Design and synthesis of 2-substituted-5-(4-trifluoromethylphenyl-sulphonamido)benzoxazole derivatives as human GST P1-1 inhibitors

Figures & data

Scheme 1. Synthetic pathway of 5-(4-trifluoromethylphenylsulphonamido)benzoxazole derivatives. Reagents and conditions: (A) PPA, 170–200 °C, 1.5–2.5 h; (B) Pyridine and dichloromethane, RT, 16 h.

Figure 1. (a) Binding sites of dimeric hGST P1-1 enzyme (pdb ID 2GSS and 6GSS): the protein structure is represented in solid ribbon secondary type. (b) Docking pose of compound 5f and Vh in 6GSS. (c) Docking pose of Vh*: sulphonyl group revealed H bonds with SH and glycine NH of GSH, CF₃ group of the compound showed halogen bond with Cys101, compound had interactions with Pro9 (alkyl hydrophobic), Val35 (pi-alkyl), Ile104 (pi-alkyl), and Tyr108 (pi–pi). (d) Docking pose of 5f*: sulphonyl group revealed H bond with Gln51 and Tyr108, compound had interactions with Arg13 (electrostatic), Lys44 (alkyl hydrophobic), Tyr108 (pi–pi), and GSH (pi-sulfur). (e) Docking pose of Vd*: sulphonyl group revealed H bonds with Tyr108 and glycine NH of GSH and CF₃ group revealed H bond with Tyr109, compound had interactions with Phe8 (pi–pi), Val10 (pi-alkyl), Val35 (pi-alkyl), and Tyr108 (pi–pi). (f) Docking pose of Vk*: sulphonyl group revealed H bond with Glycine NH of GSH, CF₃ group of the compound showed halogen bond with Ile104, compound had interactions with Phe8 (pi–pi), pro9 (pi-alkyl and alkyl hydrophobic), Ile104 (pi-alkyl and alkyl hydrophobic), Tyr108 (pi–pi), and GSH (pi-sigma). *The protein structure is represented in flat ribbon style, GSH and all the ligands are seen in stick representation.

Table 1. Docking results.

Comp. code	Binding energy(kcal/mol)	Interacted residues (van der Waals contact distance <4 Å)
Va	–9.12	Phe8^[a], Pro9, Val10^[b], Thr34, Val35^[b] (2.82 Å), Trp38, Gln39, Gln51, Ile104, Tyr108^[a], Gln205, Asn206, GSH
Vb	–15.79	Phe8^[a], Pro9, Val10, Val33, Thr34, Val35^[b], Gln51, Cys101, Ile104^[b], Ser105, Tyr108^[a] (2.53 Å), Gln205, Asn206, GSH^a (2.62 Å)
Vc	–10.50	Phe8^[a], Pro9, Val10^[b], Arg13, Thr34, Val35 (2.94 Å), Gln51, Cys101, Ile104^[b], Ser105, Tyr108^[a] (2.83 Å), Gln205, GSH
Vd	–15.98	Tyr7, Phe8^[a], Pro9, Val10^[b], Val33, Thr34, Val35^[b], Ile104, Tyr108^[a] (3.09 Å), Thr109 (2.93 Å), Pro202, Gln205, GSH^a (2.79 Å)
Ve	–12.06	Phe8, Pro9, Val10, Arg13, Thr34, Val35^[b], Cys101, Ile104^[b], Tyr108^[a], Gln205, GSH
Vf	–19.95	Phe8^[a], Pro9, Val10^[b], Arg13, Thr34, Val35, Gln51, Cys101, Ile104^[b], Ser105, Tyr108 (2.99 Å), Gln205, GSH^[d]
Vg	–13.01	Tyr7, Phe8, Pro9^[b], Val10, Val33, Thr34, Val35^[b], Gln51, Cys101, Ile104^[b], Ser105, Tyr108^[d], Gln205, GSH^a ^[c] (2.21 Å)
Vh	–21.92	Phe8, Pro9^[e], Val10, Arg13, Val35^[b], Gln51, Cys101^[x], Ile104^[b], Ser105, Tyr108^[a], Gln205, GSH^a^,^b^,^[c] (2.32, 1.46 Å)
Vi	–6.01	Phe8^[a], Pro9^[b], Val10^[b], Arg13, Val35, Gln51, Cys101 (2.69 Å), Ile104^[b], Ser105, Tyr108^[a], Gln205, GSH^a (2.40 Å)
Vj	–19.84	Tyr7, Phe8, Pro9, Val10, Arg13, Val33, Thr34, Val35^[b], Gln51, Cys101, Ile104^[b], Ser105, Tyr108^[a], Gln205, GSH^a (2.32 Å)
Vk	–21.08	Tyr7, Phe8^[a], Pro9^[b,e], Val10, Arg13, Val33, Thr34, Val35^[b], Gln51, Cys101, Ile104^[x,b,e], Ser105, Tyr108^[a], Gln205, GSH^[c] (2.22 Å)
5f	–15.79	Tyr7, Phe8, Val10, Arg13^[f], Val35, Trp38, Gln39, Lys44^[e], Gln51 (2.42 Å), Ile104, Tyr108 (1.94 Å^) [a], Gln205, GSH^[g]
EA	–10.65	Phe8^[b], Val10, Arg13 (2.27 Å), Val35, Trp38, Gln39, Ile104, Tyr108^[b], Pro202, Gln205, GSH^b (2.42 Å)

Bold: H-bonds, [x]: halogen bonds, [a]: pi–pi interactions, [b]: pi-alkyl interactions, [c]: pi-sigma interactions, [d]: pi-donor interactions, [e]: alkyl-hydrophobic interactions, [f]: electrostatic interactions, [g]: pi-sulphur interactions

^a H bond revealed with glycine NH of GSH.

^b H bond revealed with SH proton of GSH.

Table 2. The structures of the tested sulfonamidobenzoxazoles and their in vitro hGST P1-1 inhibitory effects.

Comp. code	R	R1	X	IC50 (μm)
Va	H	CF3	–	8.41 ± 0.8
Vb	Cl	CF3	–	8.40 ± 0.3
Vc	F	CF3	–	10.00 ± 0.4
Vd	Br	CF3	–	9.00 ± 2.1
Ve	C2H5	CF3	–	8.30 ± 2.0
Vf	CH3	CF3	–	10.00 ± 0.8
Vg	H	CF3	CH2	10.00 ± 1.1
Vh	Cl	CF3	CH2	8.91 ± 1.2
Vi	F	CF3	CH2	8.75 ± 3.1
Vj	Br	CF3	CH2	15.80 ± 1.6
Vk	CH3	CF3	CH2	8.95 ± 0.3
5f [16]	Cl	NO2	CH2	10.20 ± 1.9
EA				10.37 ± 1.1

Ertan-Bolelli T, Musdal Y, Bolelli K, et al. Synthesis and biological evaluation of 2-substituted-5-(4-nitrophenylsulfonamido)benzoxazoles as human GST P1-1 inhibitors, and description of the binding site features. ChemMedChem. 2014;9:984–992.

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