Use of combinatorial and multiple parallel synthesis methodologies for the development of anti-infective natural products

In an astonishingly short time, combinatorial and multiple parallel synthetic methodologies for the synthesis of small drug-like molecules have transformed the practice of medicinal chemistry and are now in general use. Large focused and unfocused arrays of chemicals can now be produced and tested rapidly for the purpose of pharmacological evaluation. Rapid biological assays capable of performing tens of thousands of assays per week provide a driving force for the rapid generation of new chemical entities. Novel chemical strategies adapted to these purposes are represented by numerous research articles. The primary emphasis of much of this work has, however, been focused upon wholly synthetic substances. Whereas natural products can be considered to be nature's combinatorial libraries and continue to provide many important therapeutic substances, they are under represented for the most part in the literature of combinatorial chemistry. Indeed, there are those who believe that natural products are archaic in the face of these new methods. This paper addresses this question from the vantage point of representing the search for novel chemotherapeutic agents active against bacterial, fungal and viral pathogens by demonstrating that combinatorial and natural products methodologies are not antithetical but can be complimentary.