{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T15:09:48Z","timestamp":1788966588368,"version":"build-2803163510"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,9]]},"abstract":"\n Background and purpose:<\/jats:title>\n \n Phosphodiesterase 7A (PDE7A) is an attractive therapeutic target for the treatment of inflammatory, autoimmune, and neurodegenerative disorders through modulation of intracellular cAMP levels. However, the development of highly potent and selective PDE7A inhibitors remains challenging. This study aimed to design, synthesize, and evaluate 2-chloroquinazoline and fused 1,2,4-triazolo[4,3-\n c<\/jats:italic>\n ]quinazoline derivatives as potential PDE7A inhibitors, supported by molecular docking, molecular dynamics simulations, and\n in silico<\/jats:italic>\n toxicity prediction.\n <\/jats:p>\n <\/jats:sec>\n \n Experimental approach:<\/jats:title>\n \n A series of 2-chloroquinazoline derivatives\n 4a\u2013f<\/jats:bold>\n and their fused 1,2,4-triazolo[4,3-c]quinazoline counterparts\n 5a<\/jats:bold>\n \u2013\n d<\/jats:bold>\n were synthesized as phosphodiesterase 7A (PDE7A) inhibitors. The synthesized compounds were evaluated for their\n in vitro<\/jats:italic>\n inhibitory activity against phosphodiesterase 7A (PDE7A) and were compared with theophylline and BRL50481, a selective PDE7 inhibitor.\n <\/jats:p>\n <\/jats:sec>\n \n Findings\/Results:<\/jats:title>\n \n All compounds demonstrated enzyme inhibition ranging from 0.062 to 1.35 \u03bcM;. Derivatives\n 5c<\/jats:bold>\n and\n 5d<\/jats:bold>\n exhibited the most potent inhibitory effects, with IC\n 50<\/jats:sub>\n values of 0.076 and 0.062 \u03bcM;, respectively, and were not significantly different from BRL50481 (IC\n 50<\/jats:sub>\n = 0.034 \u03bcM;), while being significantly more potent than theophylline (IC\n 50<\/jats:sub>\n = 0.539 \u03bcM;). These compounds, together with\n 4c<\/jats:bold>\n and\n 5a<\/jats:bold>\n , showed superior inhibitory activity compared with theophylline. Molecular docking and molecular dynamics studies were performed to investigate binding interactions and stability within the PDE7A active site.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion and implications:<\/jats:title>\n \n Compounds\n 5c<\/jats:bold>\n and\n 5d<\/jats:bold>\n displayed high binding affinity and stability within the active site. Their interactions with key amino acid residues support their potential as effective PDE7A inhibitors. Predicted toxicity data indicated a favorable safety profile across 30 toxicity endpoints, supporting their further development.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.4103\/rps.rps_195_25","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T10:21:05Z","timestamp":1788949265000},"page":"702-715","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["Synthesis, in vitro and in silico evaluation of quinazoline and triazoloquinazoline derivatives as PDE7A inhibitors"],"prefix":"10.4103","volume":"21","author":[{"given":"Afaf A.","family":"El-Malah","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy, King Abdul Aziz University, Pharmaceutical Chemistry Department, Jeddah, 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdy M.","family":"Gineinah","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, King Abdul Aziz University, Pharmaceutical Chemistry Department, Jeddah, 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maan T.","family":"Khayat","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, King Abdul Aziz University, Pharmaceutical Chemistry Department, Jeddah, 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thikryat","family":"Neamatallah","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdul Aziz University, Jeddah, 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amr","family":"Sonousi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt"},{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Gulf Medical University, Ajman, United Arab 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