Tautomerism of N-(3,4-dichlorophenyl)-1H-indazole-5-carboxamide – A new selective, highly potent and reversible MAO-B inhibitor

The tautomeric properties of an N -(3,4-dichlorophenyl)-1 H -indazole-5-carboxamide (NTZ-1006, 2 ) derivative, developed as highly potent, reversible and selective MAO-B inhibitor useful for the treatment of Parkinson's disease (PD) and other neurological disorders, have been studied both experimentally and theoretically. The theoretical data (M06–2X, B3LYP and MP2-4 quantum chemical calculations) have shown that due to aromaticity reasons the 1 H tautomer strongly dominates over the 2 H form. There are no substantial spectral changes by changing the solvent and the concentration, which leads to a conclusion that compound 2 exists in solution as 1 H tautomer and its tautomerism is not influenced by the solvents and the concentration. The results are in line with the understanding for the tautomerism of 1 H -indazole and shows that substitution at the C5 position in the indazole unit does not influence the tautomeric state. The isolated crystal structure of 2 is in an excellent agreement with the computation in respect of the most stable tautomer. Combined single X-ray/molecular modeling studies including HYdrogen-DEsolvation (HYDE) analysis provided not only insights into the enzyme–inhibitor interaction within the binding site of the human MAO-B isoform, but also a valuable information regarding the most stable 1H-indazole tautomeric form of NTZ-1006 that contributes to its high potency against hMAO-B enzyme (IC 50 0.586 nm) and selectivity (>17000-fold) over the hMAO-A isoenzyme. • The calculations and the experiment clearly show the existence of the 1H-tautomer only in the studied compound 2 (NTZ-1006). • 1 H -indazole tautomeric forms appears to be favorable under physiological conditions. • High inhibitory potency and selectivity of the studied MAO-B inhibitors 2 – 4 is due to their 1 H -indazole tautomeric forms.