Design and Synthesis of Enzyme Inhibitors as Anti-infective, Anticancer, and Neuroprotective Agents

Enzyme inhibition is an important strategy in drug development. Enzyme inhibitors have been used as therapeutic agents in the treatment of various diseases. Three enzymes dihydrofolate reductase (DHFR), phosphatidyl-inositol-3-kinase (PI-3K) and cathepsin B are targeted to develop anti-infective, anticancer and neuroprotective agents. Hospital and community-acquired, complicated skin and soft tissue infections, often attributed to Staphylococcus aureus and Streptococcus pyogenes, present a significant health burden that is associated with increased health care costs and mortality. Optimized propargyl-linked antifolates containing a key pyridyl substituent display antibacterial activity against both methicillin-resistant S. aureus and S. pyogenes at MIC values below 0.1 μg/mL and minimal cytotoxicity against mammalian cells. Candida glabrata and Candida albicans the causative agents in an increasing number of systemic fungal infections, are insensitive to many clinically used antifungal agents and therefore a compelling target for new drug discovery. Based on structural data, a series of propargyl-linked antifolates have been designed and synthesized to target both the organisms. The lead compounds have MIC values of 1 μg/mL against both the organisms making the folate pathway viable to treat fungal infections. Bacillus anthracis, the causative agent of anthrax, was also targeted with propargyl linked antifolates resulting in an inhibitor with nano molar potency.;Steroidal chemistry was utilized to make simplified analogs of complex natural products wortmannin and viridin as phosphoinositide-3-kinases (PI3K) inhibitors that have potent anticancer properties. This chemistry was then extended to Wieland-Miescher ketone to synthesize non-steroidal PI3K inhibitors. The weak cathepsin B and L inhibitor Z-Phe-Ala-diazomethylketone (PADK) enhances lysosomal cathepsin levels at low concentration, thereby eliciting protective clearance of PHF-tau and Aβ42 in hippocampus and other brain regions. We utilized PADK as a departure point to develop non-peptidic structures with the hydroxyethyl isostere. The first-in-class modulators SD1002 and SD1003 exhibit improved levels of cathepsin up-regulation, but almost complete removal of cathepsin inhibitory properties as compared to PADK. Isomers of the lead compound SD1002 were synthesized and the modulatory activity was determined to be stereo-selective. In addition, the lead compound was tested in transgenic mice with results indicating protection against AD-type protein accumulation pathology.