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

Abstract

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 and VII). Most of the compounds activated hCA I, IV and VII in the micromolar range, with KAs ranging between 3.46 and 80.5 μM, whereas they were not active towards hCA II (KAs > 100 μM). Two natural compounds, namely l-(+)-ergothioneine (1) and melatonin (2), displayed KAs towards hCA VII in the nanomolar range after evaluation by a CO2 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.

Inhibitory Effects of Diketopiperazines from Marine-Derived Streptomyces puniceus on the Isocitrate Lyase of Candida albicans

“…Recently, the interest in these compounds has increased due to their various characteristics. Diketopiperazines possess a number of diverse biological properties, such as antimicrobial activity [12], antitumor activity [14], antiviral activity [15], inhibition of quorum-sensing signaling [16], plant-growth promotion [17], inhibition of carbonic anhydrases [18], and inhibition of aflatoxin production [19].…”

Activation of carbonic anhydrases from human brain by amino alcohol oxime ethers: towards human carbonic anhydrase VII selective activators

“…histamine shows a 10 nM K A s against hCAs VA and XIV but is a micromolar activator of the remaining isoforms) 1 . The molecule of histamine has been extensively modified ( Figure 3 ), including substituents on the imidazole C atoms ( A ) 41 , 42 , replacing the imidazole ring with other heterocycles, such as 2,4,6-trisubstituted pyridinium ( B ), 1,3,4-thiadiazole ( C ) or a combination of these two ring systems ( D ) 43 , 44 and functionalising the NH 2 group, as in carboxamides/ureas/thioureas ( E ) 45 , sulphonamides ( F ) 46 , arylsulfonylureas ( G ) 47 , bis-histamine ( H ) 48 , 49 , oligopeptides 49 , 50 , or imidazole/imidazoline derivatives of the alkaloyd spinaceamine 51 , 52 and drug clonidine 53 ( Figure 3 ) were reported to possess improved CA activatory profile when potency and isoform selectivity are concerned.…”

Sulfur, selenium and tellurium containing amines act as effective carbonic anhydrase activators

“…2,14 Histamine (Figure 1) was one of the first CA activator (CAA) discovered 15 and also one of the most investigated scaffold for designing novel ones. 16,17 X-ray crystal structure of CA-Histamine has been reported in the 90's showing the mechanism of activation, where the molecule participates to the rate-determining step of the catalytic cycle, facilitating the formation of the nucleophilic species of the enzyme. 15 In the last years, our group focused on new molecules with activating propriety against CAs, most of which amines of the general formula Ar-CH 2 CH(R)NHR'.…”