title: In vitro antimalarial studies of novel artemisinin biotransformed products and its derivatives.
abstract: Biotransformation of antimalarial drug artemisinin by fungi Rhizopus stolonifer afforded three sesquiterpenoid derivatives. The transformed products were 1α-hydroxyartemisinin (3), 3.0%, a new compound, 10β-hydroxyartemisinin, 54.5% (4) and deoxyartemisinin (2) in 9% yield. The fungus expressed high-metabolism activity (66.5%). The chemical structures of the compounds were elucidated by 1D, 2D NMR spectrometry and mass spectral data. The major compound 10β-hydroxyartemisinin (4) was chemically converted to five new derivatives 5-9. All the compounds 3-9 were subjected for in vitro anti-malarial activity. 10β-Hydroxy-12β-arteether (8), IC50 at 18.29nM was found to be 10 times better active than its precursor 4 (184.56nM) and equipotent antimalarial with natural drug artemisinin whereas the α-derivative 9 is 3 times better than 4 under in vitro conditions. Therefore, the major biotransformation product 4 can be exploited for further modification into new clinically potent molecules. The results show the versatility of microbial-catalyzed biotransformations leading to the introduction of a hydroxyl group at tertiary position in artemisinin in derivative (3).
authors.affiliation: Medicinal Chemistry Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Gaur
authors.affiliation: Molecular Bio-prospection Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India.
authors.forename: Mahendra P
authors.initials: MP
authors.lastname: Darokar
authors.affiliation: Analytical Chemistry Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India.
authors.forename: P V
authors.initials: PV
authors.lastname: Ajayakumar
authors.affiliation: Microbial Technology and Plant Pathology Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India.
authors.forename: Ram Sajiwan
authors.initials: RS
authors.lastname: Shukla
authors.affiliation: Medicinal Chemistry Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India. Electronic address: bhakunirs2000@yahoo.com.
authors.forename: Rajendra Singh
authors.initials: RS
authors.lastname: Bhakuni
mesh_terms: D000962:Antimalarials / Q000097:blood / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D037621:Artemisinins / Q000097:blood / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001711:Biotransformation; D004739:England; D006801:Humans; D007194:India; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects; D012233:Rhizopus / Q000737:chemistry* / Q000378:metabolism; D012717:Sesquiterpenes / Q000737:chemistry
chemical_list: C000594758:10beta-hydroxyartemisinin; D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; C055261:deoxyartemisinin; C031327:artemisinin; C055141:artemotil
keywords: Antimalarial; Artemisinin; In-vitro; Metabolism