Synthesis, structural assignments, and antiinfective activities of 3-0-benzyl-carvotacetone and 3-hydroxy-2-isopropyl-5-methyl-p-benzoquinone

Authors: MASILA, VERONICA - Makerere University; NDAKALA, ALBERT - University Of Nairobi; BYAMUKAMA, ROBERT - Makerere University; MIDIWO, JACOB - University Of Nairobi; KAMAU, RAHAB - University Of Dar Es Salaam; WANG, MEI - University Of Mississippi; KUMARIHAMY, MALLIKA - University Of Mississippi; ZHAO, JIANPING - University Of Mississippi; HEYDREICH, MATTHIAS - Potsdam Institute; MUHAMMAD, ILIAS - University Of Mississippi

Submitted to: Natural Product Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/9/2020
Publication Date: 1/30/2020
Citation: Masila, V.M., Ndakala, A.J., Byamukama, R., Midiwo, J.O., Kamau, R.W., Wang, M., Kumarihamy, M., Zhao, J., Heydreich, M., Muhammad, I. 2020. Synthesis, structural assignments, and antiinfective activities of 3-0-benzyl-carvotacetone and 3-hydroxy-2-isopropyl-5-methyl-p-benzoquinone. Natural Product Research. https://doi.org/10.1080/14786419.2020.1716346.
DOI: https://doi.org/10.1080/14786419.2020.1716346

Interpretive Summary: Malaria is a parasitic disease that affects approximately 219 million and kills 435,000 people each year worldwide, majority being children under the age of 5 years and pregnant women. The parasites are known to develop resistance against some of these drugs, hence need to develop new drugs with less toxic and new mechanism of action towards the P. falciparum parasites. Carvotacetones are monoterpene cyclohexanone derivatives mainly isolated from fungi, mushrooms, bacteria, worms, and the plants from the genus Sphaeranthus. Some of these cyclic unsaturated monoterpenes exhibit antimicrobial, antiplasmodial, antiproliferative and antitumor activities. The cyclohexenone core of these compounds is considered as a potential new class of small molecule “pharmacophore” for antitumor drug leads which targets multi-drug resistant (MDR) tumours. The paper here describes a short strategy to synthesis of several bio active carvotacetone derivatives together with other small molecules from piperitone to investigate their anti-plasmodial and antimicrobial activities. This is the first report of the antiplasmodial and anticryptococcal activity of 3-hydroxy-2-isopropyl-5- methyl-p-benzoquinone.

Technical Abstract: Carvotacetones are monoterpene cyclohexanone derivatives exhibiting antimicrobial, antiplasmodial, antiproliferative, and antitumor activities. 3-Acetoxy-5,7-dihydroxycarvotacetone isolated from Sphaeranthus bullatus has been reported to possess moderate anti-plasmodial (IC50 values of 0.60 and 0.68 µg/mL against chloroquine sensitive (D6) and chloroquine resistant (W2) strains of Plasmodium falciparum) and cytotoxic activities. The paper here describes a short strategy to synthesis of several carvotacetone derivatives namely, 3-hydroxy-2-isopropyl-5-methyl-p-benzoquinone and 3-O-benzyl-carvotacetone together with other small molecules from (R) (-)-piperitone as the starting material to investigate their anti-plasmodial and antimicrobial activities. 3-O-Benzyl-piperitol was prepared by Luche reduction of (R) (-)-piperitone to cis-piperitol, followed by benzylation. Riley oxidation of 3-O-benzyl-piperitol afforded corresponding ketones 3-O-benzyl-carvotacetone, 3-hydroxy-2-isopropyl-5-methyl-p-benzoquinone, and 3-benzyloxy-4-isopropylcyclohex-1-enecarbaldehyde. 3-hydroxy-2-isopropyl-5-methyl-p-benzoquinone exhibited antiplasmodial activity against chloroquine-sensitive (D6) and resistant (W2) strains of P. falciparum with IC50 values of 0.69 and 0.65 µg/mL and an antifungal activity against Cryptococcus neoformans with an IC50 value of 3.11 µg/mL, compared to reference standard fluconazole (IC50 value of 1.87 µg/mL). This is the first report of the antiplasmodial and anticryptococcal activity of 3-hydroxy-2-isopropyl-5- methyl-p-benzoquinone.