TY - JOUR
T1 - Structure-activity analysis of CJ-15,801 analogues that interact with Plasmodium falciparum pantothenate kinase and inhibit parasite proliferation
AU - Spry, Christina
AU - Sewell, Alan L.
AU - Hering, Yuliya
AU - Villa, Mathew V.J.
AU - Weber, Jonas
AU - Hobson, Stephen J.
AU - Harnor, Suzannah J.
AU - Gul, Sheraz
AU - Marquez, Rodolfo
AU - Saliba, Kevin J.
N1 - Publisher Copyright:
© 2017 Elsevier Masson SAS
PY - 2018/1/1
Y1 - 2018/1/1
N2 - Survival of the human malaria parasite Plasmodium falciparum is dependent on pantothenate (vitamin B5), a precursor of the fundamental enzyme cofactor coenzyme A. CJ-15,801, an enamide analogue of pantothenate isolated from the fungus Seimatosporium sp. CL28611, was previously shown to inhibit P. falciparum proliferation in vitro by targeting pantothenate utilization. To inform the design of next generation analogues, we set out to synthesize and test a series of synthetic enamide-bearing pantothenate analogues. We demonstrate that conservation of the R-pantoyl moiety and the trans-substituted double bond of CJ-15,801 is important for the selective, on-target antiplasmodial effect, while replacement of the carboxyl group is permitted, and, in one case, favored. Additionally, we show that the antiplasmodial potency of CJ-15,801 analogues that retain the R-pantoyl and trans-substituted enamide moieties correlates with inhibition of P. falciparum pantothenate kinase (PfPanK)-catalyzed pantothenate phosphorylation, implicating the interaction with PfPanK as a key determinant of antiplasmodial activity.
AB - Survival of the human malaria parasite Plasmodium falciparum is dependent on pantothenate (vitamin B5), a precursor of the fundamental enzyme cofactor coenzyme A. CJ-15,801, an enamide analogue of pantothenate isolated from the fungus Seimatosporium sp. CL28611, was previously shown to inhibit P. falciparum proliferation in vitro by targeting pantothenate utilization. To inform the design of next generation analogues, we set out to synthesize and test a series of synthetic enamide-bearing pantothenate analogues. We demonstrate that conservation of the R-pantoyl moiety and the trans-substituted double bond of CJ-15,801 is important for the selective, on-target antiplasmodial effect, while replacement of the carboxyl group is permitted, and, in one case, favored. Additionally, we show that the antiplasmodial potency of CJ-15,801 analogues that retain the R-pantoyl and trans-substituted enamide moieties correlates with inhibition of P. falciparum pantothenate kinase (PfPanK)-catalyzed pantothenate phosphorylation, implicating the interaction with PfPanK as a key determinant of antiplasmodial activity.
KW - Antimalarial
KW - CJ-15,801
KW - Pantothenate
KW - Pantothenate kinase
KW - Plasmodium falciparum
UR - http://www.scopus.com/inward/record.url?scp=85037638438&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2017.08.050
DO - 10.1016/j.ejmech.2017.08.050
M3 - Article
C2 - 29233590
AN - SCOPUS:85037638438
SN - 0223-5234
VL - 143
SP - 1139
EP - 1147
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -