Lead Optimization of Second-Generation Acridones as Broad-Spectrum Antimalarials

Abstract

The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. With increasing drug resistance and the absence of a clinically available vaccine, there is an urgent need for novel, affordable, and safe drugs for prevention and treatment of malaria. Previously we described a novel antimalarial acridone chemotype that is potent against both blood-stage and liver-stage malaria parasites. Here we describe an optimization process that has produced a second-generation acridone series with significant improvements in efficacy, metabolic stability, pharmacokinetics, and safety profiles. These findings highlight the therapeutic potential of dualstage targeting acridones as novel drug candidates for further preclinical development.

New Scalable Synthetic Routes to ELQ-300, ELQ-316, and Other Antiparasitic Quinolones

“…30 The copper-mediated coupling of 4-trifluoromethoxyphenol 3 and ethyl 2-(4-bromophenyl)acetate 11 with copper(I) chloride (CuCl), N,N-dimethylglycine (DMG) as a copper(I) chloride chelator, and potassium carbonate (K 2 CO 3 ) in DMF at 160 °C for 90 min afforded the diaryl ether 12 (Scheme 3). 31,32 The reaction was monitored by GC−MS and was determined to be complete when 11 was consumed. The product 12 was isolated with a yield of 48− 60% by high vacuum distillation, a method that facilitated the nearly complete removal of copper.…”

“…Moreover, process safety for the synthesis of aryl(TMP)iodonium salts has been evaluated, including thermal stability of intermediates, and the synthesis was deemed safe within the operating temperature window. 32 Based on the cost and availability of starting materials, aryl iodide 15 was selected as one of the coupling partners (Scheme 4). Large-scale oxidation of 15 proceeded smoothly under slightly modified literature conditions to deliver >200 g of unsymmetrical diaryliodonium salt 16 in 84% yield.…”

(Trifluoromethoxy)Phenylboronic Acids: Structures, Properties, and Antibacterial Activity

“…The syntheses of all isomers of (trifluoromethoxy)phenylboronic acids have been previously reported [ 13 , 14 , 15 ]. The title compounds have been numerously used in synthetic applications, mostly enabling the introduction of the trifluoromethoxyphenyl fragment [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ].…”

Inibidores de Desmetilase Lisina-Específica 1 (LSD1) como candidatos a agentes antineoplásicos

“…Dentre os métodos do CADD estão o ancoramento molecular (docking) e a triagem virtual (virtual screening) que foram as técnicas abordadas neste trabalho. Ressalta-se, contudo, que em todos os casos, as propriedades biológicas devem ser determinadas experimentalmente, sendo necessário a utilização de ensaios padronizados e validados com alta qualidade (KANCHARLA et al, 2020;SCAPIN et al, 2018;GUIDO et al, 2010).…”

“…No geral, as moléculas também podem ser estudadas para avaliar variedade de outras ações, a fim de estabelecer o seu mecanismo de ação e seletividade. Isso tem a vantagem de demonstrar efeitos tóxicos inesperados e, em certas ocasiões, revelar uma ação terapêutica não prevista anteriormente (KANCHARLA et al, 2020;SCAPIN et al, 2018;HUGLES et al, 2011;BARREIRO, 2002).…”