dc.description.abstract | Leishmaniasis is a disease complex instigated by a protozoan parasite of the genus Leishmania.
Contemporary chemotherapies for leishmaniasis employ pentamidine (1), amphotericin B (2) and
pentavalent antimonials (3). The efficacy of these drugs has deteriorated due to drug resistance.
The drugs also pose unbearable side effects owing to their toxicity. Some metabolites from the
genus Pentas (family Rubiaceae) have been reported to show antiprotozoal activity against
Plasmodium species, but no studies on antileishmanial activity have been done. The study was
focused on investigating five Pentas species for antileishmanial principles. The CH2Cl2/CH3OH
(1:1) extracts of the roots and/or stems of Pentas bussei, P. longiflora, P. micrantha, P. parvifolia
and P. zanzibarica were subjected to a combination of chromatographic separations resulting in
the isolation of 14 compounds. The pure compounds were characterized by utilizing 1H NMR, 13C
NMR, 1H-1H COSY, HMBC, HSQC and MS. The crude extract from the roots of Pentas parvifolia
yielded busseihydroquinone B (51). The stem bark of Pentas parvifolia yielded β-stigmasterol (50)
and β-amyrin (95). The aerial parts of P. parvifolia yielded vanillic acid (96), p-hydroxybenzoic
acid (97) and protocatechuic acid (98). The aerial part of P. bussei yielded β-stigmasterol (50), a
homoprenylated naphthoquinone (55), busseihydroquinone A (7), busseihydroquinone B (51),
busseihydroquinone C (52) and methyl-8-hydroxy-1,4,6,7-tetramethoxy-2-naphthoate (47), which
is a new compound. The aerial parts of P. micrantha yielded 2-methoxy-3-methyl-anthracene-
9,10-dione (72). The stem bark of P. zanzibarica yielded rubiadin-1-methyl ether (65) and rubiadin
(64). The roots of Pentas longiflora yielded pentalongin (74). Pentalongin (74) showed
antileishmanial activity (IC50 = 11 μM) against the antimony sensitive strain of Leishmania
donavani (MHOM/IN/83/AG83). It also generated a substantial amount of nitric oxide in the cell
culture (IC50 = 1.08 μM) relative to the positive control, miltefosine (4), (IC50 = 1.11 μM).
Busseihydroquinone A (7) was oxidized with silver (I) oxide to yield 1-hydroxy-4,6-dimethoxy-
7,8-dioxo-7,8-dihydro-naphthalene-2-carboxylic acid methyl ester (99). Through computational
modelling, the inhibitory potential of phytochemicals from the genus Pentas for Leishmania
infantum trypanothione reductase was studied using UCSF Chimera 1.15. Among the studied
compounds, schimperiquinone A (92) exhibited the highest affinity for the binding site of the
receptor; with a binding energy of -10.9 kcal/mol. Anthraquinones generally showed superior
inhibitory potency for Leishmania infantum trypanothione reductase than naphthoquinones.
Overall, the phytochemicals from the genus Pentas showed sustained hydrogen bonds with
Thr335, Lys60 and Cys52; these amino acid residues assist FAD to achieve a proper orientation
towards the catalytic site of the enzyme. Therefore, the quinones from the genus Pentas have the
potential to guide the development of antileishmanial drug agents. Given the distinctive binding
mode of some of the anthraquinones and naphthoquinones observed here, the compounds should
be subjected to in vitro and in vivo studies. | en_US |