TY - JOUR
T1 - Structure–Activity Relationships and Antiplasmodial Potencies of Novel 3,4-Disubstituted 1,2,5-Oxadiazoles
AU - Hochegger, Patrick
AU - Hermann, Theresa
AU - Dolensky, Johanna
AU - Seebacher, Werner
AU - Saf, Robert
AU - Pferschy-Wenzig, Eva Maria
AU - Kaiser, Marcel
AU - Mäser, Pascal
AU - Weis, Robert
N1 - Publisher Copyright:
© 2023 by the authors.
PY - 2023/10
Y1 - 2023/10
N2 - The 4-substituted 3-amino-1,2,5-oxadiazole 1 from the Malaria Box Project of the Medicines for Malaria Venture foundation shows very promising selectivity and in vitro activity against Plasmodium falciparum. Within the first series of new compounds, various 3-acylamino analogs were prepared. This paper now focuses on the investigation of the importance of the aromatic substituent in ring position 4. A number of new structure–activity relationships were elaborated, showing that antiplasmodial activity and selectivity strongly depend on the substitution pattern of the 4-phenyl moiety. In addition, physicochemical parameters relevant for drug development were calculated (logP and ligand efficiency) or determined experimentally (CYP3A4-inhibition and aqueous solubility). N-[4-(3-ethoxy-4-methoxyphenyl)-1,2,5-oxadiazol-3-yl]-3-methylbenzamide 51 showed high in vitro activity against the chloroquine-sensitive strain NF54 of P. falciparum (PfNF54 IC50 = 0.034 µM), resulting in a very promising selectivity index of 1526.
AB - The 4-substituted 3-amino-1,2,5-oxadiazole 1 from the Malaria Box Project of the Medicines for Malaria Venture foundation shows very promising selectivity and in vitro activity against Plasmodium falciparum. Within the first series of new compounds, various 3-acylamino analogs were prepared. This paper now focuses on the investigation of the importance of the aromatic substituent in ring position 4. A number of new structure–activity relationships were elaborated, showing that antiplasmodial activity and selectivity strongly depend on the substitution pattern of the 4-phenyl moiety. In addition, physicochemical parameters relevant for drug development were calculated (logP and ligand efficiency) or determined experimentally (CYP3A4-inhibition and aqueous solubility). N-[4-(3-ethoxy-4-methoxyphenyl)-1,2,5-oxadiazol-3-yl]-3-methylbenzamide 51 showed high in vitro activity against the chloroquine-sensitive strain NF54 of P. falciparum (PfNF54 IC50 = 0.034 µM), resulting in a very promising selectivity index of 1526.
KW - 1,2,5-oxadiazoles
KW - antimalarial
KW - CYP3A4-inhibition
KW - Plasmodium falciparum
KW - solubility
UR - http://www.scopus.com/inward/record.url?scp=85174693301&partnerID=8YFLogxK
U2 - 10.3390/ijms241914480
DO - 10.3390/ijms241914480
M3 - Article
C2 - 37833929
AN - SCOPUS:85174693301
SN - 1661-6596
VL - 24
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 19
M1 - 14480
ER -