Modeling And Synthesis Of Antiplasmodial Naphthoquinones From Natural Products Of Kenya

Abstract

While there have been many approved drugs for treatment and prevention of malaria, drug resistance has compromised the efficacy of some of them necessitating the development of new antimalarial drugs. Using computer aided drug discovery (CADD), this study exploited a newly validated enzyme target; Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH), for antimalarial drug discovery. Natural products of Kenya containing 1,4-naphthoquinone scaffold were targeted for investigation. To facilitate the CADD studies, a searchable web based in silico database; the Mitishamaba database (http://Mitishamba.uonbi.ac.ke/) consisting of 1102 bioactive natural products of Kenya was developed. An assessment on the relevance of the database in drug discovery proved that 55.4% of the compounds in the Mitishamba database fell within the lead space and therefore ideal for drug discovery. In search for new PfDHODH inhibitors, the 1,4-napthoquinones in the Mitishamba database were subjected to binding studies. Psychorubin (5) which has previously been established to be active against Plasmodium falciparum emerged as the best structure, which was modelled to generate a number of analogs, out of which 2-acetylamino-1,4 naphthoquinone (38) and 2-amino-1,4- naphthoquinone (39) were synthesized and biologically evaluated against Plasmodium falciparum. 2,4-Dinitro-1-naphthol (35), which was one of the intermediates in the synthesis of compound 39 was also tested and found to exhibit activity of 1.67 ± 0.20 μg/ml against the chloroquine resistant K1 isolate and 4.22 ± 2.99 μg/ml against the chloroquine sensitive 3D7 isolate. Compound 38 had an activity of 8.23 ± 1.67 μg/ml against the chloroquine resistant K1 isolate and 3.86 ± 1.21 μg/ml against the chloroquine sensitive 3D7 isolate, while compound 39 had an activity of 24.74 ± 3.56 μg/ml against the chloroquine resistant K1 isolate and 12.51 ± 1.19 μg/ml against the chloroquine sensitive 3D7 isolate. The promising antiplasmodial activities of the computational models demonstrate that the Mitishamba database can be used in lead design and a source of lead compounds for drug discovery.