From DC18 to MR07: A Metabolically Stable 4, 4′‐Oxybisbenzoyl Amide as a Low‐Nanomolar Growth Inhibitor of P. falciparum. (26th September 2022)

• Record Type: Journal Article
• Authors: Bassanini, Ivan; Parapini, Silvia; Basilico, Nicoletta; Taramelli, Donatella; Romeo, Sergio
• Is Part Of: ChemMedChem. Volume 17:Number 21(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-09-26
• Subjects: Plasmodium falciparum -- Antimalarials -- Malaria -- In silico pharmacophore mapping -- In vitro metabolic stability; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202200355
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: To improve the metabolic stability of a 4, 4′‐oxybisbenzoyl‐based novel and potent (nanomolar‐range IC50 ) antiplasmodial agent previously described by us, in silico ‐guided structure‐activity relationship (SAR) campaigns have been conducted to substitute its peptide decorations with more metabolically stable residues. The effects of the various structural modifications were then correlated with the antiplasmodial activity in vitro in phenotypic assays. Among the several derivatives synthetized and compared with the 3D‐pharmacophoric map of the original lead, a novel compound, characterized by a western tert ‐butyl glycine residue and an eastern 1 S, 2 S ‐aminoacyclohexanol, showed low‐nanomolar‐range antiplasmodial activity, no signs of cross‐resistance and, most importantly, 47‐fold improved Phase I metabolic stability when incubated with human liver microsomes. These results highlight the efficacy of in silico ‐guided SAR campaigns which will allow us to further optimize the structure of the new lead aiming at testing its efficacy in vivo using different routes of administration. Abstract : Improving the metabolitc stability profile : An in silico ‐driven structure‐activity relationship campaign (SAR) was performed to optimize the structure of a peptide decorated 4, 4′‐oxybisbenzoyl amide, named DC18, which showed outstanding antiplasmodial activity but poor metabolic stability in vitro . The novel lead compound, MR07, possesses low‐nanomolar activity and high metabolic stability in vitro in murine and human models.