Semisynthetic Derivatives of Selected Amaryllidaceae Alkaloids as a New Class of Antimycobacterial Agents

Molecules

卷:26

Abdullah Al Mamun¹  Marcela Šafratová¹  Anna Hošťálková¹  Jana Maříková¹  Lucie Cahlíková¹  Kateřina Breiterová¹  Daniela Hulcová¹  Eliška Kohelová¹  Negar Maafi¹  Lucie Nováková²  Klára Konečná³  Adéla Diepoltová³  Ondřej Janďourek³  Jiří Kuneš⁴  Darja Koutová⁵ 

[1] ADINACO Research Group, Department of Pharmaceutical Botany, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic;

[2] Department of Analytical Chemistry, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic;

[3] Department of Biological and Medical Sciences, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic;

[4] Department of Bioorganic and Organic Chemistry, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic;

[5] Department of Medical Biochemistry, Faculty of Medicine, Charles University, Simkova 870, 500 03 Hradec Kralove, Czech Republic;

关键词: Amaryllidaceae;    tuberculosis;    galanthamine;    3-O-methylpancracine;    analogues;    antimycobacterial activity;   

DOI  :  10.3390/molecules26196023

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown