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A series of pyrazolo[1,5\u2010<jats:italic>a<\/jats:italic>]pyrimidine\u2010based compounds <jats:bold>3a\u2013l<\/jats:bold> and <jats:bold>5a\u2013f<\/jats:bold> were prepared by the direct cyclo\u2010condensation reaction of 5\u2010amino\u20101<jats:italic>H<\/jats:italic>\u2010pyrazoles <jats:bold>1a, b<\/jats:bold> with 2\u2010(arylidene)malononitriles and 3\u2010(dimethylamino)\u20101\u2010aryl\u2010prop\u20102\u2010en\u20101\u2010ones, respectively. The structures of the new pyrazolo[1,5\u2010<jats:italic>a<\/jats:italic>]pyrimidine compounds were confirmed via spectroscopic techniques. The in vitro biological activities of all pyrazolo[1,5\u2010<jats:italic>a<\/jats:italic>]pyrimidines <jats:bold>3a\u2013l<\/jats:bold> and <jats:bold>5a\u2013f<\/jats:bold> were evaluated by assaying total antioxidant capacity, iron\u2010reducing power, the scavenging activity against 1\u2010diphenyl\u20102\u2010picryl\u2010hydrazyl (DPPH) and 2, 2'\u2010azinobis\u2010(3\u2010ethylbenzothiazoline\u20106\u2010sulfonic acid) (ABTS) radicals, anti\u2010diabetic, anti\u2010Alzheimer, and anti\u2010arthritic biological activities. All compounds displayed good to potent bioactivity, and three compounds <jats:bold>3g, 3h<\/jats:bold>, and <jats:bold>3l<\/jats:bold> displayed the most active derivatives. Among these derivatives, compound <jats:bold>3l<\/jats:bold> exhibited the highest antioxidant (total antioxidant capacity [TAC]\u2009=\u200983.09\u2009mg gallic acid\/g; iron\u2010reducing power [IRP]\u2009=\u200947.93\u2009\u00b5g\/ml) and free radicals scavenging activities with (DPPH\u2009=\u200918.77\u2009\u00b5g\/ml; ABTS\u2009=\u200940.44%) compared with ascorbic acid (DPPH\u2009=\u20094.28\u2009\u00b5g\/ml; ABTS\u2009=\u200938.84%). Furthermore, compound <jats:bold>3l<\/jats:bold> demonstrated the strongest inhibition of \u03b1\u2010amylase with a percent inhibition of 72.91\u2009\u00b1\u20090.14 compared to acarbose\u2009=\u200967.92\u2009\u00b1\u20090.09%. Similarly, it displayed acetylcholinesterase inhibition of 62.80\u2009\u00b1\u20090.06%. However, compound 3i showed a significantly higher inhibition percentage for protein denaturation and proteinase at 20.66\u2009\u00b1\u20090.00 and 26.42\u2009\u00b1\u20090.06%, respectively. Additionally, some in silico ADMET properties were predicted and studied. Finally, molecular docking simulation was performed inside the active site of \u03b1\u2010amylase and acetylcholinesterase to study their interactions.<\/jats:p>","DOI":"10.1002\/ddr.22008","type":"journal-article","created":{"date-parts":[[2022,11,16]],"date-time":"2022-11-16T01:05:55Z","timestamp":1668560755000},"page":"3-24","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":79,"title":["In vitro enzymatic evaluation of some pyrazolo[1,5\u2010<i>a<\/i>]pyrimidine derivatives: Design, synthesis, antioxidant, anti\u2010diabetic, anti\u2010Alzheimer, and anti\u2010arthritic activities with molecular modeling simulation"],"prefix":"10.1002","volume":"84","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4771-716X","authenticated-orcid":false,"given":"Ashraf S.","family":"Hassan","sequence":"first","affiliation":[{"name":"Organometallic and Organometalloid Chemistry Department National Research Centre Dokki Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3636-1767","authenticated-orcid":false,"given":"Nesrin M.","family":"Morsy","sequence":"additional","affiliation":[{"name":"Organometallic and Organometalloid Chemistry Department National Research Centre Dokki Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4848-0731","authenticated-orcid":false,"given":"Wael M.","family":"Aboulthana","sequence":"additional","affiliation":[{"name":"Biochemistry Department, Biotechnology Research Institute National Research Centre Dokki Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8542-7465","authenticated-orcid":false,"given":"Ahmed","family":"Ragab","sequence":"additional","affiliation":[{"name":"Chemistry Department, Faculty of Science (Boys) Al\u2010Azhar University Nasr City Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,11,15]]},"reference":[{"key":"e_1_2_11_2_1","first-page":"79","article-title":"Synthesis, characterization and biological evaluation of new fused triazine derivatives based on 6\u2010methyl\u20103\u2010thioxo\u20101,2,4\u2010triazin\u20105\u2010one","volume":"73","author":"Abd El\u2010All A. 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