Six new ether phospholipid analogues encompassing constituents
from cashew nut shell liquid as the lipid portion were synthesized
in an effort to valorize byproducts of the cashew industry toward
the generation of potent compounds against Chagas disease. Anacardic
acids, cardanols, and cardols were used as the lipid portions and
choline as the polar headgroup. The compounds were evaluated for their in vitro antiparasitic activity against different developmental
stages of Trypanosoma cruzi. Compounds 16 and 17 were found to be the most potent against T. cruzi epimastigotes, trypomastigotes, and intracellular
amastigotes exhibiting selectivity indices against the latter 32-fold
and 7-fold higher than current drug benznidazole, respectively. Hence,
four out of six analogues can be considered as hit-compounds toward
the sustainable development of new treatments for Chagas disease,
based on inexpensive agro-waste material.
This study aimed to estimate the absorption, distribution, metabolism and excretion
(ADME) properties and safety of LDT5, a lead compound for oral treatment of benign
prostatic hyperplasia that has previously been characterized as a multi-target
antagonist of α1A-, α1D-adrenoceptors and 5-HT1A
receptors. The preclinical characterization of this compound comprised the evaluation
of its in vitro properties, including plasma, microsomal and
hepatocytes stability, cytochrome P450 metabolism and inhibition, plasma protein
binding, and permeability using MDCK-MDR1 cells. De-risking and preliminary safety
pharmacology assays were performed through screening of 44 off-target receptors and
in vivo tests in mice (rota-rod and single dose toxicity). LDT5
is stable in rat and human plasma, human liver microsomes and hepatocytes, but
unstable in rat liver microsomes and hepatocytes (half-life of 11 min). LDT5 is
highly permeable across the MDCK-MDR1 monolayer (Papp ∼32×10-6
cm/s), indicating good intestinal absorption and putative brain penetration. LDT5 is
not extensively protein-bound and is a substrate of human CYP2D6 and CYP2C19 but not
of CYP3A4 (half-life >60 min), and did not significantly influence the activities
of any of the human cytochrome P450 isoforms screened. LDT5 was considered safe
albeit new studies are necessary to rule out putative central adverse effects through
D2, 5-HT1A and 5-HT2B receptors, after chronic
use. This work highlights the drug-likeness properties of LDT5 and supports its
further preclinical development.
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