Anti-folate antimalarials with dual-binding modes and their preparation
The present invention is anti-folate antimalarials with dual-binding modes of the general formula (I) [refer to structure in the abstract] wherein R 1 and R 2 which may be the same or different are independently selected from methyl or ethyl or alkylphenyl, R 3 is independently hydrogen, halide, lower alkyl substituted with ester, carboxylic, amide, and ether. Linker is X(CH 2 )nY wherein X and Y which may be the same or different are independently selected from oxygen, carbon, nitrogen, substituted phenyl where n is an integer from 1 to 2-6, or pharmaceutically acceptable salts therefore. The anti-folate antimalarials with dual-binding modes act as novel inhibitors with good inhibition constants against wild-type, double (C59R+SIOSN), triple (N51+C59R+SIOSN, C59R+S 1 OSN+I164L), and quadruple (N51+C59R+S108N+I164L) mutant enzymes. The compounds are also effective against wild type (Tm4/S.2) and mutants (K1CB1, W2, Cs1-2 and V1/S) malaria parasites.
1. An anti-folate antimalarials compound with dual-binding modes of a general formula (I)
wherein
R 1 and R 2 which may be the same, or different, are independently selected from methyl or ethyl or alkylphenyl,
R 3 is independently hydrogen, halide, lower alkyl substituted with ester, carboxylic, amide, and ether: and
linker is X(CH 2 ) n Y wherein X and Y which may be the same, or different, are independently selected from oxygen, carbon, nitrogen, substituted phenyl where n is an integer from 1 to 2-6, or a pharmaceutically acceptable salts.
2. The compound of claim 1 wherein the formula (I) comprises
A. 5-(3′-(3″-(2,4-diamino-6-ethylpyrimidin-5-yloxy)propoxy)phenyl)-6-ethylpyrimidine-2,4-diamine,
B. 5-(4′-(3″-(2,4-diamino-6-ethylpyrimidin-5-yloxy)propoxy)phenyl)-6-ethylpyrimidine-2,4-diamine,
C. 5-(4′-(3″-(4″-(2,4-diamino-6-ethylpyrimidin-5-yl)phenoxy)propoxy)phenyl)-6-ethylpyrimidine-2,4-diamine,
D. 5-(4′-(3″-(2,4-diamino-6-ethylpyrimidin-5-yloxy)propoxy)phenyl)-6-ethylpyrimidine-2,4-diamine dihydrochloride, and
E. 5-(4′-(3″-(4″-(2,4-diamino-6-ethylpyrimidin-5-yl)phenoxy)propoxy)phenyl)-6-ethylpyrimidine-2,4-diamine dihydrochloride.
3. The compound of claim 1 , wherein the compound contains two types of pharmacophores in a single molecule that inhibits both wild-type and multiple-mutant DHFRs of P. falciparum.
4. The compound of claim 1 , wherein the compound A binds wild-type DHFR enzyme with a rigid end at the active site having the 2,4-diamino pyrimidine ring interacted with D54 and a rigid phenyl moiety in the close vicinity of S108.
5. The compound of claim 1 , wherein the compound A binds to V1/S enzyme using a flexible alkoxy group to interact with D54 and to avoid steric clash with N108 located in close proximity.