2-(2-indolyl-)-4(3H)-quinazolines derivates as new inhibitors of AChE: design, synthesis, biological evaluation and molecular modelling

Figures & data

Figure 1.  Structures of donepezil, galantamine and rivastigmine.

Figure 2.  Structures of 2-(2-indolyl-)-4(3H)-quinazolines (2IQ) and rutaecarpine (Ru).

Scheme 1.  Synthesis of 6-aminoalkanamido-substituted 2-(1H-indol-2-yl)quinazolin-4(3H)-one derivatives (3a–j). Reagents and conditions: (i) orthoesters, reflux, 3 h; (ii) tryptamine, 115°C, 3 h; (iii) HCI, AcOH, reflux, 1 h; (iv) (v) 10% Pd/C, H2, MeOH, 8 h; (vi) ClCO(CH₂)_nCl, CH₂Cl₂, reflux and (vii) HNR₂, EtOH, KI, reflux (‘R-’ are shown in Table 1).

Scheme 2.  Synthesis of 4-substituted 2-(1H-indol-2-yl)quinazolin-4(3H)-one derivatives (9a and 9b). Reagents and conditions: (i) POCl₃, PhN(CH₂CH₃)₂/Ph, reflux, 6 h and (ii) H₂N(CH₂)₃NR₂, EtOH, KI, reflux; (‘R-’ are shown in Table 1).

Table 1.  In vitro inhibition IC₅₀^a and selectivity index of derivatives 3a–j and 9a–b on AChE and BuChE.

Compound	―NR2	n	AChE inhibition^b, nM	BuChE inhibition^c, nM	Selectivity index^a
2IQ			>10,000	>10,000	—
3a	―N(CH2CH3)2	1	502.5 ± 0.7	1,4750 ± 10	29.35
3b		1	326.6 ± 1.0	3103 ± 2	9.50
3c		1	147.9 ± 1.0	1,0160 ± 20	68.70
3d		1	2015 ± 2	3,2170 ± 30	15.97
3e		1	>10,000	>10,000	—
3f	―N(CH2CH3)2	2	276.3 ± 1.0	2429 ± 1	8.79
3g		2	100.2 ± 0.3	403.2 ± 0.1	4.02
3h		2	20.97 ± 0.06	7322 ± 9	349.17
3i		2	1258 ± 1	5,1600 ± 40	41.02
3j		2	>10,000	>10,000	—
9a	―N(CH3)2		>10,000	>10,000	—
9b	―N(CH2CH3)2		>10,000	>10,000	—
Tacrine			222.7 ± 2.3	29.98 ± 0.27	0.1

^a Mean ± SD of at least three independent measurements.

^b 50% inhibitory concentration (means ± SEM of at least four independent experiments) of AChE from electric eel.

^c 50% inhibitory concentration (means ± SEM of at least four independent experiments) of BuChE from equine serum.

^d Selectivity Index for AChE = IC₅₀ (BuChE) / IC₅₀ (AChE).

Figure 3.  Lineweaver–Burk plots of the inhibition kinetics of AChE (A) and BuChE (B) by compound 3h.

Figure 4.  (Colour online) Docking models of compound–enzyme complex. Representations of compound 3h (A, B) and 9a (C, D) interacting with residues in the binding site of TcAChE (A, C) and HuBuChE (B, D). The compounds are rendered in green stick models, and the residues are rendered in golden sticks. Pictures are created with PyMOL²⁷.

Seeliger D, de Groot BL. Ligand docking and binding site analysis with PyMOL and Autodock/Vina. J Comput Aided Mol Des 2010;24:417–422.

 PubMed Web of Science ®Google Scholar