Maneesh Paul-Satyaseela1, Periasamy Hariharan2, Thirunavukkarasu Bharani2, Jonathan S Franklyne2, Thangapazham Selvakumar2, Kuppusamy Bharathimohan2, Chenniappan Vinoth Kumar2, Virendra Kachhadia2, Shridhar Narayanan3, Sridharan Rajagopal4, Gopalan Balasubramanian2
1Drug Discovery Research, Orchid Pharma Ltd., Chennai, Tamil Nadu; Samrud Foundation for Health and Research/St. Martha’s Hospital, Bengaluru, Karnataka, India.
2Drug Discovery Research, Orchid Pharma Ltd., Chennai, Tamil Nadu, India.
3Foundation for Neglected Disease Research, Sri Krishnadevaraya Research Centre, Sir M. Visvesvaraya Institute of Technology, Bengaluru, Karnataka, India.
4Jubilant Biosys Ltd., 96, Industrial Suburb 2nd Stage, Yeshwantpur, Bengaluru, Karnataka, India.
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 with N-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 of Candida albicans ATCC 90028 and C. albicans ATCC 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 against C. albicans ATCC 90028 and C. albicans ATCC 64550, respectively. The majority of the NHCs potentiated the fluconazole activity markedly as CCI of fluconazole against C. albicans ATCC 90028 reduced to 0.25 μg/ml. Similarly, CCI of fluconazole against C. albicans ATCC 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 against C. albicans.
Keywords: Antifungals, candidiasis, fluconazole, histone deacetylase inhibitors, hydroxamates.