1. Novel thieno[2,3-d]pyrimidines: their design, synthesis, crystal structure analysis and pharmacological evaluation.
- Author
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Adepu R, Rambabu D, Prasad B, Meda CL, Kandale A, Krishna GR, Reddy CM, Chennuru LN, Parsa KV, and Pal M
- Subjects
- Animals, Cell Line, Crystallography, X-Ray, Cyclohexanones chemistry, Humans, Hydrogen Bonding, Mice, Models, Molecular, Phosphodiesterase 4 Inhibitors chemical synthesis, Phosphodiesterase 4 Inhibitors chemistry, Phosphodiesterase 4 Inhibitors pharmacology, Pyrimidines chemical synthesis, Pyrimidines pharmacology, Thiophenes chemical synthesis, Thiophenes pharmacology, Tumor Necrosis Factor-alpha antagonists & inhibitors, Tumor Necrosis Factor-alpha chemistry, Tumor Necrosis Factor-alpha metabolism, Pyrimidines chemistry, Thiophenes chemistry
- Abstract
Novel thieno[2,3-d]pyrimidines containing a cyclohexane ring fused with a six- or five-membered heterocyclic moiety along with a benzylic nitrile were designed as potential inhibitors of PDE4. Expeditious synthesis of these compounds was carried out via a multi-step sequence consisting of a few key steps such as Gewald reaction, Dieckmann type cyclisation and Krapcho decarboxylation. This newly developed strategy involved construction of the thienopyrimidine ring followed by the cyclohexanone moiety and subsequently the fused heterocyclic ring. A number of thieno[2,3-d]pyrimidine based derivatives were synthesized using this method some of which showed promising PDE4B inhibitory properties. One of them was tested for PDE4D inhibition in vitro and dose dependent inhibition of TNF-α. A few selected molecules were docked into the PE4B protein the results of which showed good overall correlations to their observed PDE4B inhibitory properties in vitro. The crystal structure analysis of representative compounds along with hydrogen bonding patterns and molecular arrangement present within the molecule is described.
- Published
- 2012
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