STRUCTURE-ACTIVITY ANALYSIS

MAGL inhibitors: the results indicate a directly proportional correlation of the potency of the inhibitory effect (pIC50) with the value of ENAt, (4-14) number of hydrogen acceptors  (5-11) and molecular weight (250-550 g/mol) and inversely proportional with that of hydrogen donors. The lipophilic character does not significantly influence the ability to inhibit MAGL.

The analysis of the types of cyclic structures indicated 56 individual nuclei, the most frequent being the benzene nucleus, piperazine, benzotriazole, piperidine and tetrazole. The thiazole nucleus stands out for its presence in 13 compounds, of which 12 belong to set A (92.3% effectiveness). The azetidinic core is present in 13 structures and has an efficiency index of 84.6%.

Analysis of the Bemis-Murcko skeletons resulted in a total of 149 individual skeletons indicating great structural diversity. They contain between 1 and 6 cyclic structures.. A number of 46 BM-type molecular skeletons have an efficiency value above 50%. All these skeletons contain a minimum of two and a maximum of six cyclic structures. A common structural feature is observed for all these molecular skeletons, the cyclic nuclei are joined directly to each other or by means of a very small number of linking atoms.

The potency of the FAAH inhibitory effect (pIC50) is correlated with the number of nHAt atoms and molecular weight. An increased lipophilic character, a high number of hydrogen bond acceptors (4-9) and the presence of aromatic nuclei (2-5) are advantageous. The presence of a reactive group capable of blocking the catalytic center can be a sufficient element, in the absence of other structural characteristics

Bemis-Murcko skeletons favorable for an FAAH inhibitory effect contain at least two cyclic structures and generally have an elongated, flexible cylinder-type shape similar to that of anandamine, the enzyme's natural substrate. It is observed that the architecture of FAAH inhibitors can vary relatively much, if a certain conformational profile is respected.

The analysis of the types of cyclic structures in the structure of FAAH inhibitors indicated 120 individual cores, the most frequent being the benzene core (91.6%), piperazine (30.4%), pyridine (23.6%), oxazole (12.4 %) and pyrimidine (7.6%). The thiazole nucleus stands out for its presence in 39 compounds, of which 25 belong to set A (efficacy 64.1%). Similarly, the isoxazolidine nucleus present in 29 structures and with an efficiency index of 70.4%. The relative position of the heteroatoms in the heterocycles is essential for the potency of the inhibitory effect. The greater this distance, the lower its usefulness on the FAAH inhibitory effect.