title: Design, synthesis, and In vitro antituberculosis activity of 2(5H)-Furanone derivatives.
abstract: 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. © 2016 IUBMB Life, 68(8):612-620, 2016.
authors.affiliation: Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, SAMRC Centre for TB Research, DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, Stellenbosch University, Tygerberg, Cape Town, South Africa.
authors.forename: Andile H
authors.initials: AH
authors.lastname: Ngwane
authors.affiliation: CSIR Biosciences, Pioneering Health Sciences, Pretoria, South Africa.
authors.forename: Jenny-Lee
authors.initials: JL
authors.lastname: Panayides
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch, South Africa.
authors.forename: Franck
authors.initials: F
authors.lastname: Chouteau
authors.affiliation: Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, SAMRC Centre for TB Research, DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, Stellenbosch University, Tygerberg, Cape Town, South Africa.
authors.forename: Lubabalo
authors.initials: L
authors.lastname: Macingwana
authors.affiliation: Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, SAMRC Centre for TB Research, DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, Stellenbosch University, Tygerberg, Cape Town, South Africa.
authors.forename: Albertus
authors.initials: A
authors.lastname: Viljoen
authors.affiliation: Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, SAMRC Centre for TB Research, DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, Stellenbosch University, Tygerberg, Cape Town, South Africa.
authors.forename: Bienyameen
authors.initials: B
authors.lastname: Baker
authors.affiliation: Department of Clinical Laboratory Sciences, Division of Medical Microbiology, University of Cape Town, Rondebosch, South Africa.
authors.forename: Eliya
authors.initials: E
authors.lastname: Madikane
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa.
authors.forename: Carmen
authors.initials: C
authors.lastname: de Kock
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa.
authors.forename: Lubbe
authors.initials: L
authors.lastname: Wiesner
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch, South Africa.
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
authors.affiliation: CSIR Biosciences, Pioneering Health Sciences, Pretoria, South Africa.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Parkinson
authors.affiliation: CSIR Biosciences, Pioneering Health Sciences, Pretoria, South Africa.
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Mmutlane
authors.affiliation: Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, SAMRC Centre for TB Research, DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, Stellenbosch University, Tygerberg, Cape Town, South Africa.
authors.forename: Paul
authors.initials: P
authors.lastname: van Helden
authors.affiliation: Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, SAMRC Centre for TB Research, DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, Stellenbosch University, Tygerberg, Cape Town, South Africa.
authors.forename: Ian
authors.initials: I
authors.lastname: Wiid
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D016466:CHO Cells / Q000187:drug effects / Q000382:microbiology; D003412:Cricetulus; D004357:Drug Synergism; D004977:Ethambutol / Q000008:administration & dosage; D005663:Furans / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000472:pathogenicity; D012293:Rifampin / Q000008:administration & dosage; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D005663:Furans; D004977:Ethambutol; D007538:Isoniazid; D012293:Rifampin
keywords: antimycobacterial; cytotoxicity; furanone; selective; synergy; synthetic