Future medicinal chemistry · 2026
Novel isocoumarin-pyrazole hybrids: synthesis, characterization, and investigation of their carbonic anhydrase inhibitory activities.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Onyilmaz Mehmet, Degirmenci Mustafa, Giovannuzzi Simone, Supuran Claudiu T, Koca Murat
Аннотация
AIM: Selective inhibition of tumor-associated carbonic anhydrase (CA) isoforms IX and XII is a key challenge in anticancer drug discovery, as most inhibitors cause off-target inhibition of cytosolic enzymes. We addressed this by designing and synthesizing a series of isocoumarin - pyrazole hybrids from isocoumarin - chalcone scaffolds and evaluating their potential as selective CA IX/XII inhibitors.
MATERIALS AND METHODS: Hybrids (5a-5o) were prepared via cyclization with substituted phenylhydrazines under reflux. Structures were confirmed by FT-IR and NMR analyses. Inhibition of hCA I, II, IX, and XII was determined using a stopped-flow CO2 hydration assay following enzyme - inhibitor preincubation.
RESULTS: All compounds were obtained in good yields. No significant activity was observed against cytosolic hCA I and II, whereas all derivatives inhibited tumor-associated hCA IX and XII at low-to-medium micromolar levels. Electron-donating substituents improved potency, with compounds 5a and 5g being the most active.
CONCLUSION: This study shows that isocoumarin - pyrazole hybrids achieve selective inhibition of hCA IX and XII without affecting off-target isoforms. The results expand the chemical space of non-classical CA inhibitors and offer insights for the rational design of selective anticancer agents. Future work will focus on optimizing potency and evaluating efficacy in cellular tumor models.
MATERIALS AND METHODS: Hybrids (5a-5o) were prepared via cyclization with substituted phenylhydrazines under reflux. Structures were confirmed by FT-IR and NMR analyses. Inhibition of hCA I, II, IX, and XII was determined using a stopped-flow CO2 hydration assay following enzyme - inhibitor preincubation.
RESULTS: All compounds were obtained in good yields. No significant activity was observed against cytosolic hCA I and II, whereas all derivatives inhibited tumor-associated hCA IX and XII at low-to-medium micromolar levels. Electron-donating substituents improved potency, with compounds 5a and 5g being the most active.
CONCLUSION: This study shows that isocoumarin - pyrazole hybrids achieve selective inhibition of hCA IX and XII without affecting off-target isoforms. The results expand the chemical space of non-classical CA inhibitors and offer insights for the rational design of selective anticancer agents. Future work will focus on optimizing potency and evaluating efficacy in cellular tumor models.