title: Novel hydroxamates potentiatedin vitroactivity of fluconazole againstCandida albicans.
abstract: A set of 12 novel hydroxamate compounds (NHCs), structurally designed as inhibitors of histone deacetylase (HDAC) enzyme, were synthesized at our facility. These were adamantane derivatives withN-hydroxyacetamide as pharmacophore, and each of these compounds was tested for potentiating activity on fluconazole. The concentration of fluconazole which completely inhibited (concentration of complete inhibition [CCI]) the growth ofCandida albicansATCC 90028 andC. albicansATCC 64550 was determined by micro-dilution method in the absence and presence of NHCs. The CCI of fluconazole without the NHC combination was 64 μg/ml and 1024 μg/ml againstC. albicansATCC 90028 andC. albicansATCC 64550, respectively. The majority of the NHCs potentiated the fluconazole activity markedly as CCI of fluconazole againstC. albicansATCC 90028 reduced to 0.25 μg/ml. Similarly, CCI of fluconazole againstC. albicansATCC 64550 reduced to 4-8 μg/ml in combination with majority of NHCs while the best activity was displayed by the compound 1 with a reduction of CCI to 0.5 μg/ml. The study results revealed the potential usage of hydroxamate derivatives, structurally designed as HDAC inhibitors to enhance the activity of fluconazole againstC. albicans.
authors.affiliation: Drug Discovery Research, Orchid Pharma Ltd., Chennai, Tamil Nadu, India; Samrud Foundation for Health and Research/St. Martha's Hospital, Bengaluru, Karnataka, India.
authors.forename: Maneesh
authors.initials: M
authors.lastname: Paul-Satyaseela
authors.affiliation: Drug Discovery Research, Orchid Pharma Ltd., Chennai, Tamil Nadu, India.
authors.forename: Periasamy
authors.initials: P
authors.lastname: Hariharan
authors.affiliation: Drug Discovery Research, Orchid Pharma Ltd., Chennai, Tamil Nadu, India.
authors.forename: Thirunavukkarasu
authors.initials: T
authors.lastname: Bharani
authors.affiliation: Drug Discovery Research, Orchid Pharma Ltd., Chennai, Tamil Nadu, India.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Franklyne
authors.affiliation: Drug Discovery Research, Orchid Pharma Ltd., Chennai, Tamil Nadu, India.
authors.forename: Thangapazham
authors.initials: T
authors.lastname: Selvakumar
authors.affiliation: Drug Discovery Research, Orchid Pharma Ltd., Chennai, Tamil Nadu, India.
authors.forename: Kuppusamy
authors.initials: K
authors.lastname: Bharathimohan
authors.affiliation: Drug Discovery Research, Orchid Pharma Ltd., Chennai, Tamil Nadu, India.
authors.forename: Chenniappan Vinoth
authors.initials: CV
authors.lastname: Kumar
authors.affiliation: Drug Discovery Research, Orchid Pharma Ltd., Chennai, Tamil Nadu, India.
authors.forename: Virendra
authors.initials: V
authors.lastname: Kachhadia
authors.affiliation: Foundation for Neglected Disease Research, Sri Krishnadevaraya Research Centre, Sir M. Visvesvaraya Institute of Technology, Bengaluru, Karnataka, India.
authors.forename: Shridhar
authors.initials: S
authors.lastname: Narayanan
authors.affiliation: Jubilant Biosys Ltd., 96, Industrial Suburb 2nd Stage, Yeshwantpur, Bengaluru, Karnataka, India.
authors.forename: Sridharan
authors.initials: S
authors.lastname: Rajagopal
authors.affiliation: Drug Discovery Research, Orchid Pharma Ltd., Chennai, Tamil Nadu, India.
authors.forename: Gopalan
authors.initials: G
authors.lastname: Balasubramanian
keywords: Antifungals; candidiasis; fluconazole; histone deacetylase inhibitors; hydroxamates