From structural diversity to enzyme inhibition: Heterometallic Co-M maleate complexes as novel carbonic anhydrase and AChE modulators

Abstract

The interaction of cobalt maleate bis-hydrogene with acetates and nitrates of Cu(II), Fe(II), Ni(II) and Zn(II) has been studied. It was found that depending on the nature of the metal ion, concentration of the reagents and anion, either heterometallic maleate or polymeric heterometallic maleate of the composition of [CoxM1x(OOCCH--CHCOOH).(H2O)2]n can be formed. The composition and structure of the obtained complexes were studied by IR, electron spectroscopy, EPR, cyclic voltammetry, and thermogravimetric analyses. The molecular and crystal structures of monomeric maleate and polymeric Cu-Co maleate were established by X-ray. The activities of metal complexes against various proteins these are hCA I protein (PDB ID: 2CAB), hCA II protein (PDB ID: 5AML), and AChE (PDB ID: 4M0E) were compared. Enzyme inhibition studies demonstrated that the heterometallic Co-Cu (1Cu(II)) and Co-Fe (3Fe(II)) maleate complexes exhibited remarkable inhibitory activity against hCA I, hCA II, and acetylcholinesterase (AChE). The 1Cu(II) complex inhibited hCA I and hCA II with IC50 values of 45.81 and 32.18 & micro;M and K-i values of 38.80 and 23.91 & micro;M, respectively. Notably, these values were approximately two-fold lower than those obtained for the reference inhibitor acetazolamide (AZA) (IC50 = 87.05 and 70.37 & micro;M for hCA I and hCA II, respectively), indicating superior inhibitory potency. Similarly, the 3Fe(II) complex displayed IC50 values of 55.87 & micro;M (hCA I) and 43.15 & micro;M (hCA II), which were also markedly lower than those of AZA, confirming the enhanced carbonic anhydrase inhibitory activity of the heterometallic complexes. Notably, both complexes showed potent AChE inhibition, particularly 3Fe(II), with an IC50 of 3.25 & micro;M and K-i of 1.87 & micro;M, outperforming the standard inhibitor tacrine.