Abstract

Bisphosphonates are the most commonly prescribed drugs for the treatment of osteoporosis and other bone illnesses. Some of them have also shown antiparasitic activity. In search of improving the pharmacological profile of commercial bisphosphonates, our group had previously developed first row transition metal complexes with N-containing bisphosphonates (NBPs). In this work, we extended our studies to heteroleptic palladium–NBP complexes including DNA intercalating polypyridyl co-ligands (NN) with the aim of obtaining potential multi-target species. Complexes of the formula [Pd(NBP)₂(NN)]·2NaCl·xH₂O with NBP = alendronate (ale) or pamidronate (pam) and NN = 1,10 phenanthroline (phen) or 2,2′-bipyridine (bpy) were synthesized and fully characterized. All the obtained compounds were much more active in vitro against T. cruzi (amastigote form) than the corresponding NBP ligands. In addition, complexes were nontoxic to mammalian cells up to 50–100 µM. Compounds with phen as ligand were 15 times more active than their bpy analogous. Related to the potential mechanism of action, all complexes were potent inhibitors of two parasitic enzymes of the isoprenoid biosynthetic pathway. No correlation between the anti-T. cruzi activity and the enzymatic inhibition results was observed. On the contrary, the high antiparasitic activity of phen-containing complexes could be related to their ability to interact with DNA in an intercalative-like mode. These rationally designed compounds are good candidates for further studies and good leaders for future drug developments.

Graphic abstract

Four new palladium heteroleptic complexes with N-containing commercial bisphosphonates and DNA intercalating polypyridyl co-ligands were synthesized and fully characterized. All complexes displayed high anti-T. cruzi activity which could be related to the inhibition of the parasitic farnesyl diphosphate synthase enzyme but mainly to their ability to interact DNA.

中文翻译：

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多目标杂合双膦酸钯配合物。

摘要

双膦酸盐是治疗骨质疏松症和其他骨骼疾病的最常用处方药。其中一些还显示出抗寄生虫活性。为了改善商业化双膦酸酯的药理作用，我们小组先前开发了第一排过渡金属配合物与含N的双膦酸酯（NBPs）。在这项工作中，我们将研究扩展到包括DNA插入聚吡啶基共配体（NN）的杂合钯-NBP复合物，目的是获得潜在的多目标物种。式[Pd（NBP）₂（NN）]·2NaCl· x H _{2的配合物}合成了NBP =阿仑膦酸盐（ale）或帕米膦酸盐（pam）和NN = 1,10菲咯啉（phen）或2,2'-联吡啶（bpy）的O，并对其进行了充分表征。与相应的NBP配体相比，所有获得的化合物在体外对T. cruzi（ama形目）的活性都高得多。此外，复合物对50-100 µM的哺乳动物细胞无毒。以phen为配体的化合物的活性是其bpy类似物的15倍。与潜在的作用机理有关，所有复合物都是类异戊二烯生物合成途径的两种寄生酶的有效抑制剂。抗克氏锥虫之间无相关性观察到活性和酶抑制结果。相反，含phen的复合物的高抗寄生虫活性可能与它们以嵌入样模式与DNA相互作用的能力有关。这些经过合理设计的化合物是进一步研究的良好候选者，也是未来药物开发的良好领导者。

图形摘要

四个新的钯杂配配合与Ñ含商业的二膦酸盐和DNA嵌入多吡啶共配位体的合成和完全表征。所有复合物均显示出高的抗克氏锥虫活性，这可能与抑制寄生的法呢基二磷酸合磷酸酶有关，但主要与它们与DNA相互作用的能力有关。