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-1,4naphthoquinone
(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

 

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