Publications by authors named "Vivian Padin-Irizarry"

Preclinical and clinical development of numerous small molecules is prevented by their poor aqueous solubility, limited absorption, and oral bioavailability. Herein, we disclose a general prodrug approach that converts promising lead compounds into aminoalkoxycarbonyloxymethyl (amino AOCOM) ether-substituted analogues that display significantly improved aqueous solubility and enhanced oral bioavailability, restoring key requirements typical for drug candidate profiles. The prodrug is completely independent of biotransformations and animal-independent because it becomes an active compound via a pH-triggered intramolecular cyclization-elimination reaction.

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During the past decade, artemisinin as an antimalarial has been in the spotlight, in part due to the Nobel Prize in Physiology or Medicine awarded to Tu Youyou. While many studies have been completed detailing the significant increase in activity resulting from the dimerization of natural product artemisinin, activity increases unaccounted for by the peroxide bridge have yet to be researched. Here we outline the synthesis and testing for antimalarial activity of artemisinin dimers in which the peroxide bridge in one-half of the dimer is reduced, resulting in a dimer with one active and one deactivated artemisinin moiety.

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Article Synopsis
  • New amino-artemisinins like artemiside and artemisone show strong activity against late-stage malaria gametocytes and work well with methylene blue, enhancing treatment effectiveness.
  • Researchers have synthesized new derivatives from DHA-piperazine, expanding the range of amino-artemisinins for potential therapies against both asexual and sexual blood stages of malaria.
  • These new compounds not only demonstrate higher potency than existing medicines like artemiside and artemisone but also show promise in effectively targeting artemisinin-resistant malaria strains, paving the way for innovative combination therapies.
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  • Plasmodium parasites face oxidative stress throughout their life cycle, relying on antioxidants like glutathione (GSH) and thioredoxin (Trx) to mitigate damage.
  • Disrupting specific genes involved in GSH production or regeneration leads to reduced GSH levels, growth deficits, and noticeable changes in parasite morphology, including smaller size and more cytoplasmic vacuoles compared to wild type.
  • Despite the reduced GSH impacting nuclear DNA damage and oxidative stress responses, the mutant parasites exhibit increased expression of genes for detoxification and DNA synthesis, hinting at adaptive strategies to survive and proliferate.
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