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Previously, we reported a novel benzimidazole\u2010based FLT3 inhibitor, 4ACP, with nanomolar activities against FLT3\u2010ITD and FLT3\u2010TKD mutants, showing selective cytotoxicity against FLT3\u2010ITD<jats:sup>+<\/jats:sup> AML cell lines. In this study, we synthesized 31 derivatives by modifying the 4\u2010acetamidophenyl group and varying substituents at <jats:italic>N<\/jats:italic>1\u2010phenyl and C2 positions. We identified compound <jats:bold>21l<\/jats:bold> (3\u2010acetamidophenyl) as the most potent derivative (FLT3\u2010TKD(D835Y) IC<jats:sub>50<\/jats:sub>\u2009=\u20091.47\u2009nM). Linking <jats:bold>21l<\/jats:bold> to a solvent\u2010accessible group yielded compound <jats:bold>22b<\/jats:bold>, which exhibited a sub\u2010nanomolar activity against FLT\u2010TKD(D835Y) mutant with an IC<jats:sub>50<\/jats:sub> value of 0.48\u2009nM. Compound <jats:bold>22b<\/jats:bold> showed preferential antiproliferative activities against MOLM\u201014, MV4\u201011, MOLM\u201014\u2010D835Y, and MOLM\u201014\u2010F691L AML cell lines with IC<jats:sub>50<\/jats:sub> values of 16.1, 10.5, 26.5, and 160.3\u2009nM, respectively. <jats:bold>22b<\/jats:bold> induced dose\u2010dependent inhibition of FLT3, ERK, STAT5, and S6 phosphorylation, G0\/G1 cell\u2010cycle arrest, and apoptotic cell death at low nanomolar concentrations in MOLM\u201014 and MOLM\u201014\u2010D835Y cells. It was more selective for FLT3\u2010dependent cell lines, showing about 80\u2010fold selectivity toward FLT3\u2010TKD(D835Y) over KIT, indicating relative safety and lower myelosuppression potential. The molecular dynamics study of 4ACP and <jats:bold>22b<\/jats:bold> was conducted to explain the significant changes in activity resulting from subtle structural alterations. Altogether, these findings establish <jats:bold>22b<\/jats:bold> as a potent mutant FLT3 inhibitor, warranting further investigation and optimization to target resistant AML.<\/jats:p>","DOI":"10.1002\/ardp.70002","type":"journal-article","created":{"date-parts":[[2025,5,10]],"date-time":"2025-05-10T04:25:33Z","timestamp":1746851133000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Structural Optimization and MD Simulation Study of Benzimidazole Derivatives as Potent Mutant FLT3 Kinase Inhibitors Targeting AML"],"prefix":"10.1002","volume":"358","author":[{"given":"Nada Alaa","family":"El\u2010Deen","sequence":"first","affiliation":[{"name":"Pharmaceutical Chemistry Department, Faculty of Pharmacy Ain Shams University  Abbassia Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"RosaAnna","family":"DeFilippis","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology University of California  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1709-1183","authenticated-orcid":false,"given":"Amal Kamal","family":"Abdel\u2010Aziz","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy Ain Shams University  Abbassia Cairo Egypt"},{"name":"Department of Experimental Oncology IEO, European Institute of Oncology IRCCS  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6563-8265","authenticated-orcid":false,"given":"Sandra N.","family":"Milik","sequence":"additional","affiliation":[{"name":"Pharmaceutical Chemistry Department, Faculty of Pharmacy Ain Shams University  Abbassia Cairo Egypt"},{"name":"School of Chemistry University of Leeds  Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suhana","family":"Patel","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology University of California  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad I.","family":"Ismail","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy The British University in Egypt  Al\u2010Sherouk City Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar","family":"Khaled","sequence":"additional","affiliation":[{"name":"Pharmaceutical Chemistry Department, Faculty of Pharmacy Ain Shams University  Abbassia Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2999-1798","authenticated-orcid":false,"given":"Tarek Erfan","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Pharmaceutical Chemistry Department, Faculty of Pharmacy Ain Shams University  Abbassia Cairo Egypt"},{"name":"Department of Chemistry Georgia State University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayatullah Gamal","family":"Abdelfattah","sequence":"additional","affiliation":[{"name":"Pharmaceutical Chemistry Department, Faculty of Pharmacy Ain Shams University  Abbassia Cairo Egypt"},{"name":"Department of Chemistry Georgia State University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eslam M. 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