Novel thieno[2,3-d]pyrimidines: their design, synthesis, crystal structure analysis and pharmacological evaluation.
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.
Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500046, India.
Raju
R
Adepu
D
D
Rambabu
Bagineni
B
Prasad
Chandana Lakshmi T
CL
Meda
Ajit
A
Kandale
G Rama
GR
Krishna
C Malla
CM
Reddy
Lakshmi N
LN
Chennuru
Kishore V L
KV
Parsa
Manojit
M
Pal
D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D003512:Cyclohexanones / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D051379:Mice; D008958:Models, Molecular; D058988:Phosphodiesterase 4 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism
D003512:Cyclohexanones; D058988:Phosphodiesterase 4 Inhibitors; D011743:Pyrimidines; D013876:Thiophenes; D014409:Tumor Necrosis Factor-alpha; C036468:cyclohexanone