Investigation into novel thiophene- and furan-based 4-amino-7-chloroquinolines afforded antimalarials that cure mice

Opsenica, Igor; Verbić, Tatjana Ž.; Tot, Mikloš; Sciotti, Richard J.; Pybus, Brandon; Djurković–Djaković, Olgica; Slavic, Ksenija; Šolaja, Bogdan A.

doi:10.1016/j.bmc.2015.02.061

Cited by 20 publications

(23 citation statements)

References 29 publications

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“…FClAQ1 even afforded complete cure. Such discordance has been previously reported for some thiophene-and furan-based aminoquinolines synthesized by the same group [24]. The discrepancy between in vitro and in vivo effects suggests that the antimalarial efficacy of such compounds is due to their metabolites, rather than the compounds themselves.…”

Section: Discussionmentioning

confidence: 64%

Examination of the antimalarial potential of experimental aminoquinolines: poor in vitro effect does not preclude in vivo efficacy

Srbljanović

Štajner

Konstantinović

et al. 2017

International Journal of Antimicrobial Agents

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Malaria remains a major disease in the developing world and globally is the most important parasitic disease causing significant morbidity and mortality. Because of widespread resistance to conventional antimalarials, including chloroquine (CQ), new drugs are urgently needed. Here we report on the antimalarial efficacy, both in vitro and in vivo, of a series of aminoquinoline derivatives with adamantane or benzothiophene as a carrier. In vitro efficacy was evaluated by a lactate dehydrogenase (LDH) assay in cultures of a CQ-sensitive (3D7) and CQ-resistant (Dd2) strain of Plasmodium falciparum. Of a series of 26 screened compounds, 12 that exerted a growth inhibition rate of ≥50% were further examined in vitro to determine the 50% inhibitory concentration (IC) values. Nine compounds shown in preliminary experiments to be non-toxic in vivo were evaluated in C57BL/6 mice infected with Plasmodium berghei ANKA strain using a modified Thompson test. All nine compounds examined in vivo prolonged the survival of treated versus untreated mice, four of which afforded ≥60% survival. Most notably, two of these compounds, both with the adamantane carrier, afforded complete cure (100% survival and parasite clearance). Interestingly, one of these compounds had no in vitro effect against the CQ-resistant P. falciparum strain. Better in vivo compared with in vitro results suggest a role for compound metabolites rather than the compounds themselves. The results presented here point to adamantane as a carrier that enhances the antimalarial potential of aminoquinolines.

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Section: Discussionmentioning

confidence: 64%

Examination of the antimalarial potential of experimental aminoquinolines: poor in vitro effect does not preclude in vivo efficacy

Srbljanović

Štajner

Konstantinović

et al. 2017

International Journal of Antimicrobial Agents

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“…As the isomeric products 7 and 8 could be easily separated, we proceeded with further transformations. Vinyl bromides 7 and 8 and the previously synthesized thiepine 4 were successfully coupled with a series of arylboronic acids under Suzuki cross‐coupling reaction conditions, affording compounds 9 – 18 in moderate‐to‐excellent yields (Scheme ). The compound 7 was coupled with thiophenols via the palladium‐catalyzed reaction, using the 1,1′‐bis(diphenylphosphino)ferrocene (dppf) as a ligand, as shown in the Scheme .…”

Section: Resultsmentioning

confidence: 99%

Synthesis and anti‐Candida activity of novel benzothiepino[3,2‐c]pyridine derivatives

et al. 2016

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A novel series of thiepine derivatives were synthesized and evaluated as potential antimicrobials. All the synthesized compounds were evaluated for their antimicrobial activities in vitro against the fungi Candida albicans (ATCC 10231), C. parapsilosis (clinical isolate), Gram-negative bacterium Pseudomonas aeruginosa (ATCC 44752), and Gram-positive bacterium Staphylococcus aureus (ATCC 25923). Synthesized compounds showed higher antifungal activity than antibacterial activity, indicating that they could be used as selective antimicrobials. Selected thiepines efficiently inhibited Candida hyphae formation, a trait necessary for their pathogenicity. Thiepine 8-phenyl[1]benzothiepino[3,2-c]pyridine (16) efficiently killed Candida albicans at 15.6 μg/mL and showed no embryotoxicity at 75 μg/mL. Derivative 8-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl][1]benzothiepino[3,2-c]pyridine (23) caused significant hemolysis and in vitro DNA interaction. The position of the phenyl ring was essential for the antifungal activity, while the electronic effects of the substituents did not significantly influence activity. Results obtained from in vivo embryotoxicity on zebrafish (Danio rerio) encourage further structure optimizations.

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“…Now, we report on the efficacy of aminoquinolines coupled to benzothiophene and thiophene rings in inhibiting Plasmodium falciparum parasite growth and compare the obtained results with CQ and previously reported related thiophene and benzothiophene-based 4-amino-7-chloroquinoline derivatives [ 27 , 28 ], as well as other antimalarial benzothiophene derivatives.…”

Section: Introductionmentioning

confidence: 84%

Antimalarials with Benzothiophene Moieties as Aminoquinoline Partners

Konstantinović

Videnović²,

Srbljanović

et al. 2017

Molecules

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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.

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Investigation into novel thiophene- and furan-based 4-amino-7-chloroquinolines afforded antimalarials that cure mice

Cited by 20 publications

References 29 publications

Examination of the antimalarial potential of experimental aminoquinolines: poor in vitro effect does not preclude in vivo efficacy

Examination of the antimalarial potential of experimental aminoquinolines: poor in vitro effect does not preclude in vivo efficacy

Synthesis and anti‐Candida activity of novel benzothiepino[3,2‐c]pyridine derivatives

Antimalarials with Benzothiophene Moieties as Aminoquinoline Partners

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