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Design, synthesis, and In vitro antituberculosis activity of 2(5 H )‐Furanone derivatives
Author(s) -
Ngwane Andile H.,
Panayides JennyLee,
Chouteau Franck,
Macingwana Lubabalo,
Viljoen Albertus,
Baker Bienyameen,
Madikane Eliya,
de Kock Carmen,
Wiesner Lubbe,
Chibale Kelly,
Parkinson Christopher J.,
Mmutlane Edwin M.,
van Helden Paul,
Wiid Ian
Publication year - 2016
Publication title -
iubmb life
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.132
H-Index - 113
eISSN - 1521-6551
pISSN - 1521-6543
DOI - 10.1002/iub.1526
Subject(s) - ethambutol , isoniazid , cytotoxicity , mycobacterium smegmatis , chinese hamster ovary cell , mycobacterium tuberculosis , ic50 , rifampicin , chemistry , growth inhibition , minimum inhibitory concentration , cell culture , in vitro , microbiology and biotechnology , stereochemistry , antibiotics , tuberculosis , biochemistry , biology , medicine , receptor , pathology , genetics
A series of 2( 5H )‐furanone‐based compounds were synthesized from commercially available mucohalic acids. From the first‐generation compounds, three showed inhibitory activity (10 µg/mL) of at least 35% against Mycobacterium smegmatis mc 2 155 growth (Bioscreen C system). In screening the active first‐generation compounds for growth inhibition against Mycobacterium tuberculosis H37Rv, the most active compound was identified with a minimum inhibitory concentration (MIC 99 ) of 8.07 µg/mL (15.8 µM) using BACTEC 460 system. No cross‐resistance was observed with some current first‐line anti‐TB drugs, since it similarly inhibited the growth of multidrug resistant (MDR) clinical isolates. The compound showed a good selectivity for mycobacteria since it did not inhibit the growth of selected Gram‐positive and Gram‐negative bacteria. It also showed synergistic activity with rifampicin (RIF) and additive activity with isoniazid (INH) and ethambutol (EMB). Additional time‐kill studies showed that the compound is bacteriostatic to mycobacteria, but cytotoxic to the Chinese Hamster Ovarian (CHO) cell line. From a second generation library, two compounds showed improved anti‐TB activity against M. tuberculosis H37Rv and decreased CHO cell cytotoxicity. The compounds exhibited MIC values of 2.62 µg/mL (5.6 µM) and 3.07 µg/mL (5.6 µM) respectively. The improved cytotoxicity against CHO cell line of the two compounds ranged from IC 50 = 38.24 µg/mL to IC 50 = 45.58 µg/mL when compared to the most active first‐generation compound (IC 50 = 1.82 µg/mL). The two second generation leads with selectivity indices (SI) of 14.64 and 14.85 respectively, warrant further development as anti‐TB drug candidates. © 2016 IUBMB Life, 68(8):612–620, 2016