Graduation Year

2015

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Chemistry

Degree Granting Department

Chemistry

Major Professor

Roman Manetsch, Ph.D.

Committee Member

Dennis Kyle Ph.D.

Committee Member

Mark McLaughlin Ph.D.

Committee Member

Jon Antilla Ph.D.

Keywords

Malaria, Quinolones, SAR, SPR

Abstract

Although Malaria rates are on the decline due to the efforts of the World Health Organization and other organizations dedicated to the eradication of this disease, a relaxed attitude towards the development of new antimalarial entities would be flawed. Due to the emergence of resistance in the parasite, the almost 50% world-wide reduction in malarial death rates that have been produced over the past 15 years are threatening to be lost

New drugs are urgently needed and our approach focuses on the re-evaluation and optimization of the historic antimalarial ICI 56,780. Due to its causal prophylactic activity, along with its ability to prevent transmission and potent blood schizonticidal activities, it was revisited with the hopes of first understanding which functionalities were responsible to the compound's activity. Secondly, we wanted to optimize the substituents in the 3, 6 and 7-positions. Finally and most importantly, we wanted to address the cross-resistance problem of the ICI 56,780 scaffold.

Initial, analogues showed the importance of the ester in facilitating the convergence of the RI towards 1. Although those analogues lost activity in W2, TM90-C2B, and Pb, they were our first glimpse at this important trend that was later exploited in our 3-halo-6-butyl-7-(2-phenoxyethoxy)quinolin-4(1H)-one and 3-halo-6-butyl-2-methyl-7-(2-phenoxyethoxy)quinolin-4(1H)-ones which showed RI values of < 5 for our best analogues. Although our lead compound 3-bromo-6-butyl-2-methyl-7-(2-phenoxyethoxy)quinolin-4(1H) one possessed decreased activities as compared to ICI 56,780 at 2.60 nM for W2, 12.2 nM for TM90-C2B and 2.12 nM for Pb, it had 100% inhibition of parasite development on day 6 PE in our scouting assay and 61% inhibition on day 6in our Thompson model, increased from the < 2% value given by the ICI 56,780.

Solubility and unfavorable in vivo stability were still major issues for this scaffold. Therefore, a series of piperazinyl 4(1H)-quinolones with greatly enhanced solubility were designed and tested in detailed structure activity relationships and structure property relationship studies. Initial results showed that 7-piperazinyl-4(1H)-quinolones possessed greatly increased solubilities when compared to ICI 56,780 analogues. Primarily, the linker length and the piperazine core was probed. This showed that compounds with a single carbon spacer were most active. Further testing of the 6-position gave methyl 6-methyl-4-oxo-7-((4-phenylpiperazin-1-yl)methyl)-1,4-dihydroquinoline-3-carboxylate with W2 and TM90-C2B values of 0.435 nM and 147 nM respectively. Substitution on the piperazinyl phenyl gave the most active compounds however the RI of >1500 was unacceptable. Because of this, 3-halo substituents were added to these quinolones with promising results. With RIs of < 3, the compounds were promising, however they were not active in vivo. However, methyl 6-methoxy-4-oxo-7-((4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)-1,4-dihydroquinoline-3-carboxylate and methyl 6-methyl-4-oxo-7-((4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)-1,4-dihydroquinoline-3-carboxylate both gave cures in our in vivo Thomson model.

These studies highlight the potential in using detailed structural activity and structural property studies to re-evaluate and optimize historic antimalarials. These studies have introduced a new generation of soluble 4(1H)-quinolones with high potency against P. falciparum.

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