DENSITY FUNCTIONAL THEORY (DFT) METHOD ON SHORT SYNTHESIS REACTION MECHANISM OF MOLNUPIRAVIR

• Main Author: Pratiwi Meliawati, Aristia
• Format: Theses
• Language: Indonesia
• Subjects: Kimia
• Online Access: https://digilib.itb.ac.id/gdl/view/65252
• Institution: Institut Teknologi Bandung

Molnupiravir is a solid dosage prodrug whose activity is still being researched against influenza, MERS-CoV, and SARS-CoV-2 viruses. Molnupiravir is an isopropyl ester prodrug of N4-hydroxycitidine, hydrolyzed in vivo and distributed in tissues to convert it to the active form 5'-triphosphate. This active drug incorporates into the viral RNA genome causing catastrophic errors in the virus. Recent studies have reported that molnupiravir can inhibit the replication of coronaviruses, including SARS-CoV-2. Molnupiravir was initially synthesized from uridine. However, this synthesis route is not economical. Researchers from Merck, who have received a license from Ridgeback Biotherapeutics, developed the synthesis of molnupiravir from another natural material, cytidine, with a shorter synthesis step. This step involves a transesterification reaction and a transamination reaction. The transesterification reaction occurs between cytidine and isobutyrate oxime ester. In laboratory experiments, the transesterification reaction was carried out enzymatically with immobilized lipase Candida antarctica. Then, proceed with the transamination reaction of hydroxylamine sulfate on the formed intermediate. The transesterification reaction uses the 1,4-dioxane as a solvent because it produces a more optimal intermediate than other solvents. Meanwhile, isopropyl alcohol is used as the solvent in the transamination reaction. The synthesis reaction experiment was carried out in two schemes. The first scheme begins with the transesterification reaction, followed by the transamination reaction. The second scheme is the reverse reaction of the first scheme. The transamination reaction is first, followed by the reaction transesterification. So far, studies on the reaction mechanism for the synthesis of molnupiravir are still negligible. The study of reaction mechanisms is needed to understand and control the chemical reactions that take place so that they can provide economic and environmental benefits. One method that can be used to predict the mechanism of a reaction is through computational studies in quantum mechanics (QM). This computational study of the reaction mechanism uses the Density Functional Theory (DFT) method and the B3LYP level theory. The calculations were performed using the base set def2-SVP and validated with def2-TZVP(-f). Optimization of the initial structure is carried out in the gas phase with a lower base set, def2-SVP. The base set def2-SVP is also used to calculate the transition state. The geom-scan command is performed to see the possible transition states that can be formed. Based on the geom-scan results, the transesterification reaction occurs without the intermediate. At the same time, the transamination reaction occurs through the intermediate. Next, the TS optimization command was performed on both reactions.Based on calculations, the transesterification activation energy in scheme-1 is 128.09 kJ/mol and in scheme-2 is 127.90 kJ/mol. The value of the transesterification activation energy in Scheme-1 and Scheme-2 is not different significantly. The activation energy of the transamination reaction passes through two intermediates. The first is a protonation reaction with an activation energy of 106.57 kJ/mol in scheme-1 and 119.90 kJ/mol in scheme-2. It means that scheme-2 requires a higher protonation activation energy than scheme-1. The following reaction is the substitution of NH3 with NH2OH. This step involves activation energy of 146.84 kJ/mol for scheme-1 and 204.71 kJ/mol for scheme-2. Scheme-2 also requires higher activation energy than scheme-1. The final reaction is deprotonation. The reaction of scheme-1 requires activation energy of 230.63 kJ/mol, while scheme-2 requires activation energy of 359.10 kJ/mol. Overall, the transamination reaction of scheme-2 requires more energy than scheme-1. The dissolving energy calculation is also computationally calculated with the implicit solvation model. Based on calculations, isopropyl alcohol solvent stabilized energy in all transamination reactions and transesterification in scheme-1. In contrast, 1,4-dioxane stabilized the energy of transesterification in scheme-1