the type II FAS enzymes as potential targets for antimicrobial drugs that have little to no side effects in the human host. A number of inhibitors of type II FAS enzym Read More

New chemical classes of compounds must be introduced into the malaria drug development pipeline in an effort to develop new chemotherapy options for the fight against malaria. In this review we describe an iterative approach designed to identify potent inhibitors of a kinase family that collectively functions as key regulators of the cell cycle. Cyclin-dependent protein kinases (CDKs) are attractive drug targets in numerou Read More

The purpose of this review is to provide an update on our work based on the 1,4-bis(3- aminopropyl)piperazine skeleton and how it allowed our group to validate a new target. After a brief introduction where we will relate the way this substructure was introduced in our 4- aminoquinolinyl derivatives, we will present first the different libraries synthesized around this moiety: (1) libraries of sulfonamides, amides and amines d Read More

A new antimalarial pharmacological approach based on inhibition of the plasmodial phospholipid metabolism has been developed. The drugs mimic choline structure and inhibit de novo phosphatidylcholine biosynthesis. Three generations of compounds were rationally designed. Bisquaternary ammonium salts showed powerful antimalarial activity, with IC50 in the nanomolar range. To remedy their low per os absorption, bioisos Read More

Clinical manifestations of malaria primarily result from proliferation of the parasite within the hosts' erythrocytes. During this process, hemoglobin is utilized as the predominant source of nutrition. The malaria parasite digests hemoglobin within the digestive vacuole through a sequential metabolic process involving multiple proteases. Massive degradation of hemoglobin generates large amount of toxic heme. Malaria par Read More

The malaria parasite, Plasmodium falciparum, spends part of its complex life cycle within the red blood cells of a human host. During this time, the parasite alters the permeability of the red blood cell's plasma membrane to allow the uptake of nutrients, the removal of “waste” and volume and ion regulation of the infected cell. The increased permeability is due to the induction of new permeability pathways (NPP), which are obv Read More

The high level of attrition of drugs in clinical development has led pharmaceutical companies to increase the efficiency of their lead identification and development through techniques such as combinatorial chemistry and high-throughput (HTP) screening. Since the major reasons for clinical drug candidate failure other than efficacy are pharmacokinetics and toxicity, attention has been focused on assessing properties such a Read More

Norman C. Waters obtained his Ph.D. in 1996 from Drexel University (formerly Hahnemann University) working under the supervision of Professor Lawrence W. Bergman in the field of signal transduction and metabolic regulation in the budding yeast Saccharomyces cerevisiae. From 1997-2002, he served as Chief of Anti-Parasite Assay Development in the Division of Experimental Therapeutics at the Walter Reed Army Institute of Read More