Antimalarials with Benzothiophene Moieties as Aminoquinoline Partners

Abstract

Malaria is a severe and life-threatening disease caused by Plasmodium parasites that are spread to humans through bites of infected Anopheles mosquitoes. Here, we report on the efficacy of aminoquinolines coupled to benzothiophene and thiophene rings in inhibiting Plasmodium falciparum parasite growth. Synthesized compounds were evaluated for their antimalarial activity and toxicity, in vitro and in mice. Benzothiophenes presented in this paper showed improved activities against a chloroquine susceptible (CQS) strain, with potencies of IC50 = 6 nM, and cured 5/5 Plasmodium berghei infected mice when dosed orally at 160 mg/kg/day × 3 days. In the benzothiophene series, the examined antiplasmodials were more active against the CQS strain D6, than against strains chloroquine resistant (CQR) W2 and multidrug-resistant (MDR) TM91C235. For the thiophene series, a very interesting feature was revealed: hypersensitivity to the CQR strains, resistance index (RI) of <1. This is in sharp contrast to chloroquine, indicating that further development of the series would provide us with more potent antimalarials against CQR strains.

Quinolines and Quinolones as Antibacterial, Antifungal, Anti-virulence, Antiviral and Anti-parasitic Agents

“…Addition of aromatic ring, elongation of diaminoalkyl linker, and replacement of F-atom with CN-group (74-76, Fig. 11) enhance active against CQ resistant strain (Konstantinovic et al 2017). The most active benzothiophene derivate 77 cured mice infected with P. berghei when dosed orally (Fig.…”

“…While cutaneous leishmaniasis is the most common form of the disease, visceral leishmaniasis is the most serious and almost always fatal if untreated. Based on the assumption that similar chemotypes could be active against related pathogens, broad series of quinoline-like structures (Woodring et al 2015), and quinolines (Baragana et al 2015;Devine et al 2015;Konstantinovic et al 2017;Solaja et al 2008) were examined simultaneously as antimalarial, antileishmaniasis and antitrypanosomal agents, including application in combination therapy (Wijnant et al 2017).…”

New Steroidal 4-Aminoquinolines Antagonize Botulinum Neurotoxin Serotype A in Mouse Embryonic Stem Cell Derived Motor Neurons in Postintoxication Model

“… a Results are given as mean value of three independent experiments. b Syntheses of compounds 36 , 46 , 86 , 87 , 91 , 93 , 96 and 101 were reported in our previous work. 31 Syntheses of compounds 102 – 106 were reported in our previous work. 32 c Experimental Log D using reversed phase thin-layer chromatography at pH=1 (MeOH/HCl (70/30)) or pH=10 (acetone/NH 3 /H 2 O (85/5/10)). d Experimental Log D in octanol/TBS buffer at pH=7.3 using shake flask method. e Compound 24 was tested at 8 and 16 μM in pre-intoxication model and at 16 μM in 30 minutes post-intoxication model only; f In previous test the inhibition was 95.46% and K i = 0.285OM.…”

Synthesis of a New Class of Spirooxindole–Benzo[b]Thiophene-Based Molecules as Acetylcholinesterase Inhibitors

“…Benzothiophene privilege structure is among the sulfur containing fused herterocycles which are interesting in drug discovery [ 18 ]. Many lead compounds having this nucleus possess divergent pharmaceutical activities, allowing them to act as anti-inflammatory, anti-cancer, anti-diabetic, anti-oxidant, anti-microbial, anti-convulsant agents, anti-tubercular, and many more [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ].…”