Synthesis, anti-HIV activity, integrase enzyme inhibition and molecular modeling of catechol, hydroquinone and quinol labdane analogs

  • Bioorg Med Chem Lett. 2014 Jan 1;24(1):302-7. doi: 10.1016/j.bmcl.2013.11.014.
Rohan Pawar  1 ,  Tiyasa Das  2 ,  Sanjay Mishra  1 ,  Nutan  2 ,  Boskey Pancholi  2 ,  Satish K Gupta  3 ,  Sujata V Bhat  4
Affiliations
  • 1. Laboratory for Advanced Research in Natural and Synthetic Chemistry, V.G. Vaze College, Mumbai University, Mithagar Road, Mulund (East), Mumbai 400 081, India.
  • 2. National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110 067, India.
  • 3. National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110 067, India. Electronic address: [email protected].
  • 4. Laboratory for Advanced Research in Natural and Synthetic Chemistry, V.G. Vaze College, Mumbai University, Mithagar Road, Mulund (East), Mumbai 400 081, India. Electronic address: [email protected].
PMID: 24291042 DOI: 10.1016/j.bmcl.2013.11.014
Abstract

Labdane analogs with o-quinol, catechol and hydroquinone moiety have been synthesized using Diels-Alder reaction of methyl 3,4-dioxocyclohexa-1,5-diene-carboxylate, 3,4-dioxocyclohexa-1,5-diene-carboxylic acid and 3,6-dioxocyclohexa-1,4-dienecarboxylic acid with mono terpene 1,3-dienes, namely ocimene and myrcene. The resulting molecules and their derivatives were evaluated for their anti-HIV-1 activity using TZM-bl cell based virus infectivity assay. Two molecules 13 and 18 showed anti-HIV activity with IC50 values 5.0 (TI=11) and 4.6 (TI=46)μM, respectively. The compounds 17, 18 and 20 showed efficacy against HIV-1 integrase activity and showed inhibition with IC50 13.4, 11.1 and 11.5μM, respectively. The HIV-1 integrase inhibition activity of these synthetic molecules was comparable with integric acid, the natural Fungal metabolite. Molecular modeling studies for the HIV-1 integrase inhibition of these active synthetic molecules indicated the binding to the active site residues of the enzyme.

Keywords
3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide; ACN; Anti-HIV-1 activity; Computational study; Diels–Alder reaction; HIV-1 integrase inhibition; IBD; IN CCD; Labdane analogs; MTT; RT; TI; acetonitrile; integrase catalytic core domain; iodoso benzene diacetate; o-Quinol–catechol–hydroquinone moiety; room temperature; therapeutic index.