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Synthesis and biological evaluation of selected Pentacyclic Triterpenoid Hybrid derivatives
Author(s)
Afolabi, Wasiu Olalekan
Date Issued
2019
Type
Thesis
Publisher
Cape Peninsula University of Technology
Abstract
Natural products have continuously generated significant therapeutic agents and often provide substantial guide to the development of new lead formulations. Among these compounds are the pentacyclic triterpenes (PTs) of the types: betulinic acid (BA), oleanolic acid (OA), and ursolic acid (UA) that possess bioactive and several anti-infective properties.
The development of conjugate hybrid-type formulations consisting of PTs without introduction of additional structural linkers was carried out. PTs (BA, OA, UA, MA), and a flavonoid compound, 6-methyltectochrysin were extracted from plant sources including Tectona grandis, Syzygium aromaticum, Mimusops caffra, Lavandula angustifolia and Melaleuca salicina using standard methods. The starting materials were characterized using spectroscopic methods. The hybrid-type derivatives were prepared following C3 and/or C28 derivatization of the PT compounds, and the formation of PT- acid chlorides intermediates for coupling to yield C28 – C3 PT–PT hybrids, C28 – C28 PT–PT hybrids, flavonoid– PT derivatives and calixarene–PT conjugated derivatives.
The antioxidant and antimicrobial potentials of the derivatives were assessed. Preliminary in-vitro investigation showed that the hybrid combinations differed in the levels of anti-oxidative activities relative to parent PTs. MA, OA-MA mixture, flavonoid crude extract and calix[4]arene were generally more active than the hybrids, but are less potent relative to ascorbic acid positive control, except for MA. The compounds were tested against multi-drug resistant strains (MDRS) of three gram-positive (Bacillus cereus, Staphylococcus aureus, and Enterococcus faecalis) and three gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa). The hybrid derivatives containing PT–PT ester type conjugate hybrids showed antimicrobial activity (>70% inhibition) against resistant strains of B. cereus at a dosage of 55 μg/mL. The antimicrobial activities were low against the gram negative strains and generally inactive against the gram positive S. aureus. The synergistic effect was observed for the activities of crude extract of L. petersonii, which was found to be more bioactive than the purified flavonoid. The flavonoid-PT conjugates were found to be inactive antimicrobials.
The significance of derivatization of PTs and the potential to explore new hybrids of known parent bioactive compounds is an ongoing study focused on finding modifications to improve alternative therapeutic formulations from natural sources. The exploration directly coupled conjugated hybrids without additional linkers may be further explored.
The development of conjugate hybrid-type formulations consisting of PTs without introduction of additional structural linkers was carried out. PTs (BA, OA, UA, MA), and a flavonoid compound, 6-methyltectochrysin were extracted from plant sources including Tectona grandis, Syzygium aromaticum, Mimusops caffra, Lavandula angustifolia and Melaleuca salicina using standard methods. The starting materials were characterized using spectroscopic methods. The hybrid-type derivatives were prepared following C3 and/or C28 derivatization of the PT compounds, and the formation of PT- acid chlorides intermediates for coupling to yield C28 – C3 PT–PT hybrids, C28 – C28 PT–PT hybrids, flavonoid– PT derivatives and calixarene–PT conjugated derivatives.
The antioxidant and antimicrobial potentials of the derivatives were assessed. Preliminary in-vitro investigation showed that the hybrid combinations differed in the levels of anti-oxidative activities relative to parent PTs. MA, OA-MA mixture, flavonoid crude extract and calix[4]arene were generally more active than the hybrids, but are less potent relative to ascorbic acid positive control, except for MA. The compounds were tested against multi-drug resistant strains (MDRS) of three gram-positive (Bacillus cereus, Staphylococcus aureus, and Enterococcus faecalis) and three gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa). The hybrid derivatives containing PT–PT ester type conjugate hybrids showed antimicrobial activity (>70% inhibition) against resistant strains of B. cereus at a dosage of 55 μg/mL. The antimicrobial activities were low against the gram negative strains and generally inactive against the gram positive S. aureus. The synergistic effect was observed for the activities of crude extract of L. petersonii, which was found to be more bioactive than the purified flavonoid. The flavonoid-PT conjugates were found to be inactive antimicrobials.
The significance of derivatization of PTs and the potential to explore new hybrids of known parent bioactive compounds is an ongoing study focused on finding modifications to improve alternative therapeutic formulations from natural sources. The exploration directly coupled conjugated hybrids without additional linkers may be further explored.
Additional information
Thesis (DPhil (Chemistry))--Cape Peninsula University of Technology, 2019
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