During the erythrocyte stage, malaria parasite invade the red blood cell of human host, digest and degrade a huge amount of hemoglobin as a source of amino acids, consequently releasing toxic heme as a by product.7 Heme detoxification crucial for parasite sur- vival is a unique non-enzymatic efficient process characterized by conversion of free heme into non-toxic crystalline pigment hemo- zoin.8 CQ and other related drugs block the heme detoxification
⇑ Corresponding author. Tel.: +91 522 221 2411x4332; fax: +91 522 262 3405.
E-mail addresses: prem_chauhan_2000@yahoo.com, premsc58@hotmail.com (P.M.S. Chauhan).
0960-894X/$ - see front matter Ó 2010 Published by Elsevier Ltd. doi:10.1016/j.bmcl.2010.09.107
Ó 2010 Published by Elsevier Ltd.
process, thus substantial build up of heme lead to the parasite death.9 Despite the persistent heavy drug pressure of CQ for several decades, the delayed emergence of resistance to CQ is considered due to the complexity of digestive vacuole environment and the immutable nature of heme target. Multiple point mutations in
P. falciparum chloroquine resistance transporter protein (pfcrt) con- ferred resistance to CQ characterized by the substantially reduced accumulation of CQ level in food vacuole. Interaction of CQ with pfcrt induces resistance very slowly to P. falciparum owing to the com- plexity in amino acid substitutions in pfcrt.10
Cl
HN
N
HN
N CQ, 1 AQ, 2
N
HO NH
N
CF3
CF3 Mefloquine, 3
Cl
Cl
HN
N
Compound 17
N