Regioselective synthesis, biological evaluation, and molecular docking of dihydropyrimidin‐4‐ols as acetylcholinesterase inhibitors

Abstract

A new series of 3,6-disubstituted 2-(methylthio)-4-(trifluoromethyl)-3,4-dihydropyrimidin-4-ols displaying methyl, phenyl, aryl, and heteroaryl groups at the 6-position; and methyl, ethyl, allyl, and phenyl groups at the 3-position of the dihydropyrimidine ring, were synthesized and evaluated in vitro for acetylcholinesterase inhibitory activity. Seven compounds showed activity with IC values in the lower micromolar range. The compound 4-trifluoromethyl-6-(4-fluorophenyl)-3-methyl-2-methylthio-3,4-dihydropyrimidin-4-ol (6e) had the best inhibitory activity (IC 2.2 ± 0.9 μm) and this inhibition was characterized as competitive. The molecular docking study showed that the acetylcholinesterase enzyme accommodates compound 6e in its catalytic site. The enantiomers of compound 6e, present similar interactions: π-π stacking interactions between the aromatic ring of the ligand's 4-fluorophenyl moiety and the aromatic rings of the electron-rich Trp84; and H-bonds between the hydroxyl group of Tyr121 and the hydroxyl moiety from 6e. The antioxidant effect of the dihydropyrimidin-4-ols was also investigated.

Design, Synthesis, and Cholinesterase Inhibitory Activity of 4‐Substituted‐6‐(trihalomethyl)‐2‐methylsulfanyl Pyrimidines

“…Taking into account that 5 e, 5 f, and 5 g were the best inhibitors, their half-maximal inhibitory activity (IC 50 ) values (which indicate the inhibiting potency of a substance toward an enzyme [28] ) were determined for AChE and BChE (Table 3). The IC 50 values found in this work (13.8-81.6 μM) were in the same range as other pyrimidine derivatives (0.3-80 μM) [14,29] and the classical inhibitor galantamine (4-8 μM). [30] However, the tested molecules showed a weak activity when compared to the Tacrine (a well-known cholinesterase inhibitor).…”

“…In fact, pyrimidine derivatives have been shown to interact in this region. [14,29] The compounds 5 a and 5 b have a binding pose similar to that of the ammonium moiety (À NR 2 H + ), interacting with the carboxylic and indole groups from Glu199 and Trp84 residues by salt bridge and π-cation interactions, respectively-similar to the ACh substrate (see Figure 2 and Table 4). The trifluoromethyl group from 5 a and 5 b had hydrophobic interactions with Phe330, Phe331, and Tyr334.…”

“…The computational docking simulation suggested that all the molecules bind near the AChE catalytic triad (Ser200, Glu327, and His440) in a thermodynamically favorable process (▵G<0). In fact, pyrimidine derivatives have been shown to interact in this region [14,29] …”

“…[9,10] β-Alkoxyvinyl trihalomethyl ketones have proven to be successful as CCC-building blocks in the regioselective synthesis of several heterocyclic scaffolds [11][12][13] (including pyrimidine rings), easily allowing the introduction of trihalomethyl groups. [14,15] On the other hand, allylic brominated β-alkoxyvinyl trihalomethyl ketones (enones) have been far less explored in heterocyclic synthesis, especially in regard to pyrimidines. [16] Given the high chemoselectivity that has been observed in the synthesis of several heterocycles, the use of these enones in heterocyclic synthesis is now well established.…”

Trifluoromethyl β‐Enamino Diketones as Dual Substrates for the Synthesis of 5‐Benzoyl‐6‐(trifluoromethyl)pyrimidines and their Pyrimidin‐4(3H)‐one Analogues

“…Although this method is quite simple, there are two main disadvantages: two reaction steps are required; and a mixture of N 1 ‐, N 3 ‐, and O ‐alkylated products is often observed . These drawbacks are easily overcome by using 4‐alkoxy‐1,1,1‐trichloro/fluoroalk‐3‐en‐2‐ones and non‐symmetrical N ‐substituted isothioureas ( NCN ‐dinucleophile that may furnish a mixture of N 1 ‐ or N 3 ‐regioisomers, Scheme a) . In a basic medium, the trichloromethyl group is easily eliminated, thus providing the 6‐substituted‐pyrimidin‐4(3 H )‐ones (Scheme b) .…”