Multitarget anti-Alzheimer and chemotherapeutic compounds

Design and synthesis of novel disease-modifying anti-Alzheimer compounds

The elusiveness of efficacious drugs against Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder, greatly accounts for its fatal consequences. Only five drugs have been approved for the palliative treatment of AD, whereas several drug candidates directed to β-amyloid (Aβ) peptide, thought to be the main culprit of the AD, have failed to show efficacy in advanced clinical trials. This has led to the credence that Aβ is just one of the causes of AD, which might involve a complex pathological network where several key targets are jointly responsible for neurodegeneration. Accordingly, AD could be efficiently treated only through the simultaneous modulation of several key targets. We are synthesizing novel drug candidates, which have been rationally designed to hit multiple key biological targets involved in the pathological network of AD such as BACE-1, Aβ and tau aggregation, MAO-B, oxidative stress, and cholinesterases, among others.

Design and synthesis of novel chemotherapeutic agents

Human African Trypanosomiasis, caused by Trypanosoma brucei, and malaria, caused by Plasmodium species, are major protozoan parasitic diseases in developing countries, where they cause over 30,000 and 1-3 million deaths annually, respectively. Conventional treatments are inadequate due to toxicity and resistance issues. Thus, there is a desperate need for new and better drugs. We have developed several classes of compounds that display nanomolar to low micromolar anti-protozoan potencies and favorable parasite/mammalian cell selectivity indices. These compounds arise from the phenotypic screening of aminoquinoline-based compounds or from target-based rational design, in the latter case using a homology model of the target protein (Plasmodium falciparum glucose-6-phosphate dehydrogenase) and exploiting key structural differences between the active sites of the parasite and human enzymes.