Design, synthesis and antitumor evaluation of novel pyrazolo[3,4- d ]pyrimidines incorporating different amino acid conjugates as potential DHFR inhibitors

Novel pyrazolo[3,4-d]pyrimidine derivatives: design, synthesis, anticancer evaluation, VEGFR-2 inhibition, and antiangiogenic activity

“…The synthesis began with the reaction of ethyl 2-cyano-3-ethoxypropanoate and phenylhydrazine in absolute ethanol, resulting in the formation of ethyl 5-amino-1-phenyl-1 H -pyrazole-4-carboxylate ( 1 ). 54 Subsequent basic hydrolysis of compound 1 yielded 5-amino-1-phenyl-1 H -pyrazole-4-carboxylic acid ( 2 ), 55 which was further refluxed in acetic anhydride to obtain the key intermediate, 6-methyl-1-phenylpyrazolo[3,4- d ][1,3]oxazin-4(1 H )-one ( 3 ). 56 Compound 3 was then used in the reaction with p -phenylenediamine and p -aminoacetophenone, leading to the formation of the corresponding 5-(4-substituted phenyl)-1 H -pyrazolo[3,4- d ]pyrimidine-4-one derivatives, namely compounds 4 and 5 , respectively.…”

“…Compounds 1-3, and 5 were prepared according to the reported procedures. [54][55][56] Procedure for preparation of 5-(4-aminophenyl)-6-methyl-1-phenyl-1H-pyrazolo [3,4-d]pyrimidin-4(5H)-one (4). To a mixture of compound 3 (2.27 g, 0.01 mol) in butanol (10 mL), p-phenylene diamine was added (1.08 g, 0.01 mol).…”

“…The synthesis began with the reaction of ethyl 2-cyano-3ethoxypropanoate and phenylhydrazine in absolute ethanol, resulting in the formation of ethyl 5-amino-1-phenyl-1Hpyrazole-4-carboxylate (1). 54…”

Novel Para-Aminobenzoic Acid Analogs and Their Potential Therapeutic Applications

“…Most commonly, DHFR inhibitors are conventional anti-folates, including pemetrexed (PMX), pralatrexate, methotrexate (MTX), and aminopterin. The chemical structure of the MTX prototype mainly consists of three significant moieties including p-amino benzoic acid, glutamic acid, and pteridine nucleus [34]. Some 1,2,4-triazoloquinazolines were found effective as antioxidant, anti-diabetic, antimicrobial, anti-hypertensive, and anti-inflammatory compounds [35].…”

“…Phenyl-pyrazolo [3,4-d]pyrimidinyl-aminobenzoic acid and key intermediates were prepared by reacting chloro-phenylpyrazolo [3,4-d]pyrimidine with PABA. These intermediates were further reacted with 1H-benzotriazole, giving the N-acyl benzotriazole compound, which, upon condensation with numerous amino acids, gave substituted amino acid compounds [34]. Pyrazolone compounds were achieved by condensing phenyl hydrazine derivatives with ethyl acetoacetate derivatives.…”