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.
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We thank numerous colleagues at Abbott Laboratories reporting to Dr Paul Lartey for the enzymology, preparation through usual chemistry following different routes of numerous additional analogs, and for some in vivo evaluations. We thank Dr Taffy Williams and his colleagues at Panax Laboratories for additional in vivo biological testing of these substances. We thank Professor Anne Frank and her colleagues at the InterAmerican University, Hato Rey, Puerto Rico, for collection of plant material for this project and Dr Michel Jung of Hoechst, Marion, Roussel for helping with the design and construction of the combinatorial apparatus during a study leave in this laboratory. Finally, we thank the National Institutes of Health, Allergy and Infectious Diseases Institute, for research grants facilitating part of this work.
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