A Potent N‐(piperidin‐4‐yl)‐1H‐pyrrole‐2‐carboxamide Inhibitor of Adenylyl Cyclase of G. lamblia: Biological Evaluation and Molecular Modelling Studies

Abstract

In this work, we report a derivative of N-(piperidin-4-yl)-1Hpyrrole-2-carboxamide as a new inhibitor for adenylyl cyclase of Giardia lamblia which was obtained from a study using structural data of the nucleotidyl cyclase 1 (gNC1) of this parasite. For such a study, we developed a model for this specific enzyme by using homology techniques, which is the first model reported for gNC1 of G. lamblia. Our studies show that the new inhibitor has a competitive mechanism of action against this enzyme. 2-Hydroxyestradiol was used as the reference compound for comparative studies. Results in this work are important from two points of view. on the one hand, an experimentally corroborated model for gNC1 of G. lamblia obtained by molecular modelling is presented; on the other hand, the new inhibitor obtained is an undoubtedly excellent starting structure for the development of new metabolic inhibitors for G. lamblia.

Rosmarinic Acid Present in Lepechinia floribunda and Lepechinia meyenii as a Potent Inhibitor of the Adenylyl Cyclase gNC1 from Giardia lamblia

“…In this context, it was observed by in vitro assays that the excystation of G. lamblia cysts was significantly blocked when the PKA inhibitor, amide 14–22, was administered during the initial stages of excystation [ 34 , 35 ]. In fact, a notable rise in cAMP levels was observed during the early stages of trophozoite encystation as determined by in vitro methods [ 28 ], while increased trophozoite growth rates were observed when the parasite was exposed to the non-hydrolyzable cAMP analogue, di-butyryl-cAMP [ 36 ]. These findings underscore the relevance of cAMP in the growth and differentiation processes of G. lamblia , therefore highlighting the potential of gNC1 as a target for the future development of drugs to counter the parasite.…”

“…In support of this statement, the inhibition of gNC1 suggests that it is selective. Despite the fact that this enzyme belongs to a widely distributed family of enzymes present in prokaryotes and eukaryotes [ 30 , 37 ], it exhibits an approximately 30% sequence identity with its homologs found in mammals [ 36 ], which potentially will result in a specific inhibition.…”

“…Subsequently, it was described that the enzymatic properties of this domain were similar to that of soluble adenylyl cyclase from mammals [ 28 ]. More recently, using the available structural data of gNC1, an in silico model was developed for this specific enzyme using homology techniques [ 36 ]. This was the first theoretical model reported for gNC1 from G. lamblia , which demonstrated the capability of the enzyme as a biological site to search for new ligands able to inhibit its activity.…”

“…This was the first theoretical model reported for gNC1 from G. lamblia , which demonstrated the capability of the enzyme as a biological site to search for new ligands able to inhibit its activity. Using this in silico model and further validation by experimental techniques, a derivative of N -(piperidin-4-yl)-1H-pyrrole-2-carboxamide, named AMJ-147 (compound 8 ), was identified as a new inhibitor of gNC1 [ 36 ].…”

“…Taking advantage of the in silico and experimental models previously developed and the encouraging results obtained [ 36 ], in the present work, we focused our efforts on the search for potential inhibitors of gNC1 from G. lamblia within extracts obtained mostly from native species of Argentina.…”