Derivati diaminoalkiladamantana sa supstituisanim hinolinima kao inhibitori parazita Plasmodium falciparum i botulinum neurotoksina
Diaminoalkyladamantane derivatives with substituted quinolines as inhibitors of parasite Plasmodium falciparum and botulinum neurotoxin
Докторанд
Terzić-Jovanović, NatašaМентор
Šolaja, BogdanЧланови комисије
Milić, DraganaOpsenica, Igor
Đurković-Daković, Olgica
Метаподаци
Приказ свих података о дисертацијиСажетак
Rezime: Malarija je jedna od najrasprostranjenijih bolesti, koja preti približno polovini
svetske populacije i koja je u zemljama u razvoju glavni uzrok smrtnosti dece uzrasta do
5 godina. Nagli razvoj rezistentnih formi parazita na postojeće antimalarike stvara
potrebu za razvojem novih lekova. Jedna od strategija za razvoj novih lekova, kojom se
smanjuju troškovi i skraćuje vreme potrebno za pronalazak novih aktivnih supstanci je
hemijska modifikacaja postojećih hinolinskih antimalarika poznatog mehanizma
dejstva.
U okviru ove doktorske teze izvršena je sinteza serije aminohinolinskih derivata
kod koje su adamantanski fragmenti preko amido-aminskih i diaminskih premostnih
nizova povezani sa različito supstituisanim hinolinskim jezgrima. Određena je
antimalarijska aktivnost svih sintetisanih jedinjenja. Rezultati bioloških testova potvrdili
su antimalarijsku aktivnost, a dodatno je utvrđena i inhibitorna aktivnost pojedinih
derivata prema botulinum neurotoksinu tipa A (BoNT/A LC).
Bot...ulinum neurotoksini (BoNTs) sa letalnom dozom (LC50) od 1-5 ng/kg telesne
težine su najsmrtonosniji otrovi poznati čoveku. Zbog svoje velike toksičnosti, lakoće
proizvodnje i transporta svrstavaju se od Centra za kontrolu i prevenciju bolesti SAD u
A kategoriju agenasa sa najvećim rizikom za korišćenje u bioterorizmu. Nepostojanje
odobrenog farmakološkog pristupa za tretman intoksikacije, stvara veliku potrebu za
razvojem inhibitora BoNT.
U toku rada dobijeni su sledeći rezultati:
(i) Sintetisano je osam amido-adamantanskih aminohinolina (99a-d i 100a-d).
Svi sintetisani amidni derivati poseduju nedovoljno dobru in vitro antimalarijsku
aktivnost (IC50 = 6 - 1400 nM). Na osnovu indeksa rezistencije (IR) uočena je viša
aktivnost amido-adamantanskih aminohinolina prema CQS soju (D6) u poređenju sa
CQR (W2) i multirezistentnim (TM91C235) sojem. Najaktivnije jedinjenje iz ove serije pokazuje in vitro aktivnost prema CQS soju D6, 100a: IC90(D6) = 157 nM osam puta
nižu od aktivnosti CQ (IC90(D6) = 20 nM)...
Malaria is one of the most devastating diseases which threatens half the
world's population and remains a major cause of mortality among children aged < 5
years in developing countries. The wide-spread resistance of various strains to current
antimalarials potentiates the need for development of new drugs. One of the strategies
for the development of new therapeutics, that reduces costs and shortens the time
needed for the discovery of new active substances, is chemical modification of
quinoline-based drugs with known mechanism of action.
Antimalarial and BoNT/ LC inhibitory activities of variously substituted 4-
aminoquinolines coupled to adamantane carrier were described within this PhD thesis.
Botulinum neurotoxins (BoNTs) are the most potent of known toxins (LC50 = 1-
5 ng/kg). Due to ease of production, spreading and lethality BoNTs are listed as
category A biothreat agens by the U.S. Centers for Disease Control and Prevention
(CDC). The absence of an approved pharmacological appr...oach for the treatment of
intoxication, creates an urgent need to develop inhibitors BoNT.
The results are summarized as follows:
(i) Eight derivatives with an amide functionality linking the 4,7-ACQ moiety
to adamantane (99a-d and 100a-d) were synthesized. All synthesized compounds are
poorly active (IC50 = 6 - 1400 nM). Analysis of the resistance index (RI) showed that
compounds are more active against D6 strain than against the CQ-resistant W2 and
multidrug resistant TM91C235 strain. The most active amide within the series is eight
times less active (100a: IC90 (D6) = 157 nM) against the CQ- sensitive D6 strain than
CQ (IC90 (D6) = 20 nM).
(ii) The series of ten aminoquinoline derivatives in which the adamantane
fragment is connected to quinoline core through unbranched diamine linker was
synthesized (106a-d, 106i, 107a-107i and 107i). Eight out of ten synthetic derivatives exhibited better IC90 activity against CQ-sensitive D6 strain compared to CQ (1), seven
are more potent against multi-resistant C235 strain and one against MFQ-sensitive W2...
strain than MFQ (14).