Quantitative structure-activity relationship studies of [(biphenyloxy)propyl]isoxazole derivatives. Inhibitors of human rhinovirus 2 replication.
The 50% cytotoxic concentration (CC50) in HeLa cells, the 50% inhibitory concentration (IC50) against human rhinovirus 2 (HRV-2), and the selectivity index (SI = CC50/IC50) of [(biphenyloxy)propyl]isoxazole derivatives were used to develop quantitative structure-activity relationships (QSAR) based on simplex representation of molecular structure. Statistic characteristics for partial least-squares models are quite satisfactory (R2 = 0.838 - 0.918; Q2 = 0.695 - 0.87) for prediction of CC50, IC50, and SI values and permit the virtual screening and molecular design of new compounds with strong anti-HRV-2 activity. The quality of prognosis for designed compounds was additionally estimated by analysis of domain applicability for each QSAR model. A hypothesis to the effect that terminal benzene substituents must have negative electrostatic potential and definite length (approximately 5.5-5.6 A) to possess strong antiviral activity has been suggested. The quality of developed analysis, i.e., high level of antiviral action of three new designed compounds, has been confirmed experimentally.
Kuz'min
Victor E
VE
A.V. Bogatsky Physical-Chemical Institute, Odessa, Ukraine, Research Center for Antibiotics, Moscow, Russia.
Artemenko
Anatoly G
AG
Muratov
Eugene N
EN
Volineckaya
Ingrid L
IL
Makarov
Vadim A
VA
Riabova
Olga B
OB
Wutzler
Peter
P
Schmidtke
Michaela
M
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D006367:HeLa Cells; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D016018:Least-Squares Analysis; D008958:Models, Molecular; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D012229:Rhinovirus / Q000187:drug effects* / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D007555:Isoxazoles