Transforming Rhinacanthin Analogues from Potent Anticancer Agents into Potent Antimalarial Agents

Abstract

Twenty-six novel naphthoquinone aliphatic esters were synthesized by esterification of 1,4-naphthoquinone alcohols with various aliphatic acids. The 1,4-naphthoquinone alcohols were prepared from 1-hydroxy-2-naphthoic acid in nine steps with excellent yields. Twenty-four of the novel synthetic naphthoquinone esters showed significant antimalarial activity with IC(50) values in the range of 0.03-16.63 microM. The length of the aliphatic chain and the presence of C-2' substituents on the propyl chain affected the activity. Interestingly, compounds 31 and 37 showed very good antimalarial activity and were not toxic to normal Vero cells, and the PTI values of 31 (>1990.38) and 37 (1825.94) are excellent. Both 31 and 37 showed potent inhibition against P. falciparum 3D7 cyt bc(1) and no inhibition on rat cyt bc(1). They showed IC(50) values in the nanomolar range, providing full inhibition of cyt bc(1) with one molecule inhibitor bound per cyt bc(1) monomer at the Q(o) site.

Synthesis and Cytotoxic Activity of a Small Naphthoquinone Library: First Synthesis of Juglonbutin

“…Only compound 4e showed the formation of ROS in the cells after treatment with dichlorodihydrofluorescein diacetate (DCFDA) and comparison with tert ‐butyl hydroperoxide (tBHP) as reference (Figure 5). Naphthoquinones 2c , 2f , 2g , and 2j showed higher inhibitory activity on topoisomerase II than the reference compound etoposide (see Table S5 in the Supporting Information), which led to the conclusion that topoisomerase II is the major target of these naphthoquinones, which is in good agreement with the inhibition of topoisomerases I and II reported in the literature 19,30–32…”

Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action

“…Mitochondrial cyt bc 1 from S. cerevisiae has been extensively used as a model for the highly homologous complexes from P. falciparum and other pathogens that are targeted by atovaquone 25,29,34,36 . The latter is a potent inhibitor of the yeast complex 25 .…”

Biological evaluation of hydroxynaphthoquinones as anti-malarials

“…One series contained an ester at the 3-hydroxy group of atovaquone, with nanomolar anti-malarial activity; addition of long side chains decreased activity [11]. A series of 26 compounds based on the structure of rhinacanthin, a naphthoquinone with anticancer properties, was synthesized [21]; two of these had nanomolar activity and inhibited the cytochrome bc1 complex of P. falciparum . Another four hydroxynaphthoquinones were synthesized in an attempt to circumvent resistance to atovaquone, which is mediated by mutations in the mitochondrial cytochrome b gene [13].…”