New 5-, 3- and 3,5-Substituted Hydantoin Derivatives: Synthesis, In Vitro Antiplasmodial and Cytotoxic Activities, and In Silico Admet Analysis and Molecular Docking

Chin, Ee Zhen (2022) New 5-, 3- and 3,5-Substituted Hydantoin Derivatives: Synthesis, In Vitro Antiplasmodial and Cytotoxic Activities, and In Silico Admet Analysis and Molecular Docking. Masters thesis, Tunku Abdul Rahman University College.

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Abstract

Hydantoin moiety is an important structural scaffold which has been deeply studied in the fields of organic synthesis and drug development due to its wide applications. Many hydantoin derivatives have been identified as anticonvulsant, antiulcer, antiarrhythmic, antimuscarinic, antiviral, and antidiabetic agents. This research aims to design and synthesize the desired hydantoin derivatives through multi-step synthesis methods. The hydantoin derivatives obtained were evaluated for their in vitro antiplasmodial activity against the chloroquine-resistant P. falciparum 3D7 strain, in vitro cytotoxic activity against human MRC-5 cells, and in silico ADMET prediction and molecular docking. In the present study, the synthesis of 5-monosubstituted hydantoins were successfully achieved via the synthesis of hydantoin ethyl ester hydrochlorides (2a-d), the synthesis of ureido derivatives (3a-d), and the synthesis of 5-monosubstituted hydantoin derivatives (4a-d). 3-monosubstituted hydantoins (5a-d) were synthesized via the Gabriel amine approach, while compounds 6a and 6b were obtained through acylation reaction. These compounds were successfully characterized using various spectroscopic techniques, such as 1H and 13C NMR, IR, CHNS/O elemental analysis, and polarimeter, which were named ethyl 2-amino acetate 2a, ethyl 2-aminopropanoate 2b, ethyl 2-amino-2-phenylacetate 2c, ethyl 2-amino-4-(methylthio)butane 2d, ethyl 2-ureidoacetate 3a, ethyl 2-ureidopropanoate 3b, ethyl 2-phenyl-2-ureidoacetate 3c, ethyl 4-(methylthio)-2-ureidobutanoate 3d, imidazolidine-2,4-dione 4a (also known as hydantoin), 5-methylimidazolidine-2,4-dione 4b, 5-phenylimidazolidine-2,4-dione 4c, 5-(2-(methylthio)ethyl)imidazolidine-2,4-dione 4d, 3-acetylimidazolidine-2,4-dione 5a, 3-isobutyrylimidazolidine-2,4-dione 5b, 3-tosylimidazolidine-2,4-dione 5c, 3-(2-phenylacetyl)imidazolidine-2,4-dione 5d, ethyl 3-(3,5-dinitrobenzoyl)imidazoidine-2,4-dione 6a, and 3-isobutyryl-5-phenylimidazolidine-2,4-dione 6b. All these compounds were newly designed and synthesized, except for 2a-c and 4a-b. Our findings showed that compound 5c exhibited excellent in vitro antiplasmodial activity with IC50 value of 3.97 ± 0.01 nM. All hydantoin derivatives are not cytotoxic against human MRC-5 cells with an IC50 value of more than 100 μM. Remarkably, compound 5c are also one of the three best compounds that showed the lowest docking energies and lowest inhibition constants for in silico analysis. In addition, hydantoins do fit into a drug-like chemical property space. Furthermore, owing to problems with multi-drug resistance, there is a need for new drugs to treat malaria. Hydantoin is an attractive drug target to combat malaria.