N-Cinnamoylated Chloroquine Analogues as Dual-Stage Antimalarial Leads

Abstract

The control of malaria is challenged by drug resistance, and new antimalarial drugs are needed. New drug discovery efforts include consideration of hybrid compounds as potential multitarget antimalarials. Previous work from our group has demonstrated that hybrid structures resulting from cinnamic acid conjugation with heterocyclic moieties from well-known antimalarials present improved antimalarial activity. Now, we report the synthesis and SAR analysis of an expanded series of cinnamic acid derivatives displaying remarkably high activities against both blood- and liver-stage malaria parasites. Two compounds judged most promising, based on their in vitro activity and druglikeness according to the Lipinski rules and Veber filter, were active in vivo against blood-stage rodent malaria parasites. Therefore, the compounds reported represent a new entry as promising dual-stage antimalarial leads.

“Recycling” Classical Drugs for Malaria

“…189b, 194 As already mentioned in the previous section, it was found that the compounds with the dipeptide spacer (170) inhibited in vitro both hemozoin formation and development of blood-stage P. falciparum, while compounds without the spacer (171) were better falcipain-2 (FP2) inhibitors; none of the compounds was a falcipain-3 (FP3) inhibitor. In order to obtain additional knowledge about the FP2 inhibitory capacity of the latter compounds, molecular docking and MD simulations were performed to predict the structures of the complexes between the compounds with or without the dipeptide linker and FP2 (PDB code: 3BPF) or FP3 (PDB code: 3BWK).…”

“…In the case of FP2, the shorter distance between the vinyl bond of the compounds without the linker and the Cys thiolate of the enzyme than for the compounds with the spacer is in line with the experimental observation that the former were better FP2 inhibitors. 194 While molecular docking combined with realistic molecular models is able to provide static information about the most favorable host−guest configurations, MD simulations can be used to gain knowledge on the evolution of the docked configurations with time. In fact, Gomes and co-workers showed that FP2 inhibitory activities measured experimentally could be correlated with the time evolution of the distance between the vinyl bond and the enzyme's Cys thiolate determined from classical MD simulation.…”

“…194 The hybrid that best reached the goal to exert antimalarial activity by inhibiting the two expected targets, i.e. hemozoin formation conferred by the CQ pharmacophore and P. falciparum cysteine protease through the electrophilic warhead of the cinnamic moiety, was 170a.…”

Recycling antimalarial leads for cancer: Antiproliferative properties of N-cinnamoyl chloroquine analogues

“…Compounds 4-10 were prepared following a straightforward low-cost synthetic pathway, previously reported, and the analytical and structural data were in agreement with formerly published data. 13,14 Compounds' antiproliferative properties against MKN-28 (gastric cancer), Caco-2 (colorectal adenocarcinoma), MCF-7 (breast cancer) and HFF-1 (human foreskin fibroblasts) cell lines were determined according to the National Cancer Institute (NCI, USA) procedure, which uses the protein-binding dye sulforhodamine B.…”

N -Cinnamoylated Aminoquinolines as Promising Antileishmanial Agents

“…To respond to those needs, we have tested the activity of cinnamic acid conjugates of the 8-aminoquinoline primaquine (PQ) and the 4-aminoquinoline chloroquine (CQ) against L. infantum. The rationale for these tests was that (i) these conjugates have been recently reported as interesting antimalarial leads (8)(9)(10) and (ii) PQ (compound 1) and CQ (compound 3) have proven activity against several protozoans, including visceralizing Leishmania (11)(12)(13)(14)(15).…”