The search for novel antimycobacterial drugs is a matter of urgency, since tuberculosis is still one of the top ten causes of death from a single infectious agent, killing more than 1.4 million people worldwide each year. Nine Amaryllidaceae alkaloids (AAs) of various structural types have been screened for their antimycobacterial activity. Unfortunately, all were considered inactive, and thus a pilot series of aromatic esters of galanthamine, 3-O-methylpancracine, vittatine and maritidine were synthesized to increase biological activity. The semisynthetic derivatives of AAs were screened for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Ra and two other mycobacterial strains (M. aurum, M. smegmatis) using a modified Microplate Alamar Blue Assay. The most active compounds were also studied for their in vitro hepatotoxicity on the hepatocellular carcinoma cell line HepG2. In general, the derivatization of the original AAs was associated with a significant increase in antimycobacterial activity. Several pilot derivatives were identified as compounds with micromolar MICs against M. tuberculosis H37Ra. Two derivatives of galanthamine, 1i and 1r, were selected for further structure optimalization to increase the selectivity index.

ADINACO Research Group Department of Pharmaceutical Botany Faculty of Pharmacy Charles University Heyrovskeho 1203 500 05 Hradec Kralove Czech Republic

Department of Analytical Chemistry Faculty of Pharmacy Charles University Heyrovskeho 1203 500 05 Hradec Kralove Czech Republic

Department of Biological and Medical Sciences Faculty of Pharmacy Charles University Heyrovskeho 1203 500 05 Hradec Kralove Czech Republic

Department of Bioorganic and Organic Chemistry Faculty of Pharmacy Charles University Heyrovskeho 1203 500 05 Hradec Kralove Czech Republic

Department of Medical Biochemistry Faculty of Medicine Charles University Simkova 870 500 03 Hradec Kralove Czech Republic

Department of Pharmacognosy Faculty of Pharmacy Charles University Heyrovskeho 1203 500 05 Hradec Kralove Czech Republic

Zobrazit více v PubMed

Kanabalan R.D., Lee L.J., Lee T.Y., Chong P.P., Hassan L., Ismail R., Chin V.K. Human tuberculosis and Mycobacterium tuberculosis complex: A review on genetic diversity, pathogenesis and omics approaches in host biomarkers discovery. Microbiol. Res. 2021;246:126674. doi: 10.1016/j.micres.2020.126674. PubMed DOI

Tiberi S., Muñoz-Torrico M., Duarte R., Dalcolmo M., D’Ambrosio L., Migliori G.B. New drugs and perspectives for new anti-tuberculosis regimens. Pulmonology. 2018;24:86–98. doi: 10.1016/j.rppnen.2017.10.009. PubMed DOI

Koul A., Arnoult E., Lounis N., Guillemont J., Andries K. The challenge of new drug discovery for tuberculosis. Nature. 2011;469:483–490. doi: 10.1038/nature09657. PubMed DOI

Newman D.J., Cragg G.M. Natural Products as Sources of New Drugs from 1981 to 2014. J. Nat. Prod. 2016;79:629–661. doi: 10.1021/acs.jnatprod.5b01055. PubMed DOI

Patridge E., Gareiss P., Kinch M.S., Hoyer D. An analysis of FDA-approved drugs: Natural products and their derivatives. Drug Discov. Today. 2016;21:204–207. doi: 10.1016/j.drudis.2015.01.009. PubMed DOI

Okunade A.L., Elvin-Lewis M.P., Lewis W.H. Natural antimycobacterial metabolites: Current status. Phytochemistry. 2004;65:1017–1032. doi: 10.1016/j.phytochem.2004.02.013. PubMed DOI

Copp B.R., Pearce A.N. Natural product growth inhibitors of Mycobacterium tuberculosis. Nat. Prod. Rep. 2007;24:278–297. doi: 10.1039/B513520F. PubMed DOI

Kishore N., Mishra B.B., Tripathi V., Tiwari V.K. Alkaloids as potential anti-tubercular agents. Fitoterapia. 2009;80:149–163. doi: 10.1016/j.fitote.2009.01.002. PubMed DOI

Mishra S.K., Tripathi G., Kishore N., Singh R.K., Singh A., Tiwari V.K. Drug development against tuberculosis: Impact of alkaloids. Eur. J. Med. Chem. 2017;137:504–544. doi: 10.1016/j.ejmech.2017.06.005. PubMed DOI

Jin Z., Yao G. Amaryllidaceae and Sceletium alkaloids. Nat. Prod. Rep. 2019;36:1462–1488. doi: 10.1039/C8NP00055G. PubMed DOI

Nair J.J., Wilhelm A., Bonnet S.L., van Staden J. Antibacterial constituents of the plant family Amaryllidaceae. Bioorg. Med. Chem. Lett. 2017;27:4943–4951. doi: 10.1016/j.bmcl.2017.09.052. PubMed DOI

Al Mamun A., Maříková J., Hulcová D., Janoušek J., Šafratová M., Nováková L., Kučera T., Hrabinová M., Kuneš J., Korábečný J., et al. Amaryllidaceae Alkaloids of Belladine-Type from Narcissus pseudonarcissus cv. Carlton as New Selective Inhibitors of Butyrylcholinesterase. Biomolecules. 2020;10:800. doi: 10.3390/biom10050800. PubMed DOI PMC

Kornienko A., Evidente A. Chemistry, Biology, and Medicinal Potential of Narciclasine and its Congeners. Chem. Rev. 2008;108:1982–2014. doi: 10.1021/cr078198u. PubMed DOI PMC

Heinrich M., Lee Teoh H. Galanthamine from snowdrop--the development of a modern drug against Alzheimer’s disease from local Caucasian knowledge. J. Ethnopharmacol. 2004;92:147–162. doi: 10.1016/j.jep.2004.02.012. PubMed DOI

Cahlíková L., Kawano I., Řezáčová M., Blunden G., Hulcová D., Havelek R. The Amaryllidaceae alkaloids haemanthamine, haemanthidine and their semisynthetic derivatives as potential drugs. Phytochem. Rev. 2021;20:303–323. doi: 10.1007/s11101-020-09675-8. DOI

McLachlan A., Kekre N., McNulty J., Pandey S. Pancratistatin: A natural anti-cancer compound that targets mitochondria specifically in cancer cells to induce apoptosis. Apoptosis. 2005;10:619–630. doi: 10.1007/s10495-005-1896-x. PubMed DOI

Griffin C., Karnik A., McNulty J., Pandey S. Pancratistatin selectively targets cancer cell mitochondria and reduces growth of human colon tumor xenografts. Mol. Cancer Ther. 2011;10:57–68. doi: 10.1158/1535-7163.MCT-10-0735. PubMed DOI

Roy M., Liang L., Xiao X., Feng P., Ye M., Liu J. Lycorine: A prospective natural lead for anticancer drug discovery. Biomed. Pharmacother. 2018;107:615–624. doi: 10.1016/j.biopha.2018.07.147. PubMed DOI PMC

Peřinová R., Maafi N., Korábečný J., Kohelová E., De Simone A., Mamun A.A., Hulcová D., Marková J., Kučera T., Jun D., et al. Functionalized aromatic esters of the Amaryllidaceae alkaloid haemanthamine and their in vitro and in silico biological activity connected to Alzheimer’s disease. Bioorg. Chem. 2020;100:103928. doi: 10.1016/j.bioorg.2020.103928. PubMed DOI

Al Shammari L., Hulcová D., Maříková J., Kučera T., Šafratová M., Nováková L., Schmidt M., Pulkrábková L., Janoušek J., Soukup O., et al. Amaryllidaceae alkaloids from Hippeastrum X hybridum cv. Ferrari, and preparation of vittatine derivatives as potential ligands for Alzheimer´s disease. South Afr. J. Bot. 2021;136:137–146. doi: 10.1016/j.sajb.2020.06.024. DOI

Maříková J., Ritomská A., Korábečný J., Peřinová R., Al Mamun A., Kučera T., Kohelová E., Hulcová D., Kobrlová T., Kuneš J., et al. Aromatic Esters of the Crinane Amaryllidaceae Alkaloid Ambelline as Selective Inhibitors of Butyrylcholinesterase. J. Nat. Prod. 2020;83:1359–1367. doi: 10.1021/acs.jnatprod.9b00561. PubMed DOI

Koutová D., Maafi N., Havelek R., Opletal L., Blunden G., Řezáčová M., Cahlíková L. Chemical and Biological Aspects of Montanine-Type Alkaloids Isolated from Plants of the Amaryllidaceae Family. Molecules. 2020;25:2337. doi: 10.3390/molecules25102337. PubMed DOI PMC

Govindaraju K., Ingels A., Hasan M.N., Sun D., Mathieu V., Masi M., Evidente A., Kornienko A. Synthetic analogues of the montanine-type alkaloids with activity against apoptosis-resistant cancer cells. Bioorg. Med. Chem. Lett. 2018;28:589–593. doi: 10.1016/j.bmcl.2018.01.041. PubMed DOI PMC

Safratova M., Hostalkova A., Hulcova D., Breiterova K., Hrabcova V., Machado M., Fontinha D., Prudencio M., Kunes J., Chlebek J., et al. Alkaloids from Narcissus poeticus cv. Pink Parasol of various structural types and their biological activity. Arch. Pharmacal Res. 2018;41:208–218. doi: 10.1007/s12272-017-1000-4. PubMed DOI

Phelan J., Maitra A., McNerney R., Nair M., Gupta A., Coll F., Pain A., Bhakta S., Clark T.G. The draft genome of Mycobacterium aurum, a potential model organism for investigating drugs against Mycobacterium tuberculosis and Mycobacterium leprae. Int. J. Mycobacteriology. 2015;4:207–216. doi: 10.1016/j.ijmyco.2015.05.001. PubMed DOI

Piccaro G., Poce G., Biava M., Giannoni F., Fattorini L. Activity of lipophilic and hydrophilic drugs against dormant and replicating Mycobacterium tuberculosis. J. Antibiot. 2015;68:711–714. doi: 10.1038/ja.2015.52. PubMed DOI

Senousy B.E., Belal S.I., Draganov P.V. Hepatotoxic effects of therapies for tuberculosis. Nat. Rev. Gastroenterol. Hepatol. 2010;7:543–556. doi: 10.1038/nrgastro.2010.134. PubMed DOI

Kohelová E., Maříková J., Korábečný J., Hulcová D., Kučera T., Jun D., Chlebek J., Jenčo J., Šafratová M., Hrabinová M., et al. Alkaloids of Zephyranthes citrina (Amaryllidaceae) and their implication to Alzheimer’s disease: Isolation, structural elucidation and biological activity. Bioorganic Chem. 2021;107:104567. doi: 10.1016/j.bioorg.2020.104567. PubMed DOI

Kohelová E., Peřinová R., Maafi N., Korábečný J., Hulcová D., Maříková J., Kučera T., Martínez González L., Hrabinova M., Vorčáková K., et al. Derivatives of the β-Crinane Amaryllidaceae Alkaloid Haemanthamine as Multi-Target Directed Ligands for Alzheimer’s Disease. Molecules. 2019;24:1307. doi: 10.3390/molecules24071307. PubMed DOI PMC

Alkaloids of Dicranostigma franchetianum (Papaveraceae) and Berberine Derivatives as a New Class of Antimycobacterial Agents