Pm. Oneill et al., SYNTHESIS, ANTIMALARIAL ACTIVITY, AND MOLECULAR MODELING OF TEBUQUINEANALOGS, Journal of medicinal chemistry, 40(4), 1997, pp. 437-448
Tebuquine (5) is a 4-aminoquinoline that is significantly more active
than amodiaquine (2) and chloroquine (1) both in vitro and in vivo. We
have developed a novel more efficient synthetic route to tebuquine an
alogues which involves the use of a palladium-catalyzed Suzuki reactio
n to introduce the 4-chlorophenyl moiety into the 4-hydroxyaniline sid
e chain. Using similar methodology, novel synthetic routes to fluorina
ted (7a,b) and a dehydroxylated (7c) analogue of tebuquine have also b
een developed. The novel analogues were subjected to testing against t
he chloroquine sensitive HB3 strain and the chloroquine resistant K1 s
train of Plasmodium falciparum. Tebuquine was the most active compound
tested against both strains of Plasmodia. Replacement of the 4-hydrox
y function with either fluorine or hydrogen led to a decrease in antim
alarial activity. Molecular modeling of the tebuquine analogues alongs
ide amodiaquine and chloroquine reveals that the inter-nitrogen separa
tion in this class of drugs ranges between 9.36 and 9.86 Angstrom in t
heir isolated diprotonated form and between 7.52 and 10.21 Angstrom in
the heme - drug complex. Further modeling studies on the interaction
of 4-aminoquinolines with the proposed cellular receptor heme revealed
favorable interaction energies for chloroquine, amodiaquine, and tebu
quine analogues. Tebuquine, the most potent antimalarial in the series
, had the most favorable interaction energy calculated in both the in
vacuo and solvent-based simulation studies. Although fluorotebuquine (
7a) had a similar interaction energy to tebuquine, this compound had s
ignificantly reduced potency when compared with (5). This disparity is
possibly the result of the reduced cellular accumulation (CAR) of flu
orotebuquine when compared with tebuquine within the parasite. Measure
ment of the cellular accumulation of the tebuquine analogues and seven
related 4-aminoquinolines shows a significant relationship (r = 0.98)
between the CAR of 4-aminoquinoline drugs and the reciprocal of drug
IC50.