ABSTRACT
Synthesis of new 1-aryl-3-substituted propanol derivatives followed by structure-activity relationship, in silico drug-likeness, cytotoxicity, genotoxicity, in silico metabolism, in silico pharmacophore modeling, and in vivo studies led to the identification of compounds 22 and 23 with significant in vitro antiplasmodial activity against drug sensitive (D6 IC50 ≤ 0.19 µM) and multidrug resistant (FCR-3 IC50 ≤ 0.40 µM and C235 IC50 ≤ 0.28 µM) strains of Plasmodium falciparum. Adequate selectivity index and absence of genotoxicity was also observed. Notably, compound 22 displays excellent parasitemia reduction (98 ± 1%), and complete cure with all treated mice surviving through the entire period with no signs of toxicity. One important factor is the agreement between in vitro potency and in vivo studies. Target exploration was performed; this chemotype series exhibits an alternative antimalarial mechanism.
Subject(s)
Amino Alcohols/isolation & purification , Amino Alcohols/pharmacology , Antimalarials/isolation & purification , Antimalarials/pharmacology , Plasmodium falciparum/drug effects , Amino Alcohols/adverse effects , Amino Alcohols/therapeutic use , Animals , Antimalarials/adverse effects , Antimalarials/therapeutic use , Disease Models, Animal , Drug-Related Side Effects and Adverse Reactions/epidemiology , Drug-Related Side Effects and Adverse Reactions/pathology , Inhibitory Concentration 50 , Malaria, Falciparum/drug therapy , Mice , Structure-Activity Relationship , Survival Analysis , Treatment OutcomeABSTRACT
Piperazine and pyrrolidine derivatives were synthesised and evaluated for their capacity to inhibit the growth of Plasmodium falciparum chloroquine-resistant (FCR-3) strain in culture. The combined presence of a hydroxyl group, a propane chain and a fluor were shown to be crucial for the antiplasmodial activity. Five compounds of the aryl-alcohol series inhibited 50% of parasite growth at doses ≤10 µM. The most active compound 1-(4-fluoronaphthyl)-3-[4-(4-nitro-2-trifluoromethylphenyl)piperazin-1-yl] propan-1-ol was almost 20-40 times more active on P. falciparum (IC(50): 0.5 µM) than on tumorogenic and non-tumorogenic cells. In vivo it has a very weak effect; inhibiting 35% of parasite growth only, at 10 mg/kg/day against Plasmodium berghei infected mice without any impact on survival time. In silico molecular docking study and molecular electrostatic potential calculation revealed that this compound bound to the active site of Plasmodium plasmepsin II enzyme.
Subject(s)
Antimalarials/pharmacology , Malaria/drug therapy , Piperazines/pharmacology , Plasmodium berghei/drug effects , Plasmodium falciparum/drug effects , Pyrrolidines/pharmacology , Animals , Antimalarials/chemical synthesis , Antimalarials/chemistry , Antimalarials/therapeutic use , Cell Line, Tumor , Chlorocebus aethiops , Erythrocytes/parasitology , Female , Humans , Macrophages, Peritoneal/drug effects , Malaria/parasitology , Male , Mice , Mice, Inbred BALB C , Piperazines/chemical synthesis , Piperazines/chemistry , Piperazines/therapeutic use , Plasmodium berghei/growth & development , Plasmodium falciparum/growth & development , Pyrrolidines/chemical synthesis , Pyrrolidines/chemistry , Pyrrolidines/therapeutic use , Structure-Activity Relationship , Vero CellsABSTRACT
This paper describes the synthesis and in vitro antimalarial activity against a P. falciparum 3D7 strain of some new 1-aryl-3-substituted propanol derivatives. Twelve of the tested compounds showed an IC(50) lower than 1 microM. These compounds were also tested for cytotoxicity in murine J774 macrophages. The most active compounds were evaluated for in vivo activity against P. berghei in a 4-day suppressive test. Compound 12 inhibited more than 50% of parasite growth at a dose of 50 mg/kg/day. In addition, an FBIT test was performed to measure the ability to inhibit ferriprotoporphyrin biocrystallization. This data indicates that 1-aryl-3-substituted propanol derivatives hold promise as a new therapeutic option for the treatment of malaria.
