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Design and synthesis of antimalarial drugs based on a chloroquine scaffold

Dissertation
Author: Steven James Burgess
Abstract:
There are between 350 and 500 million clinical cases of malaria each year, and over 1 million deaths, with pregnant women and children under the age of 5 being most at risk. Chloroquine (CQ) became the preferred drug to treat malaria in the late 1940s, but is now rendered mostly ineffective in many parts of the world, due to widespread CQ resistance by the malaria parasite. All other malaria treatments suffer from some drawbacks, which include development of resistance, side effects including toxicity, risk for pregnant women and young children, and high cost. Some existing, non-antimalarial, drugs have been found to reverse the effects of resistance in chloroquine-resistant (CQR) Plasmodium, when co-administered with CQ. However these drugs, called reversal agents (RAs), were designed for other targets, and suffer from side effects and the need for high dose. Compound PL01 was designed to have both a CQ-like and a RA-like moiety, which resulted in in vitro IC50 values of 2.9 nM against chloroquine sensitive (CQS) Plasmodium falciparum, the malaria parasite, and 5.3 nM against CQR P. falciparum. This is an improvement over CQ's IC50 s of 6.9 nM and 102 nM against the same malaria strains. Subsequent development produced a number of analogues with IC50 values lower than CQ, with the best (PL69) having a 0.9 nM IC50 against CQS and 1.6 nM against CQR P. falciparum. This molecule is active in vivo, against P. berghei in mice. A dose of 45.7 mg/Kg/day for 4 days (the molar equivalent dose to 30 mg/Kg/day of CQ) resulted in <0.1% parasitemia after 30 days in 9 out of 10 surviving mice. Mechanistic investigations indicated that the CQ-like moiety acts like CQ against the parasite, and that the RA-like moiety acts as a reversal agent. An accumulation experiment showed uptake by the parasite was reversible by raising the pH of the digestive vacuole (DV). When viewed under a microscope, an enlarged DV with reduced hemozoin formation was apparent in drug-treated parasites. All these results support the hypothetical mechanism, and hence the design of these drugs against CQR malaria.

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Full document contains 155 pages
Abstract: There are between 350 and 500 million clinical cases of malaria each year, and over 1 million deaths, with pregnant women and children under the age of 5 being most at risk. Chloroquine (CQ) became the preferred drug to treat malaria in the late 1940s, but is now rendered mostly ineffective in many parts of the world, due to widespread CQ resistance by the malaria parasite. All other malaria treatments suffer from some drawbacks, which include development of resistance, side effects including toxicity, risk for pregnant women and young children, and high cost. Some existing, non-antimalarial, drugs have been found to reverse the effects of resistance in chloroquine-resistant (CQR) Plasmodium, when co-administered with CQ. However these drugs, called reversal agents (RAs), were designed for other targets, and suffer from side effects and the need for high dose. Compound PL01 was designed to have both a CQ-like and a RA-like moiety, which resulted in in vitro IC50 values of 2.9 nM against chloroquine sensitive (CQS) Plasmodium falciparum, the malaria parasite, and 5.3 nM against CQR P. falciparum. This is an improvement over CQ's IC50 s of 6.9 nM and 102 nM against the same malaria strains. Subsequent development produced a number of analogues with IC50 values lower than CQ, with the best (PL69) having a 0.9 nM IC50 against CQS and 1.6 nM against CQR P. falciparum. This molecule is active in vivo, against P. berghei in mice. A dose of 45.7 mg/Kg/day for 4 days (the molar equivalent dose to 30 mg/Kg/day of CQ) resulted in <0.1% parasitemia after 30 days in 9 out of 10 surviving mice. Mechanistic investigations indicated that the CQ-like moiety acts like CQ against the parasite, and that the RA-like moiety acts as a reversal agent. An accumulation experiment showed uptake by the parasite was reversible by raising the pH of the digestive vacuole (DV). When viewed under a microscope, an enlarged DV with reduced hemozoin formation was apparent in drug-treated parasites. All these results support the hypothetical mechanism, and hence the design of these drugs against CQR malaria.