Design, Synthesis, Calorimetry, and Crystallographic Analysis of 2-Alkylaminoethyl-1,1-bisphosphonates as Inhibitors of Trypanosoma cruzi Farnesyl Diphosphate Synthase

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• 作者：Srinivas Aripirala ; Sergio H. Szajnman ; Jean Jakoncic ; Juan B. Rodriguez ; Roberto Docampo ; Sandra B. Gabelli ; L. Mario Amzel
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：July 26, 2012
• 年：2012
• 卷：55
• 期：14
• 页码：6445-6454
• 全文大小：510K
• 年卷期：v.55,no.14(July 26, 2012)
• ISSN：1520-4804

文摘

Linear 2-alkylaminoethyl-1,1-bisphosphonates are effective agents against proliferation of Trypanosoma cruzi, the etiologic agent of American trypanosomiasis (Chagas disease), exhibiting IC₅₀ values in the nanomolar range against the parasites. This activity is associated with inhibition at the low nanomolar level of the T. cruzi farnesyl diphosphate synthase (TcFPPS). X-ray structures and thermodynamic data of the complexes TcFPPS with five compounds of this family show that the inhibitors bind to the allylic site of the enzyme, with their alkyl chain occupying the cavity that binds the isoprenoid chain of the substrate. The compounds bind to TcFPPS with unfavorable enthalpy compensated by a favorable entropy that results from a delicate balance between two opposing effects: the loss of conformational entropy due to freezing of single bond rotations and the favorable burial of the hydrophobic alkyl chains. The data suggest that introduction of strategically placed double bonds and methyl branches should increase affinity substantially.