Discovery of oxybisbenzoylamides as a new class of antimalarial agents

Pancotti, Andrea; Parapini, Silvia; Dell’Agli, Mario; Gambini, Luca; Galli, C.; Sangiovanni, Enrico; Bosisio, E.; Taramelli, Donatella; Romeo, Sergio

doi:10.1039/c5md00115c

Cited by 4 publications

(14 citation statements)

References 12 publications

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“…In general, all the tested compounds did not show a relevant cross‐resistance with CQ (0.40 < calculated R.I.s <2) confirming the similar inhibitory activity on both D10 and W2 strains of these 4,4’‐oxybisbenzoyl amides described before …”

Section: Resultssupporting

confidence: 79%

“…Obtained results are summarized in Table . Both 19 and 24 showed considerably higher IVSI than the parent compound 1 . Interestingly, the IVSI of 24 was found to be higher than dihydroartemisinin (DHA), equally potent but more cytotoxic than 24 in vitro .…”

Section: Resultsmentioning

confidence: 99%

“…In this work we have conducted a detailed SAR investigation about the chemical and conformational features of the 4,4’‐oxybisbenzoyl amide core identified as the pharmacophore of the potent antiplasmodial agent previously described by us (compound 1 , Figure ) …”

Section: Resultsmentioning

confidence: 99%

“…Recently, the finding of discrepancies in the relationship between the inhibition of PLMs and the actual inhibition of parasite growth promoted by these compounds, led us to further investigate the nature of their real pharmacophore. We substituted the statine residue, responsible for PLM2 inhibition, with leucine and the 4‐aminoquinolinic ring system with a basic tertiary amine . Among these novel drug candidates, compound 1 (Figure ), which doesn't present any known antimalarial pharmacophoric group, showed a remarkable antiplasmodial activity both on CQ‐sensitive (CQ−S) and CQ‐resistant (CQ−R) Pf strains.…”

Section: Introductionmentioning

confidence: 99%

“…We substituted the statine residue, responsible for PLM2 inhibition, with leucine and the 4-aminoquinolinic ring system with a basic tertiary amine. [8] Among these novel drug candidates, compound 1 (Figure 1), which doesn't present any known antimalarial pharmacophoric group, showed a remarkable antiplasmodial activity both on CQsensitive (CQÀ S) and CQ-resistant (CQÀ R) Pf strains. On the basis of these results, we concluded that compound 1 must owe its activity to a new antimalarial pharmacophore, recognized as [ the oxybisbenzoylamide core, acting through a (new) unidentified mechanism of action.…”

Section: Introductionmentioning

confidence: 99%

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Discovery and Pharmacophore Mapping of a Low‐Nanomolar Inhibitor of P. falciparum Growth

et al. 2019

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The treatment of malaria, the most common parasitic disease worldwide and the third deadliest infection after HIV and tuberculosis, is currently compromised by the dramatic increase and diffusion of drug resistance among the various species of Plasmodium, especially P. falciparum (Pf). In this view, the development of new antiplasmodial agents that are able to act via innovative mechanisms of action, is crucial to ensure efficacious antimalarial treatments. In one of our previous communications, we described a novel class of compounds endowed with high antiplasmodial activity, characterized by a pharmacophore never described before as antiplasmodial and identified by their 4,4’‐oxybisbenzoyl amide cores. Here, through a detailed structure‐activity relationship (SAR) study, we thoroughly investigated the chemical features of the reported scaffolds and successfully built a novel antiplasmodial agent active on both chloroquine (CQ)‐sensitive and CQ‐resistant Pf strains in the low nanomolar range, without displaying cross‐resistance. Moreover, we conducted an in silico pharmacophore mapping.

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Section: Resultssupporting

confidence: 79%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Discovery and Pharmacophore Mapping of a Low‐Nanomolar Inhibitor of P. falciparum Growth

et al. 2019

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Into the Fray! A Beginner's Guide to Medicinal Chemistry

Veale

2021

ChemMedChem

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Modern medicinal chemistry is a complex, multidimensional discipline that operates at the interface of the chemical and biological sciences. The medicinal chemistry contribution to drug discovery is typically described in the context of the wellrecited linear progression of the drug discovery pipeline. However, compound optimization is idiosyncratic to each project, and clear definitions of hit and lead molecules and the subsequent progress along the pipeline becomes easily blurred. In addition, this description lacks insight into the entangled relationship between chemical and pharmacological properties, and thus provides limited guidance on how innovative medicinal chemistry strategies can be applied to solve optimization problems, regardless of the stage in the pipeline. Through discussion and illustrative examples, this article seeks to provide insights into the finesse of medicinal chemistry and the subtlety of balancing chemical properties pharmacology. In so doing, it aims to serve as an accessible and simple-to-digest guide for anyone who wishes to learn about the underlying principles of medicinal chemistry, in a context that has been decoupled from the pipeline description.

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

Bassanini

Parapini²,

Parapini

et al. 2022

ChemMedChem

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To improve the metabolic stability of a 4,4'-oxybisbenzoylbased novel and potent (nanomolar-range IC 50 ) antiplasmodial agent previously described by us, in silico-guided structureactivity 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 1S,2S-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 silicoguided 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.

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Discovery of oxybisbenzoylamides as a new class of antimalarial agents

Cited by 4 publications

References 12 publications

Discovery and Pharmacophore Mapping of a Low‐Nanomolar Inhibitor of P. falciparum Growth

Discovery and Pharmacophore Mapping of a Low‐Nanomolar Inhibitor of P. falciparum Growth

Into the Fray! A Beginner's Guide to Medicinal Chemistry

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

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