Five- and Six-Membered Nitrogen-Containing Compounds as Selective Carbonic Anhydrase Activators

Adriano Mollica, Giorgia Macedonio, Azzurra Stefanucci, Simone Carradori, Atilla Akdemir, Andrea Angeli, Claudiu Supuran
2017 Molecules  
It has been proven that specific isoforms of human carbonic anhydrase (hCA) are able to fine-tune physiological pathways connected to signal processing, and that decreased CAs expression negatively influences cognition, leading to mental retardation, Alzheimer's disease, and aging-related cognitive dysfunctions. For this reason, a small library of natural and synthetic nitrogen containing cyclic derivatives was assayed as activators of four human isoforms of carbonic anhydrase (hCA I, II, IV
more » ... VII). Most of the compounds activated hCA I, IV and VII in the micromolar range, with K A s ranging between 3.46 and 80.5 µM, whereas they were not active towards hCA II (K A s > 100 µM). Two natural compounds, namely L-(+)-ergothioneine (1) and melatonin (2), displayed K A s towards hCA VII in the nanomolar range after evaluation by a CO 2 hydration method in vitro, showing a rather efficient and selective activation profile with respect to histamine, used as a reference compound. Corroborated with the above in vitro findings, a molecular modelling in silico approach has been performed to correlate these biological data, and to elucidate the binding interaction of these activators within the enzyme active site. Molecules 2017, 22, 2178 2 of 13 astrocytes, and some pyramidal neurons [8] . Many isoforms of CAs are expressed in the central nervous system (CNS) contributing to signal processing, better performance in the Morris maze test, fear memory, attention gating of memory storage, spatial learning, cerebrospinal fluid composition and turnover, and long term synaptic transmission especially in the cortex and hippocampus [9, 10] . Moreover, local pH fluctuations were shown to modulate physiological responses sustained by the NMDA receptors [11] . Up to date, CA activators are chemically represented by natural endogenous compounds (histamine, catecholamines, amino acids/peptides, carnosine) [12-20] and some synthetic derivatives (oligopeptides, pyridinium-azoles, selective serotonin reuptake inhibitors, histidine and histamine derivatives, imidazole/triazole/indazole/pyrazole/oxazole/thiadiazole derivatives) [21-32] presenting common features such as:
doi:10.3390/molecules22122178 pmid:29232847 fatcat:4tkqk22u5vhpldzzlryluwkvoq