Carbonic anhydrases activation with 3-amino-1H-1,2,4-triazole-1-carboxamides: Discovery of subnanomolar isoform II activators.
A series of ureas was prepared by reacting mono- or di- isocyanates with 3-amino-1H-1,2,4-triazole derivatives. The new carboxamides were investigated as activators of two human (h) carbonic anhydrases (CAs, EC 4.2.1.1), the physiologically relevant isoforms hCA I and II, considering the fact that they have structural resemblance to histamine, a well-known CA activator. Highly effective activators were detected in the series, with potency in the low nanomolar and subnanomolar range, depending on the substitution pattern at the 1,2,4-triazole ring and the nature of the linker between the two heterocyclic rings, in the case of the diureas. The most effective hCA II activator (KAof 0.05nM) ever reported has been evidenced in this study. Although CA activators do not have pharmacological applications for the moment, in animal models it has been shown that they enhance cognition, making them interesting for conditions in which CA activity is diminished, such as aging or Alzheimer's disease.
Institut Européen des Membranes, Adaptive Supramolecular Nanosystems Group, Place Eugène Bataillon, CC 047, F-34095 Montpellier, France.
Yann
Y
Le Duc
Institut Européen des Membranes, Adaptive Supramolecular Nanosystems Group, Place Eugène Bataillon, CC 047, F-34095 Montpellier, France.
Erol
E
Licsandru
Dipartimento di Chimica, Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Via della Lastruccia 3, 50019 Sesto Fiorentino, Firenze, Italy.
Daniela
D
Vullo
Institut Européen des Membranes, Adaptive Supramolecular Nanosystems Group, Place Eugène Bataillon, CC 047, F-34095 Montpellier, France. Electronic address: mihail-dumitru.barboiu@univ-montp2.fr.
Mihail
M
Barboiu
Dipartimento NEUROFARBA, Sezione di Scienze Farmaceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy. Electronic address: claudiu.supuran@unifi.it.
Claudiu T
CT
Supuran
D000577:Amides / Q000737:chemistry; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D002256:Carbonic Anhydrases / Q000378:metabolism*; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D066244:Proton Magnetic Resonance Spectroscopy; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*
C000591593:3-amino-1H-1,2,4-triazole; D000577:Amides; D020536:Enzyme Activators; D014230:Triazoles; D002256:Carbonic Anhydrases
1,2,4-triazole; Activator; Carbonic anhydrase; Histamine; Ureas