Design, Synthesis, and In Vitro Kinetics Study of Atenolol Prodrugs for the Use in Aqueous Formulations

Table 1

Experimental and DFT calculated kinetic and thermodynamic properties for the acid-catalyzed hydrolysis of 1–9, Inter, and atenolol ProD 1-ProD 2.

System	B3L Δ𝐻^‡d; (kcal/mol)	B3L311 Δ𝐻^‡d; (kcal/mol)	MPW1k Δ𝐻^‡d; (kcal/mol)	MP2 Δ𝐻^‡d; (kcal/mol)	log EM; (Exp)	log EM; (Calc)	Exp Δ𝐺^‡38; (kcal/mol)
(1)	27.31	27.42	25.07	25.75	7.724	8.52	23.70
(2)	13.93	14.02	11.96	10.41	15.86	18.08	17.30
(3)	24.41	23.85	22.61	21.51	7.742	11.93	21.14
(4)	34.42	—	—	—	1.255	4.81	30.70
(5)	13.25	—	—	—	15.190	15.82	19.75
(6)	23.83	—	—	—	6.962	12.76	—
(7)	24.86	—	—	—	8.568	12.57	—
(8)	24.08	—	—	—	—	6.36
(9)	17.88	—	—	—	—	21.68
Atenolol ProD 1	20.08	—		—	—	4.06
Atenolol ProD 2	15.43	—	—	—	—	13.11
Inter	39.90	—	—	—	—	—	—

B3LYP refers to values calculated by B3LYP/6-31G (d,p) method. Δ𝐻^‡ is the calculated activation enthalpic energy (kcal/mol). 𝑇Δ𝑆^‡ is the calculated activation entropic energy (kcal/mol). Δ𝐺^‡ is the calculated activation free energy (kcal/mol). EM: 𝑒^{−(Δ𝐺‡inter−Δ𝐺‡intra)/RT}. BW refers to tetrahedral intermediate breakdown calculated in water. Exp refers to experimental value. Calc refers to DFT calculated values.