New Histamine-Related Five-Membered N-Heterocycle Derivatives as Carbonic Anhydrase I Activators

Abstract

A series of histamine (HST)-related compounds were synthesized and tested for their activating properties on five physiologically relevant human Carbonic Anhydrase (hCA) isoforms (I, II, Va, VII and XIII). The imidazole ring of HST was replaced with different 5-membered heterocycles and the length of the aliphatic chain was varied. For the most interesting compounds some modifications on the terminal amino group were also performed. The most sensitive isoform to activation was hCA I (KA values in the low micromolar range), but surprisingly none of the new compounds displayed activity on hCA II. Some derivatives (1, 3a and 22) displayed an interesting selectivity for activating hCA I over hCA II, Va, VII and XIII.

Sulfonamide derivatives with benzothiazole scaffold: Synthesis and carbonic anhydrase I–II inhibition properties

“…Both compounds contain a pentacyclic ring and a heteroatom in their structure. It has been reported that the presence of –N and –S atoms in the ring structure correlates better with hCA I inhibition 56 . Our study is in agreement with this analysis.…”

“…It has been reported that the presence of -N and -S atoms in the ring structure correlates better with hCA I inhibition. 56 Our study is in agreement with this analysis. Compound 6 (K i = 0.113 ± 0.054 µM), which contains an ethyl group attached to the secondary amide in the tail, showed the second-best inhibitory property against hCA I among the compounds containing a single secondary sulfonamide.…”

Carbonic Anhydrase Activators for Neurodegeneration: An Overview

“…Specifically, above all derivatives synthesized, compounds 80, 81, and 82 showed an interesting selectivity for activating hCA I over hCA II, VA, VII, and XIII (Table 10). Compounds 80-82 could represent lead molecules to obtain new potent and selective hCA I activators [71]. and 79b, showing to be potent (KA 0.9 μM) and quite selective activators of hCA V and VII, respectively.…”

“…and 79b, showing to be potent (KA 0.9 μM) and quite selective activators of hCA V and VII, respectively. In an effort to improve both potency and selectivity, in 2022, Chiaramonte et al developed histamine-related compounds by replacing the imidazole ring with several fivemembered heterocycles (pyrrole, N1-substitued imidazole, pyrazole, etc..), and changing the length of the aliphatic chain that leads to the primary amino group [71].…”

“…Specifically, above all derivatives synthesized, compounds 80, 81, and 82 showed an interesting selectivity for activating hCA I over hCA II, VA, VII, and XIII (Table 10). Compounds 80-82 could represent lead molecules to obtain new potent and selective hCA I activators [71]. In 2016, Maccallini et al [72] attempted to join the favorable characteristics for activating CAs of heterocyclic compounds such as indazole, pyrazole, and oxazole rings with amino acids characterized by the ability to inhibit neuronal nitric oxide synthase (nNOS), which is an important activity for the treatment of neurodegenerative diseases hCA I: K A = 0.9 µM hCA VA: K A = 11.2 µM hCA VII: K A = 13.2 µM hCA XIII: K A > 100 µM [71] 2.7.4.…”