Pyrimido[4,5-e][1,4]diazepines acting as inhibitors of adenylyl cyclase of g. Lamblia: synthesis, bioassays and molecular modelling studies.

VEGA HISSI ESTEBAN; ZURITA, ADOLFO R.; ENRIZ, RICARDO D.; MANUEL NOGUERAS; JOSÉ M. DE LA TORRE; JUSTO COBO

Santiago de Compostela, España

Congreso; SEQT2022, XX National Meeting of the Spanish Society of Medicinal Chemistry; 2022

Spanish Society of Medicinal Chemistry

Giardia lamblia (G. lamblia) (also known as Giardia intestinalis or Giardia duodenalis) is ananaerobic protozoan parasite that inhabits in the small intestine of humans and other higheranimals. This parasite is the cause of giardiasis, a parasitosis of great epidemiological and clinicalimportance due to its high prevalence and pathogenicity. In previous works we demonstrated theimportance of cAMP synthesis and degradation on the growth and differentiation processes ofthe intestinal parasite G. lamblia: i) cAMP increases significantly during the encysting process oftrophozoites incubated in vitro 1 ; ii) The addition to the culture medium of the non-hydrolyzableanalog of cAMP, dbAMPc, increases the replication rate of the parasite. 2 In this context, andthrough an analysis of the G. lamblia genome, we found the complete sequence of two nucleotidylcyclase enzymes (gNC1 and gNC2) and a phosphodiesterase enzyme (gPDE), which would beresponsible for the synthesis and degradation of cAMP in this parasite. 1 In addition, we haverecently reported a structural model of sAC for G. lamblia through an exhaustive molecularmodeling study applying homology techniques. 2 Taking advantage of the information obtained inour previous article, in this work, we report a series of pyrimido[4,5-e][1,4]diazepine derivativesIV 3 (See figure 1a) as a new inhibitors for adenylyl cyclase of Giardia lamblia. Such compoundshave been arisen as potential candidates from a study using structural data of the nucleotidylcyclase 1 (gNC1) of this parasite. For this study, we used an own model for this specific enzymeby using homology techniques, which is the first model reported for gNC1 of G. 2 Our simulationsindicate that these ligands are located at the base of the ATP binding pocket, and that complexesare stabilized mainly through interactions with residues Thr 125, Phe 204, Phe 116, Leu 213 andIle 127. Our results suggest that these new inhibitors follow a competitive mechanism of actionagainst this enzyme. 2-Hydroxyestradiol was used as the reference compound for comparativestudies. Results in this work are important from two points of view. On the one hand, anexperimentally corroborated model for gNC1 of G. lamblia obtained by molecular modelling isvalidated further; on the other hand, new inhibitors possessing a new structural scaffold areexcellent starting structures for the development of new metabolic inhibitors for G. lamblia.