| dc.description.abstract | Malaria, caused by the protozoan parasites of the genus Plasmodium, is a major disease in the tropical and subtropical regions of the world. Out of the yearly 300-500 million clinical episodes, 1.5-2.7 million are lethal. To date, a large number of herbal remedies are used to treat malaria and manage related fever. Nevertheless, efficacies of most of these plants have not been proven or the active components identified. In an effort to address the problem of malaria and the associated complications, six Pentas species: P. bussei, P. lanceolata, P. longiflora, P. micrantha, P. parvifolia and P. suswaensis were phytochemically investigated.
Fractionation of the extracts was carried out using a combination of chromatographic methods including column chromatography on oxalic acid impregnated silica gel, preparative High Performance Liquid Chromatography (HPLC), Medium Pressure Liquid Chromatography (MPLC) and sephadex LH-20. Characterization of the pure compounds was done using spectroscopic techniques: mainly Nuclear Magnetic Resonance (NMR) and Mass Spectroscopy (MS) assisted by Infra Red Spectroscopy (IR) , Ultra Violet Spectroscopy (UV) and Circular Dichroism (CD). The distribution of the isolated compounds in the roots of the six Pentas species was studied using analytical HPLC and TLC.
A total of fourty one compounds categorized as naphthalene derivatives, anthraquinones and pyranonaphthoquinones were included in this thesis of which thirty one natural compounds including seven new natural products (70-73, 78, 82, 86) and ten new synthetic derivatives (87-96). This is the first report on the occurrence of eight anthraquinones and one polyoxygenated naphthalene derivative from the genus Pentas.
Four new naphthalene derivatives (70-73) were isolated from P. bussei and P. parvifolia. Anthraquinones occur in the roots of P. lanceolata, P. suswaensis and P. micrantha; eleven of which including a new anthraquinone, 5,6-dihydroxydamnacanthol (7S), were isolated from the roots of P. lanceolata. The new anthraquinone 5,6- dihydroxydamnacanthol (7S) was isolated from P. suswaensis along with twelve known anthraquonones and anthraquinone glycosides. Two new anthraquinones (5,6- dihydroxydamnacanthol (7S) and 5,6-dihydroxylucidin-ro-methyl ether (S2) were isolated from the roots of P. micrantha together with six known anthraquinones. Two pyranonaphthoquinones, pentalongin (33) and psychorubrin (SO), were isolated from the roots of P. longiflora together with the naphthalene derivative mollugin (34).
Overall, anthraquinones having carbon (CH3, CH20H, CHO, CH20CH3) substitution at C-2 were found to be the major constituents of P. lanceolata, P. micrantha and P. suswaensis; whereas pyranonaphthaquinones and naphthalene derivatives were found to be the major constituents P. longiflora, P. parvifolia and P. bussei.
The plant extracts and the isolated compounds were tested for antiplasmodial activity against chloroquine sensitive (D6) and chloroquine resistant (W2) clones. Cytotoxicity of the pure compounds was also done on MCF-7 human breast cancer cells, Significant antiplasmodial activity (ICso) was observed in the root extracts of P. lanceolata [1.33 ug/ml, against D6, 2.55 ug/ml, against W2], P. micrantha [4.00 ug/ml. against D6, 3.37 ug/ml. against W2], P. longiflora [0.93 ug/ml, against D6, 0.99 ug/ml, against W2], anthraquinones [5-31 ug/ml, against D6 and W2], naphthalene derivatives [7.45-44.50 ug/ml, against D6 and W2], and pentalongin (33) and psychorubrin (SO) [< 1 ug/ml, against D6 and W2]. Rubiadin-3-0-primveroside (52) showed synergestic effect in combination with chloroquine in vitro.
The tested compounds also exhibited different degrees of cytoxicity (LDso) as follows: naphthalene derivatives (56, 70-73) [2: 22.3 ug/ml.] and pyranonaphthoquinones [0.80 ug/ml. for pentalongin (33) and 0.89 ug/ml, for psychorubrin (80)]. The excellent antiplasmodial activity observed by the two pyranaphthaquinones (33, 80) is accompanied by comparably high cytotoxicity makes their direct application as antimalarial agents virtually impossible.
Microwave assisted syntheses of ten new (87-96) Ca-aryl, Ca-bromide and Ca-chloridc substituted analoguesofrubiadin (49) and rubiadin-l-methyl ether (51) were achieved by Suzuki-Miyaura, nickel catalyzed halogen exchange and Sonogashira cross-coupling reactions. Improvement in the in vitro antiplasmodial activity (ICso) was observed for 4- phenylrubiadin (89) [4.96 ug/rnl, against D6 and 13.97 ug/ml, against W2] and 4-(p- methoxyphenyl)rubiadin-l-methyl ether (91) [7.55 ug/ml, against D6 and 14.2 ug/ml, against W2] as compared to the parent anthraquinone. | en_US |
