Transforming rhinacanthin analogues from potent anticancer agents into potent antimalarial agents.
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.
Kongkathip
Ngampong
N
Natural Products and Organic Synthesis Research Unit (NPOS), Department of Chemistry and Center for Innovation in Chemistry, Faculty of Science, Kasetsart University, Jatujak, Bangkok 10900, Thailand. fscinpk@ku.ac.th
Pradidphol
Narathip
N
Hasitapan
Komkrit
K
Grigg
Ronald
R
Kao
Wei-Chun
WC
Hunte
Carola
C
Fisher
Nicholas
N
Warman
Ashley J
AJ
Biagini
Giancarlo A
GA
Kongsaeree
Palangpon
P
Chuawong
Pitak
P
Kongkathip
Boonsong
B
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors; D004912:Erythrocytes / Q000187:drug effects; D020128:Inhibitory Concentration 50; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D051336:Mitochondrial Membranes / Q000187:drug effects; D009285:Naphthoquinones / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D012441:Saccharomyces cerevisiae / Q000254:growth & development; D013329:Structure-Activity Relationship; D014709:Vero Cells
D000962:Antimalarials; D000970:Antineoplastic Agents; D009285:Naphthoquinones; D014450:Electron Transport Complex III; C035342:1,4-naphthoquinone