Synthesis of <i>N</i>‐alkylated pyrazolo[3,4‐<i>d</i>]pyrimidine analogs and evaluation of acetylcholinesterase and carbonic anhydrase inhibition properties
Busra Ozturk Aydin, Derya Aktaş Anıl, Yeliz Demir
Abstract
Abstract Fused pyrimidines, especially pyrazolo[3,4‐ d ]pyrimidines, are among the most preferred building blocks for pharmacology studies, as they exhibit a broad spectrum of biological activity. In this study, new derivatives of pyrazolo[3,4‐ d ]pyrimidine were synthesized by alkylation of the N1 nitrogen atom. We synthesized 3‐iodo‐1 H ‐pyrazolo[3,4‐ d ]pyrimidin‐4‐amine 2 from commercially available aminopyrazolopyrimidine 1 using N ‐iodosuccinimide as an iodinating agent. The synthesis of compound 2 started with nucleophilic substitution of 3‐iodo‐1 H ‐pyrazolo[3,4‐ d ]pyrimidin‐4‐amine with R–X (X: –OMs, –Br, –Cl), affording N ‐alkylated pyrazolo[3,4‐ d ]pyrimidine. We performed this synthesis using a weak inorganic base and the mild temperature was also used for a two‐step procedure to generate N ‐alkylated pyrazolo[3,4‐ d ]pyrimidine derivatives. Also, all compounds were tested for their ability to inhibit acetylcholinesterase (AChE) and the human carbonic anhydrase (hCA) isoforms I and II, with K i values in the range of 15.41 ± 1.39–63.03 ± 10.68 nM for AChE, 17.68 ± 1.92–66.27 ± 5.43 nM for hCA I, and 8.41 ± 2.03–28.60 ± 7.32 nM for hCA II. Notably, compound 10 was the most selective and potent CA I inhibitor with a significant selectivity ratio of 26.90.