In-vitro assessment of chromones, alkaloidsand other natural products from caribbeanplants as potential anti-tubercularsand chemopreventors

Resurgence in the tuberculosis pathogen, Mycobacterium tuberculosis, whichsignificantly reduces survival rates of persons co-infected with the immunodeficiencydisease HIV, poses a major health issue particularly for the developing countries, whichaccounts for over 95 percent of reported global HIV cases. Compounding this issue is theemergence of multiple drug resistant strains, highlighting an urgent need for the searchfor novel and effective therapies against M. tuberculosis. Arylamine N- acetyltransferase(NAT), a drug metabolizing enzyme found expressed in M. tuberculosis and responsiblefor the metabolism of the frontline anti-TB drug isoniazid has also been identified to playa significant role in its cell wall lipid synthesis. Knowledge on NAT enzyme's essentialrole in the survival of M. tuberculosis, garnered through recent nat gene knockoutexperiments in M. bovis, has identified it as a useful target in the search for antituberculartherapy. In this study we employed this molecular target in an in-vitro assay, tosearch for natural products with potential for future in-vivo examinations. Elevennovel/known compounds including tetranoterpinoids and quassinoids (at100 μM)previously extracted and purified from five rare endemic and/or indigenous Caribbeanplants, Spathelia sorbifolia, Esenbeckia pentaphylla, Peperomia amplexicaulis, Hortiaregia and Clusia havestiodes were examined for their inhibitory properties usingheterologously expressed NAT from M. Smegmatis, a homologue of M. tuberculosisNAT. Greatest inhibition was obtained for anhydrosorbifolin (65%), a chromone whose extended linear side chain appear to contribute to the increased inhibition compared withits derivatives, alloptaeroxylin which has no side chains (displayed 25% inhibition) andspatheliabischromone which has a cyclicized side chain (displayed 42% inhibition).These compounds were also examined for their inhibition of human cytochrome P450(CYP) 1, a class of enzymes comprising of CYPs1A1, 1A2 and 1B1, important in theactivation of polyaromatic hydrocarbons to their carcinogenic precursors. Resultsrevealed greatest inhibition by the alkaloid dictamnine of CYP1B1 activity with a potentIC50 value of 0.27μM. These studies show natural chromones and alkaloids as potentialanti-tuberculars and chemopreventors worth further analysis.