Novel 1,2,4-triazole and imidazole derivatives of L-ascorbic and imino-ascorbic acid: synthesis, anti-HCV and antitumor activity evaluations

Bioorganic & Medicinal Chemistry
Karlo WittineMladen Mintas

Abstract

Several novel 1,2,4-triazole and imidazole L-ascorbic acid (1, 2, 3, 5, 6 and 9) and imino-ascorbic acid (4, 7 and 8) derivatives were prepared and evaluated for their inhibitory activity against hepatitis C virus (HCV) replication and human tumour cell proliferation. Compounds 6 and 9 exerted the most pronounced cytostatic effects in all tumour cell lines tested, and were highly selective for human T-cell acute lymphoblastic leukaemia cells (CEM/0) with IC(50)s of 10 ± 4 and 7.3 ± 0.1 μM, respectively. Unlike compound 9, compound 6 showed no toxicity in human diploid fibroblasts. One of the possible mechanisms of action of compound 6 accounting for observed cytostatic activity towards haematological malignancies might be inhibition of inosine monophosphate dehydrogenase (IMPDH) activity, a key enzyme of de novo purine nucleotide biosynthesis providing the cells with precursors for DNA and RNA synthesis indispensable for cell growth and division, which has emerged as an important target for antileukemic therapy. In addition, this compound proved to be the most potent inhibitor of the hepatitis C virus replication as well. However, observed antiviral effect was most likely associated with the effect that the compound exerted on ...Continue Reading

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Citations

Sep 10, 2014·Journal of Enzyme Inhibition and Medicinal Chemistry·Grzegorz CholewińskiKrystyna Dzierzbicka
Jun 7, 2013·Medicinal Research Reviews·Ling ZhangCheng-He Zhou
Apr 20, 2016·Cancer Biotherapy & Radiopharmaceuticals·Raghuvir H GaonkarMita C Debnath
Jul 31, 2019·Antioxidants·Andrijana Meščić MacanSilvana Raić-Malić
May 3, 2020·British Journal of Pharmacology·Steve P H AlexanderMichael Spedding
Aug 25, 2020·Arabian Journal for Science and Engineering·Yazala Jyothsna PragathiRudraraju Ramesh Raju
Dec 9, 2014·Acta Crystallographica. Section E, Structure Reports Online·Santosh R KoteRay J Butcher
Oct 31, 2019·Organic Letters·Stefanie N GeigleAlexander L Satz

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