Ngwane, AHPanayides, Jenny-LeeChouteau, FMacingwana, LViljoen, ABaker, BMadikane, EDe Kock, CWiesner, LChibale, KParkinson, CJMmutlane, EMVan Helden, PWiid, I2017-01-172017-01-172016-01Ngwane, A.H., Panayides, J.L., Chouteau, F., Macingwana, L., Viljoen, A., Baker, B., Madikane, E., De Kock, C., Wiesner, L., Chibale, K., Parkinson, C.J., Mmutlane, E.M., Van Helden, P. and Wiid, I. 2016. Design, synthesis, and in vitro antituberculosis activity of 2(5H)-Furanone derivatives. International Union of Biochemistry and Molecular Biology Life. 68, pp. 612-620.1521-6543doi: 10.1002/iub.1526http://www.ncbi.nlm.nih.gov/pubmed/27346745http://hdl.handle.net/10204/8910Copyright:2016 Wiley Online Library:Due to copyright restrictions, the attached PDF file only contains the abstract of the full text item. For access to the full text item, please consult the publisher's website. The definitive version of the work is published in the International Union of Biochemistry and Molecular Biology Life.68,pp. 612-20.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 (MIC99 ) 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 IC50 = 38.24 µg/mL to IC50 =45.58 µg/mL when compared to the most active first-generation compound (IC50 =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.enAntimycobacterialFuranoneCytotoxicitySynergyArticleNgwane, A., Panayides, J., Chouteau, F., Macingwana, L., Viljoen, A., Baker, B., ... Wiid, I. (2016). Design, synthesis, and in vitro antituberculosis activity of 2(5H)-Furanone derivatives. http://hdl.handle.net/10204/8910Ngwane, AH, Jenny-Lee Panayides, F Chouteau, L Macingwana, A Viljoen, B Baker, E Madikane, et al "Design, synthesis, and in vitro antituberculosis activity of 2(5H)-Furanone derivatives." (2016) http://hdl.handle.net/10204/8910Ngwane A, Panayides J, Chouteau F, Macingwana L, Viljoen A, Baker B, et al. Design, synthesis, and in vitro antituberculosis activity of 2(5H)-Furanone derivatives. 2016; http://hdl.handle.net/10204/8910.TY - Article AU - Ngwane, AH AU - Panayides, Jenny-Lee AU - Chouteau, F AU - Macingwana, L AU - Viljoen, A AU - Baker, B AU - Madikane, E AU - De Kock, C AU - Wiesner, L AU - Chibale, K AU - Parkinson, CJ AU - Mmutlane, EM AU - Van Helden, P AU - Wiid, I AB - 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 (MIC99 ) 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 IC50 = 38.24 µg/mL to IC50 =45.58 µg/mL when compared to the most active first-generation compound (IC50 =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. DA - 2016-01 DB - ResearchSpace DP - CSIR KW - Antimycobacterial KW - Furanone KW - Cytotoxicity KW - Synergy LK - https://researchspace.csir.co.za PY - 2016 SM - 1521-6543 T1 - Design, synthesis, and in vitro antituberculosis activity of 2(5H)-Furanone derivatives TI - Design, synthesis, and in vitro antituberculosis activity of 2(5H)-Furanone derivatives UR - http://hdl.handle.net/10204/8910 ER -