New antifungals targeting the synthesis of fungal sphingolipids

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ABSTRACT The ultimate goal of this proposal renewal entitled, “New antifungals targeting the synthesis of fungal sphingolipids”, is to continue the optimization of our 3rd generation compounds that we generated using the previous funding cycle, with the ultimate goal to subject 1-5 compounds at the end of the renewal to preclinical studies and file an Investigational New Drug (IND) with the Food Drug Administration (FDA) for the treatment of invasive fungal infections (IFI). IFIs are increasingly responsible for serious life-threatening conditions, particularly in individuals with compromised immunity. For the past 10 years, we have been working on the research and development of a new class of antifungal agents directed against the synthesis of fungal but not mammalian sphingolipids. The initial discovery of N’-(3-bromo-6-hydroxybenzylidene)-2-methylbenzohydrazide (BHBM) as the hit compound from library screening lead us to initiate an intensive research program involving the combinatorial/parallel synthesis of BHBM derivatives and the assessment of a structure-activity relationship. This program allowed us to synthesize a 3rd-generation compounds more efficacious than the antifungals currently used in the clinic. Our 3rd-generation compounds have secured intellectual property (IP) and a start-up company (MicroRid Technologies Inc.) with licensing options was co-funded, bringing the necessary expertise to further develop these potent antifungal compounds. We now seek to optimize pharmacokinetics, toxicology properties without losing antifungal activity. We initiated the synthesis of several hundred compounds to create a 3rd generation compounds based on D13 (Aim 1) that will be assessed for antifungal activity and mechanism of action (Aim 2). A few selected compounds will be subjected to toxicology and intensive PK studies (Aim 3), and, finally, one compound will ultimately be selected for IND filing. Our experience, expertise, and ongoing effort in this area of antifungal research and the partnership between Stony Brook University, the Long Island High Tech Incubator, and MicroRid Technologies Inc. place us in a very unique position to achieve these goals.