Benzoxaborole Antimalarial Agents. Part 4. Discovery of Potent 6-(2-(Alkoxycarbonyl)pyrazinyl-5-oxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles

Abstract

A series of 6-hetaryloxy benzoxaborole compounds was designed and synthesized for a structure–activity relationship (SAR) investigation to assess the changes in antimalarial activity which result from 6-aryloxy structural variation, substituent modification on the pyrazine ring, and optimization of the side chain ester group. This SAR study discovered highly potent 6-(2-(alkoxycarbonyl)pyrazinyl-5-oxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles (9, 27–34) with IC50s = 0.2–22 nM against cultured Plasmodium falciparum W2 and 3D7 strains. Compound 9 also demonstrated excellent in vivo efficacy against P. berghei in infected mice (ED90 = 7.0 mg/kg).

Current data regarding the structure-toxicity relationship of boron-containing compounds

“…This is due to the improvement found in the properties of some medicinal compounds when boron moieties are added (Soriano-Ursúa, 2014a), such as increased affinity for the corresponding receptor and improved efficacy (Soriano-Ursúa, 2015;Zhang, 2015). The latter property results from more stable molecules with prolonged half-life and activity (Bowers, 2013;Soriano-Ursúa, 2015).…”

“…Boron can also modify the chemical behavior of a molecule (as an acid or base) in vivo by changing the partition coefficient (logP), luminescence, or spectroscopy spectra (Endo, 2003;Zheng, 2008;Liu, 2012a). This can be useful for identifying or activating some drug targets.…”

A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue

“…Benzoxaboroles are boron-containing compounds that have shown potent activity against a wide range of infectious pathogens, including bacteria 5 6 , fungi 7 and protozoans 8 9 10 11 12 . The highly electrophilic nature of the boron component of these compounds leads to interaction with a variety of protein targets via reversible covalent bonds 13 14 , with identified targets including leucyl-tRNA synthetase (LeuRS) 6 7 , phosphodiesterase 4 (PDE4) 15 16 and β-lactamase 17 .…”

Design, Synthesis and X‐ray Crystal Structure of Iodinated Benzoboroxole Derivatives by Consecutive Metal–Iodine Exchange of 3,4,5‐Triiodoanisole

“…[3b], Furthermore, 5‐cyanophenoxybenzoboroxole 4 and 5‐dicyanophenoxybenzoboroxole 4′ revealed anti‐inflammatory activity against psoriasis, a common skin disease, which causes chronic inflammation (AN‐2728, AN‐2798, Figure ) . Other derivatives were reported to have activity against psoriasis and to treat pneumococcus infection diseases ( 5 and 6 , Figure ) . Lastly and more recently, substituted 7‐iodobenzo[ c ][1,2]oxaborole‐1,6(3 H )‐diols ( 7 and 8 , Figure ), the first reported iodinated benzoboroxole derivatives, were developed for controlling endoparasites both in animals and agriculture…”