Diaminoalkyladamantane derivatives with substituted quinolines as inhibitors of parasite Plasmodium falciparum and botulinum neurotoxin

Rezime: Malarija je jedna od najrasprostranjenijih bolesti, koja preti približno polovinisvetske populacije i koja je u zemljama u razvoju glavni uzrok smrtnosti dece uzrasta do5 godina. Nagli razvoj rezistentnih formi parazita na postojeće antimalarike stvarapotrebu za razvojem novih lekova. Jedna od strategija za razvoj novih lekova, kojom sesmanjuju troškovi i skraćuje vreme potrebno za pronalazak novih aktivnih supstanci jehemijska modifikacaja postojećih hinolinskih antimalarika poznatog mehanizmadejstva.U okviru ove doktorske teze izvršena je sinteza serije aminohinolinskih derivatakod koje su adamantanski fragmenti preko amido-aminskih i diaminskih premostnihnizova povezani sa različito supstituisanim hinolinskim jezgrima. Određena jeantimalarijska aktivnost svih sintetisanih jedinjenja. Rezultati bioloških testova potvrdilisu antimalarijsku aktivnost, a dodatno je utvrđena i inhibitorna aktivnost pojedinihderivata prema botulinum neurotoksinu tipa A (BoNT/A LC).Botulinum neurotoksini (BoNTs) sa letalnom dozom (LC50) od 1-5 ng/kg telesnetežine su najsmrtonosniji otrovi poznati čoveku. Zbog svoje velike toksičnosti, lakoćeproizvodnje i transporta svrstavaju se od Centra za kontrolu i prevenciju bolesti SAD uA kategoriju agenasa sa najvećim rizikom za korišćenje u bioterorizmu. Nepostojanjeodobrenog farmakološkog pristupa za tretman intoksikacije, stvara veliku potrebu zarazvojem 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 antimalarijskuaktivnost (IC50 = 6 - 1400 nM). Na osnovu indeksa rezistencije (IR) uočena je višaaktivnost amido-adamantanskih aminohinolina prema CQS soju (D6) u poređenju saCQR (W2) i multirezistentnim (TM91C235) sojem. Najaktivnije jedinjenje iz ove serije pokazuje in vitro aktivnost prema CQS soju D6, 100a: IC90(D6) = 157 nM osam putanižu od aktivnosti CQ (IC90(D6) = 20 nM)...Malaria is one of the most devastating diseases which threatens half theworld's population and remains a major cause of mortality among children aged < 5years in developing countries. The wide-spread resistance of various strains to currentantimalarials potentiates the need for development of new drugs. One of the strategiesfor the development of new therapeutics, that reduces costs and shortens the timeneeded for the discovery of new active substances, is chemical modification ofquinoline-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 ascategory A biothreat agens by the U.S. Centers for Disease Control and Prevention(CDC). The absence of an approved pharmacological approach for the treatment ofintoxication, 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 moietyto adamantane (99a-d and 100a-d) were synthesized. All synthesized compounds arepoorly active (IC50 = 6 - 1400 nM). Analysis of the resistance index (RI) showed thatcompounds are more active against D6 strain than against the CQ-resistant W2 andmultidrug resistant TM91C235 strain. The most active amide within the series is eighttimes less active (100a: IC90 (D6) = 157 nM) against the CQ- sensitive D6 strain thanCQ (IC90 (D6) = 20 nM).(ii) The series of ten aminoquinoline derivatives in which the adamantanefragment is connected to quinoline core through unbranched diamine linker wassynthesized (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), sevenare more potent against multi-resistant C235 strain and one against MFQ-sensitive W2...strain than MFQ (14)