title: Design and synthesis of new potent inhibitors of farnesyl pyrophosphate synthase.
abstract: Predictive QSAR models for the inhibition activities of nitrogen-containing bisphosphonates (N-BPs) against farnesyl pyrophosphate synthase (FPPS) from Leishmania major (LeFPPS) were developed using a data set of 97 compounds. The QSAR models were developed through the use of Artificial Neural Networks and Random Forest learning procedures. The predictive ability of the models was tested by means of leave-one-out cross-validation; Q(2)values ranging from 0.45-0.79 were obtained for the regression models. The consensus prediction for the external evaluation set afforded high predictive power (Q(2)=0.76 for 35 compounds). The robustness of the QSAR models was also evaluated using a Y-randomization procedure. A small set of 6 new N-BPs were designed and synthesized applying the Michael reaction of tetrakis (trimethylsilyl) ethenylidene bisphosphonate with amines. The inhibition activities of these compounds against LeFPPS were predicted by the developed QSAR models and were found to correlate with their fungistatic activities against Candida albicans. The antifungal activities of N-BPs bearing n-butyl and cyclopropyl side chains exceeded the activities of Fluconazole, a triazole-containing antifungal drug. In conclusion, the N-BPs developed here present promising candidate drugs for the treatment of fungal diseases.
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Prokopenko
authors.forename: Vasyl
authors.initials: V
authors.lastname: Kovalishyn
authors.forename: Michael
authors.initials: M
authors.lastname: Shevchuk
authors.forename: Iryna
authors.initials: I
authors.lastname: Kopernyk
authors.forename: Larysa
authors.initials: L
authors.lastname: Metelytsia
authors.forename: Vadim
authors.initials: V
authors.lastname: Romanenko
authors.forename: Sergey
authors.initials: S
authors.lastname: Mogilevich
authors.affiliation: Institute of Bioorganic Chemistry & Petrochemistry, National Academy of Sciences of Ukraine, Kyiv-94, 02660, Murmanska, 1, Ukraine. vkovalishyn@yahoo.com.
authors.forename: Valery
authors.initials: V
authors.lastname: Kukhar
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry* / Q000494:pharmacology; D001185:Artificial Intelligence; D002176:Candida albicans / Q000187:drug effects; D004164:Diphosphonates / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors*; D018320:Leishmania major / Q000201:enzymology; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D004164:Diphosphonates; D051228:Geranyltranstransferase