Preparation of Lipophilic Derivatives of <i>para</i>-Aminosalicylic Acid for Antimicrobial Drug Design

Interference with folic acid metabolism in pathogenic micro-organisms is a productive approach for the design of new anti-infectives. Such materials out-compete the natural substrates, inhibiting folate synthetase. They prevent cellular replication of the pathogen and promote the health of the infected host. Investigations of <i>para</i>-aminosalicylic acid (PAS) and its congeners as antifolates have had a long and distinguished history, but much still remains to be learned about the specific roles of structural features leading to successful antimicrobial activity. The subject of this report is the preparation of a number of stable lipophilic derivatives of PAS, using the methods of synthetic organic chemistry. Our focus was on the development of a set of well-characterized structurally related materials that might be used as probes to clarify the particular role of lipophilicity in PAS antifolate drug action. The lipophilicities (<i>C</i>log <i>P</i>) of the new compounds in this cohort range in a graduated way from a low of approximately 1 to a high of nearly 11. We anticipate that this range of values could be of use in explorations of factors crucial to the antifolate drug efficacy of PAS and its derivatives. Biological assessments in vitro of the new compounds against <i>Mycobacterium tuberculosis</i> are provided, as one example of a pathogen-specific application.