Synthesis of new pyridothienopyrimidinone derivatives as Pim-1 inhibitors

Abstract

Four series of pyridothienopyrimidin-4-one derivatives were designed and prepared to improve the pim-1 inhibitory activity of the previously reported thieno[2,3-b]pyridines. Significant improvement in the pim-1 inhibition and cytotoxic activity was achieved using structure rigidification strategy via ring closure. Six compounds (6c, 7a, 7c, 7d, 8b and 9) showed highly potent pim-1 inhibitory activity with IC50 of 4.62, 1.18, 1.38, 1.97, 8.83 and 4.18 μM, respectively. Four other compounds (6b, 6d, 7b and 8a) showed moderate pim-1 inhibition. The most active compounds were tested for their cytotoxic activity on three cell lines [MCF7, HCT116 and PC3]. Compounds 7a [the 2-(2-chlorophenyl)-2,3-dihydro derivative] and 7d [the 2-(2-(trifluoromethyl)-phenyl)-2,3-dihydro derivative] displayed the most potent cytotoxic effect on the three cell lines tested consistent with their highest estimated pim-1 IC50 values.

Synthesis of new pyridothienopyrimidinone and pyridothienotriazolopyrimidine derivatives as pim-1 inhibitors

“…Schemes 1 and 2 outline the synthesis of the target compounds. In the current work, 3-amino-5-bromo-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide (2) was prepared by alkaline hydrolysis of the 3-aminothieno[2,3- b ]pyridine-2-carbonitrile 1 as reported by Naguib et al 9 . Compound 2 was then reacted with different aldehydes in glacial acetic acid to afford 2-aryl-8-bromo-2,3-dihydropyrido[3′,2′:4,5]thieno[3,2- d ]pyrimidin-4( 1H )-ones 3a–j.…”

“…All reagents and solvents were purified and dried by standard techniques. 3-Amino-5-bromo-4,6-dimethylthieno[2,3- b ]pyridine-2-carbonitrile ( 1 ) and 3-amino-5-bromo-4,6-dimethylthieno[2,3- b ]pyridine-2-carboxamide (2) were prepared according to the published methods 9 , 12 .…”

“…Recently, we had reported the identification of pyridothienopyrimidin-4-one derivatives IV as potent pim-1 inhibitors 9 . These derivatives were developed through structure rigidification strategy via ring closure of their precursors thieno[2,3- b ]pyridines III 10 to ensure the presence of the carbonyl group at proper orientation for binding with the enzyme.…”

“…Indeed, our efforts led to significant improvement in the enzyme inhibitory activity as well as the cytotoxic activity. The most potent inhibitors were the 2-aryl-2,3-dihydro derivatives Va–c that exhibited pim-1 inhibition in the range of 1.18–1.97 µM 9 . However, the aryl groups used in that study were all bearing ortho substitution to mimic the structure of the previously published benzofuropyrimidinone derivative VI 11 ( Figure 2 ).…”

Synthesis of Compounds of the Pyrimidine Series Based on the Reactions of 3-Arylmethylidenefuran-2(3H)-ones with N,N-Binucleophilic Reagents

“…In the market, there are some approved, effective, well-known medicines containing pyrimidine moieties ( Figure 1 ), such as antimicrobial agent Trimethoprim [ 9 ], antiparkinsonian agent Piribedil [ 10 ], and antiviral medication Aciclovir (Zovirax) [ 11 ], etc. Currently, the interest in pyrimidin-containing biologically active compounds is still significant [ 12 , 13 , 14 ].…”