The development of novel C-2, C-8, and N-9 trisubstituted purines as inhibitors of TNF-α production

Regioselective Control of the SNAr Amination of 5-Substituted-2,4-Dichloropyrimidines Using Tertiary Amine Nucleophiles

“…The addition of i Pr 2 NEt base allowed complete consumption of 1 with formation of the three products 2a , 3a , and 4a (C-2 and C-4 disubstitution) in a ratio of 2a : 3a : 4a of 10/0.2/1.6, as determined by the integration of the H-6 resonance in the 1 H NMR spectrum of the final reaction mixture. This result is in accord with the extensive literature precedent for preferential nucleophilic substitution at C-4 in these S N Ar reactions (citing recent literature examples of C-4 selective S N Ar and where the presence of a product from competing C-2 substitution is not noted). ,− ,,− ,− …”

“…2,4-Dichloropyrimidines that are further substituted at C-5 with an electron-withdrawing substituent (notably cyano, nitro, or trifluoromethyl) are particularly useful starting materials, yielding (upon further synthetic transformation) pyrimidine-containing structures with biological activity. The breadth of biologically active pyrimidine, and pyrimidine-derived, structures is expansive. , The synthetic objectives of several examples are cited herein: adenosine A 2A receptor antagonist; HIV non-nucleoside reverse transcriptase inhibitor; VLA-4 integrin antagonist; inhibitor of falcipain protease; inhibitor of stearoyl-CoA desaturase; and inhibitors of human kinases. − The S N Ar reactions of these pyrimidines (whether with carbon, nitrogen, or oxygen nucleophiles) invariably occur rapidly (often in minutes) at low temperatures (ambient and below), with excellent yields and outstanding regioselectivity for nucleophilic displacement of the C-4 halogen . Indeed, with many amine nucleophiles, this regioselectivity is so good that the accompanying experimentals often fail to acknowledge the possible presence of a minor product from competing substitution at C-2.…”

“…When silica gel chromatography of these chloro-5-nitropyrimidines is necessary, the shortest possible flash column should be used. The removal of small amounts of the 2-chloro-5-nitropyrimidin-4-amine by exploiting the generally greater solubility in organic solvents of the 2-chloro-5-nitropyrimidin-4-amine compared to the 4-chloro-5-nitropyrimidin-2-amine may be advisible. ,, Last, 4-chloro-5-nitropyrimid-2-amines are not shelf-stable (stored in a vial at room temperature, without explicit effort to exclude atmospheric moisture, results in significant levels of decomposition over a period of months) and they react with certain solvents (such as DMF and DMSO) at elevated temperatures.…”

Identification of (1E, 3E)-1, 3-bis [(2-hydroxy- 1-naphthyl) methylene] Urea as Mutated MAP Kinase P38 Inhibitor through Reverse Pharmacophore Mapping Approach: Green Synthesis, Characterisation and in silico Docking analysis

“…The reverse docking server Pharm Mapper showed a large positive Z'-score of 2.916 with PDB id: 2GTN protein. 21 Hence, this protein was selected as the target to perform docking studies on all the Schiff base molecules. The active site in the target protein was determined by analyzing the binding pattern of (2-(2, 6-difluorophenoxy)-n-(2-fluorophenyl) -9-isopropyl-9h-purin-8-amine) [LIE] which is co-crystallized and available in the 2GTN was used as control.…”

Systematically Mitigating the p38α Activity of Triazole-based BET Inhibitors

“…Cocrystal structures with p38α indicate that one of the inhibitor’s pyrimidine nitrogen atoms serves as a hydrogen bond acceptor, and the exocyclic N–H is a hydrogen bond donor (Figure ); both interactions are made to the M109 peptide backbone in p38α (Figure ). − If the exocyclic N–H was replaced by an ether linkage, there would no longer be a hydrogen bond donor, which would weaken binding to p38α . Hypothetically, binding to M109 could be further minimized by replacing the pyrimidine nitrogen with a C–H unit (pyridine), which would not be a suitable hydrogen bond acceptor.…”