6-Substituted Triazolyl Benzoxaboroles as Selective Carbonic Anhydrase Inhibitors: In Silico Design, Synthesis, and X-ray Crystallography

Benzoxaborole is currently a scaffold of great relevancein medicinalchemistry. In 2016, it was reported to be a new and valuable chemotypefor designing carbonic anhydrase (CA) inhibitors. Herein, using an in silico design, we report the synthesis and characterizationof substituted 6-(1H-1,2,3-triazol-1-yl)benzoxaboroles.6-Azidobenzoxaborole was described for the first time as a molecularplatform to prepare libraries of inhibitors by a copper(I)-catalyzedazide-alkyne cycloaddition via a click chemistrystrategy. With inhibition constants below 30 nM, some derivatives,such as compound 20, showed efficacy as selective hCAVII and IX inhibitors. The design hypothesis was validated by crystallographicinvestigation on the hCA II/20 adduct, which providedexplanations over the different inhibition behavior observed againstthe five evaluated hCA isoforms. Overall, this study identified 20 as a new promising lead compound to develop novel anticanceragents targeting the tumor-associated hCA IX but also potent neuropathicpain relievers targeting hCA VII.

Automated summary

In this study, substituted 6-(1H-1,2,3-triazol-1-yl)benzoxaboroles were synthesized and characterized using in silico design. The 6-azidobenzoxaborole was introduced as a molecular platform for preparing libraries of inhibitors through a click chemistry strategy. Compound 20 showed high selectivity as hCAVII and IX inhibitors with inhibition constants below 30 nM. Crystallographic investigation validated the design hypothesis and provided explanations for the different inhibition behavior observed against five hCA isoforms. Overall, compound 20 was identified as a promising lead compound to develop novel anticancer agents targeting hCA IX and potent neuropathic pain relievers targeting hCA VII.