KENDUIWO, CAROLINE CHEPKIRUI

Photo
KENDUIWO, CAROLYNE
Project Title
PHYTOCHEMICAL ANALYSES OF MUNDULEA SERICEA, TEPHROSIA UNIFLORA (LEGUMINOSAE) AND, STREBULUS USAMBARENSIS (MORACEA) FOR ANTI-INFECTIVE PRINCIPLES
Degree Name
DOCTOR OF PHILOSOPHY IN CHEMISTRY
Project Summary

Infectious diseases are a public health concern, as they cause serious illnesses in humans. Among infectious diseases, malaria, leishmaniasis, and bacterial diseases account for about a million fatalities per year. Globally, two hundred million cases of malaria were reported in 2019, with over four hundred thousand fatalities. Africa is the epicentre of malaria, accounting for at least 94 percent of all reported cases. Similarly, the World Health Organization reports 30,000 new infections of visceral leishmaniasis yearly, with 20,000 deaths. Incidences of cancer and coinfection with bacteria have been reported in malaria and leishmaniasis patients. Cancer accounted for about ten million fatalities and 19.3 million new cases globally. To reduce the burden of these diseases, chemotherapies are widely practiced. However, drug –resistance has been a persistent problem. In addition, the most effective drugs are costly and/or toxic, necessitating the continuous search for novel drugs. Plant derived heterocyclic compounds, including flavonoids have been
reported to show activities against pathogenic infections and cancer. Thus, the antimalarial, antileishmanial, anticancer, and antibacterial properties of some members of the Leguminosae and Moraceae families which are known to be rich sources of flavonoids and other phenolics were studied. Hence, phytochemical analysis of the dichloromethane/methanol (1:1) extracts of Mundulea sericea and Tephrosia uniflora (both Leguminosae) and Strebulus usambarensis (Moraceae) yielded thirty-one compounds. Phytochemical analysis of S. usambarensis stems and roots resulted in the identification of three novel naphtho-benzofuran derivatives, named usambarin A (110), B (111), and C (112). Eight new naphthalene derivatives named usambarin D (113), E (114), F(115), G (116), H (117), I (118), and L (125), phenyl-1-benzoxepin derivative (120), two flavans (119 and 126), and four known compounds. Similarly, the analysis of the stems and roots of M. sericea yielded ten known compounds; three flavanonols, two flavanols, an isoflavone, one rotenoid, two pterocarpans, and the sterol stigmasterol. Phytochemical investigation of the stems of T. uniflora also yielded one new -hydroxydihydrochalcone (134) and three known compounds (an isoflavone, -hydroxydihydrochalcone and a rotenoid). NMR, X-ray crystallography, UV spectroscopy, electronic circular dichroism and mass spectrometry were used to determine their structures.

The crude extract of M. sericea roots exhibited antiplasmodial effect against chloroquine-resistant (W2) (IC50 of 0.6 μg/mL) and chloroquine-sensitive (3D7) (IC50 1.8 μg/mL) strains of Plasmodium falciparum. Among the major compounds from this plant, lupinifolinol (129) (IC50 of 2.0 μM against the W2 strain, and 6.6 μM against the 3D7 strain), and mundulinol (64) (IC50 of 5.9 μM
against the W2 strain and 2.4 μM against the 3D7 strain) were active. The antileishmanial activity of selected compounds was tested against L. donovani strains, both antimony-sensitive (MHOM/IN/83/AG83) and antimony-resistant (MHOM/IN/89/GE1), of which sericetin (130) was active against antimony-sensitive (IC50 5.0 M) and antimony-resistant (IC50 38.0 μM) strains. Dehydrolupinifolinol (128) was also active against the antimony-sensitive strain (IC50 9.0 μM). The isolated compounds from S. usambarensis were tested against E. coli and B. subtilis.

Usambarin D (113) had moderate antibacterial activity against B. subtilis (MIC = 9.0 M), however, the other compounds examined were inactive (MIC >100 M). All the tested compounds were inactive against E. coli. Some of the identified compounds from S. usambarensis and M. sericea were investigated for their cytotoxicity against; lung (A549), breast (MCF-7), immortal human hepatocytes (LO2), liver (HepG2), and human lung/bronchus cells (epithelial virus-transformed, BEAS-2B) cancer cell lines. Usambarins A (EC50 of 65 μM) and B (EC50 of 92 μM) were weakly cytotoxic against the breast cancer cell line, while compounds 114, 115, 119, 120, and 122 were not cytotoxic to MCF-7 with EC50 > 200 μM. The current study has revealed that M. sericea, S. usambarensis, and T.uniflora possess a spectrum of metabolites with unique structural features with potential in the development of antimalarial, anticancer, antibacterial and antileishmanial agents.