Synthesis and biological evaluation of benzhydryl-based antiplasmodial agents possessing Plasmodium falciparum chloroquine resistance transporter (PfCRT) inhibitory activity

Autor: Robert L. Summers, Annette Habluetzel, Stefania Lamponi, Sandra Gemma, Rowena E. Martin, Sarah H. Shafik, Stefano Federico, Reto Caldelari, Donatella Taramelli, Luca Pozzetti, Giuseppe Campiani, Sarah D'Alessandro, Stefania Butini, Simone K. Babij, Nicola Relitti, Sofia Tapanelli
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Primaquine
Xenopus
Protozoan Proteins
Pharmacology
01 natural sciences
Mice
Parasitic Sensitivity Tests
Chloroquine
Drug Discovery
Protein Isoforms
Antimalarial Agent
Chloroquine resistance
Cytotoxicity
Mice
Inbred BALB C
0303 health sciences
Molecular Structure
biology
Chemistry
Drug Resistance
Microbial
Hep G2 Cells
General Medicine
Female
medicine.drug
PfCRT
Plasmodium falciparum
Chemosensitization
Small Molecule Libraries
Antimalarials
Structure-Activity Relationship
03 medical and health sciences
Anopheles
parasitic diseases
medicine
Gametocyte
Animals
Humans
Benzhydryl Compounds
Liver-stage antimalarial
030304 developmental biology
Xenopus oocytes
010405 organic chemistry
Clotrimazole
Organic Chemistry
Membrane Transport Proteins
Transporter
biology.organism_classification
0104 chemical sciences
Malaria
Drug Design
NIH 3T3 Cells
Popis: Due to the surge in resistance to common therapies, malaria remains a significant concern to human health worldwide. In chloroquine (CQ)-resistant (CQ-R) strains of Plasmodium falciparum, CQ and related drugs are effluxed from the parasite’s digestive vacuole (DV). This process is mediated by mutant isoforms of a protein called CQ resistance transporter (PfCRT). CQ-R strains can be partially re-sensitized to CQ by verapamil (VP), primaquine (PQ) and other compounds, and this has been shown to be due to the ability of these molecules to inhibit drug transport via PfCRT. We have previously developed a series of clotrimazole (CLT)-based antimalarial agents that possess inhibitory activity against PfCRT (4a,b). In our endeavor to develop novel PfCRT inhibitors, and to perform a structure-activity relationship analysis, we synthesized a new library of analogues. When the benzhydryl system was linked to a 4-aminoquinoline group (5a-f) the resulting compounds exhibited good cytotoxicity against both CQ-R and CQ-S strains of P. falciparum. The most potent inhibitory activity against the PfCRT-mediated transport of CQ was obtained with compound 5k. When compared to the reference compound, benzhydryl analogues of PQ (5i,j) showed a similar activity against blood-stage parasites, and a stronger in vitro potency against liver-stage parasites. Unfortunately, in the in vivo transmission blocking assays, 5i,j were inactive against gametocytes.
Databáze: OpenAIRE
Externí odkaz: