@conference{
author = "Srbljanović, Jelena and Štajner, Tijana and Bauman, Neda and Lijeskić, Olivera and Opsenica, Igor and Šolaja, Bogdan and Bobić, Branko",
year = "2023",
abstract = "With an estimated 247 million cases annually and 619.000 deaths (in 2021) malaria remains a major
disease of the developing world and globally the most important parasitic disease. Because of
widespread resistance to available antimalarials including chloroquine (CQ) and its derivatives, new
drugs are urgently needed. Here we report on the antimalarial efficacy of new 4-aminoquinoline
derivatives, with modifications at the linker and at the quinoline nucleus.
In vitro screening was performed by the lactate dehydrogenase assay, based on measurement of the
plasmodial lactate dehydrogenase activity in both a CQ-sensitive (3D7) and a CQ-resistant (Dd2)
strain of Plasmodium falciparum, with a CQ as a control. In vivo antimalarial activity was investigated
in C57BL/6 mice infected with Plasmodium berghei ANKA strain by the modified Thompson test.
Compounds were first tested for toxicity. A total of 37 compounds were screened in vitro. Of the 22
that passed the first screening, 18 had IC50 values lower than CQ in the Dd2 strain while only one
was efficient in the 3D7 strain. However, even 15 compounds showed in vivo activity, significantly
(P<0.05) prolonging survival of treated vs. untreated mice. Among these, seven compounds afforded
the survival of 20–100% of treated mice up to Day 31, with or without the detection of parasites
in peripheral blood.
Most importantly, three of these, including ClAQ1, FClAQ1 and ClAQ8, afforded survival of 100% of
animals, the first two at 80 and 160 mg/kg/day and the last only at 160 mg/kg/day.Survival was associated with complete parasite clearance, as shown by both microscopy and qPCR.
Of note, continuous monitoring of parasitemia allowed the observation of a potentially important
phenomenon, that a number of compounds were able to confer resistance to cerebral malaria and
afford a switch to hyperparasitaemia to mice prone to the neurological syndrome.
By comparing the antimalarial activity of this group of novel compounds, we found that even minor
structural modifications substantially affect activity. The results of this extensive study are important,
as they may guide future work involving structural modifications of aminoquinolines, and as a contribution
to the knowledge in the field of malarial chemotherapy., Malarija ostaje globalno najznačajnija parazitska infekcija sa procenjenih 247 miliona slučajeva
i 619.000 smrtnih slučajeva godišnje (2021.). Zbog široko rasprostranjene rezistencije na dostupne
antimalarike, uključujući hlorokvin (CQ) i njegove derivate, hitno su potrebni novi lekovi.
U ovom istraživanju ispitana je potencijalna antimalarijska aktivnost 37 novosintetisanih aminohinolina
sa hemijskim modifikacijama na aminohinolinskom jezgru i bočnom lancu. In vitro skrining aktivnosti
jedinjenja vršen je kolorimetrijskim esejom laktat dehidrogenaze na dva soja Plasmodium falciparum,
osetljivim (3D7) i rezistentnim (Dd2) na CQ, uz CQ kao pozitivnu kontrolu. Aktivnost u in
vivo sistemu je ispitana na ženkama miševa soja C57Bl/6 inficiranim ANKA sojem Plasmodium berghei
primenom modifikovanog Thompson-ovog testa. Ispitivanju aktivnosti jedinjenja prethodila je
faza kliničkog praćenja zdravih životinja terapiranih eksperimentalnim jedinjenjima. Od 37 jedinjenja
ispitanih u fazi in vitro skrininga, 22 koja su inhibirala ≥50% rast bar jednog od dva soja P. falciparum
odabrana su za titraciju do IC50 vrednosti.
Prema soju rezistentnom na CQ, 18 jedinjenja se pokazalo aktivnijim od CQ, dok je među njima samo
jedno jedinjenje bilo aktivnije i prema osetljivom soju. Čak 15 jedinjenja ispitanih u in vivo sistemu
značajno je produžilo život inficiranim životinjama u odnosu na kontrolnu grupu (P < 0.05).
Među njima, sedam jedinjenja je omogućilo preživljavanje 20–100% tretiranih miševa do dana 31, sa
ili bez nalaza parazita u perifernoj krvi. Posebno treba istaći tri jedinjenja koja su dovela do izlečenja
svih tretiranih životinja, ClAQ1 i FClAQ1 (80 i 160 mg/kg/dan) i ClAQ8 (160 mg/kg/dan).Preživljavanje je bilo praćeno i kompletnim klirensom parazita što je dokazano mikroskopskim pregledom
razmaza kao i qPCR analizom krvi i tkiva jetre preživelih životinja. Važno je pomenuti da
je kontinuirano praćenje parazitemije svih tretiranih miševa omogućilo da se zapazi potencijalno
značajan fenomen.
Naime, neka jedinjenja su omogućila da miševi postanu otporni na razvoj cerebralne malarije
i uzrokovala da miševi skloni razvoju neurološkog sindroma tolerišu preživljavanje sa izuzetno velikim
brojem parazita. Poređenjem antimalarijske aktivnosti novosintetisanih aminohinolina uočeno je da
i male strukturne promene u velikoj meri menjaju aktivnost. Rezultati ovog opsežnog istraživanja
su od značaja za buduća istraživanja strukturne modifikacije aminohinolina i doprinose proširenju
znanja u oblasti hemioterapije malarije.",
publisher = "Belgrade: Serbian Society for Microbiology",
journal = "23 UMS Series "Emerging infectious diseases: Are we ready for new evolutionary challenges?”, 30 March - 01 April, 2023, Belgrade, Serbia – E Abstract Book",
title = "Experimental treatment of malaria – new perspectives, Eksperimentalna terapija malarije – novi vidici",
pages = "92-89",
url = "https://hdl.handle.net/21.15107/rcub_rimi_1453"
}
