Design, synthesis and evaluation of 2-aryl benzoxazoles as promising hit for the A_2A receptor

Figures & data

Figure 1. Selective adenosine A_2A receptor antagonists.

Figure 2. Molecular modelling-guided design. (A) Representation of various modulations around the benzoxazole scaffold. (B) Predicted binding mode of ZM-241385 in the apoA2AR-T4E pocket (dark) compared with the X-ray binding mode (gray). (C) Putative binding mode of compound F1 in the apoA2AR-T4E pocket.

Scheme 1. Reagents and conditions: (a) i) ArCO₂H, SOCl₂, DMF, DCM, ii) Et₃N, EtOAc, aminophenol (1a–d); iii) NaOH, EtOH/H₂O, then 6 M HCl, 60–80% over 2 steps; (b) APTS, toluene, reflux, 70–80%, (c) T3P^® (50% in EtOAc), DIPEA, 3,4-dimethoxybenzoic acid, 35%.

Scheme 2. Reagents and conditions: (a) NBS, benzoyl peroxide, CCl₄, reflux/hυ (230 W), 60–75%; (b) R₂R₁NH, Et₃N, acetone, 50–85%; (c) TFA, DCM, 60%; (d) KCN, EtOH/H₂O, 50–60%; (e) H₂O/H₂SO₄/AcOH, reflux, 60–70%; (f) i) SOCl₂, toluene; ii) secondary amine, Et₃N, EtOAc, 50–60%; (g) LiAlH₄, THF, 60–75%; (h) i) dimethyl malonate, K₂CO₃, acetone; ii) NaOH, H₂O then 6 M HCl; iii) DMF, reflux, 40–43%.

Scheme 3. Reagents and conditions: (a) LiAlH₄, THF, 86%; (b) MsCl, Et₃N, DCM, quant.; (c) secondary amine, K₂CO₃, DMF, 60 °C, 25–28%.

Table 1. A_2A receptor affinity and cytotoxicity data of compounds A1–8, B1–6 and C1–3.

Scheme 4. Reagents and conditions: (a) hydrazine hydrate, Pd/C (10%), EtOH, 81%; (b) 1-(benzyloxy)-4-(2-bromoethyl)benzene, K₂CO₃, DMF, 70 °C, 15%; (c) H₂, Pd/C (10%), MeOH, 48%; (d) N-chloroethylpiperidine, K₂CO₃, DMF, 70 °C, 8%; (e) bromoacetylbromide, NEt₃, DCM, 75%; (f) for F1–3, secondary amine, K₂CO₃, acetone, 48–90%; (g) for F4, i) boc-piperazine, K₂CO₃, acetone, ii) 6 M HCl, MeOH, 72%.

Table 2. A_2A receptor affinity and cytotoxicity data of compounds D1, E1–2 and F1–4.

Table 3. Preliminary ADME studies of F1.

			Permeability Caco-2-(10^−6 cm/s)^c
Cpd.	Solubility (μm) PBS, pH 7.4^a	PPB (%)^b	A/B	B/A	LogD7.4^d	HLM^e t1/2 (min)	Clint^f (μl/min/mg)
F1	184	83	50	24	2.33	11	630

^aEvaluated after 24 h stirring. ^bPPB = plasma protein binding. Compound was tested at 10 μm concentration. ^cPermeability = Compound was tested at 10 μm concentration at pH 6.5/7.4. ^dDetermined between a mixture PBS_7.4/octanol. ^eHLM = human liver microsome. ^fCl_int = Compound was tested at 0.1 μm concentration.