{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T12:21:48Z","timestamp":1785932508258,"version":"3.56.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Chem."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>The urgent need for novel antibacterial agents against drug-resistant Gram-positive pathogens, particularly Methicillin-resistant Staphylococcus aureus (MRSA), drives this research. This study aimed to synthesize and evaluate a series of N\u2019-substituted methylene-4-chlorobenzohydrazide derivatives as potential anti-MRSA agents.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Sixteen target compounds\n                      <jats:bold>(C1\u2013C16)<\/jats:bold>\n                      were synthesized from commercial ethyl 4-chlorobenzoate via ester aminolysis and condensation. Their structures were confirmed by\n                      <jats:sup>1<\/jats:sup>\n                      H NMR,\n                      <jats:sup>13<\/jats:sup>\n                      C NMR, and HRMS. Biological evaluations included\n                      <jats:italic>in vitro<\/jats:italic>\n                      antibacterial assays against a panel of bacteria, cytotoxicity (VERO cells), hemolytic activity, mechanistic studies (membrane targeting, depolarization, permeability, content leakage, ROS generation), biofilm inhibition, and resistance development assessment. Drug-likeness properties were also analyzed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Two novel\n                      <jats:bold>(C1, C16)<\/jats:bold>\n                      and fourteen known analogues were obtained. The series showed weak activity against Gram-negative bacteria but potent inhibition against various Gram-positive bacteria, including MRSA. Compound\n                      <jats:bold>C12<\/jats:bold>\n                      emerged as the optimal derivative, exhibiting the strongest broad-spectrum anti-Gram-positive activity (MIC = 26 \u03bcM) and high selectivity.\n                      <jats:bold>C12<\/jats:bold>\n                      showed no significant cytotoxicity or hemolysis at effective concentrations. It specifically targeted phosphatidylglycerol (PG) in the bacterial membrane, causing rapid membrane depolarization, increased permeability, leakage of intracellular proteins\/DNA, ROS burst, and bactericidal effects. Furthermore,\n                      <jats:bold>C12<\/jats:bold>\n                      inhibited S. aureus biofilm formation and displayed a very low propensity for spontaneous resistance development. It demonstrated moderate metabolic stability and suitable lipophilicity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      Compound\n                      <jats:bold>C12<\/jats:bold>\n                      represents a promising anti-MRSA lead compound. It combines potent antibacterial activity with a unique multi-mechanistic action targeting the cell membrane, a favorable biosafety profile, and a low resistance risk. These merits warrant further in-depth investigation and development.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fchem.2026.1753350","type":"journal-article","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T07:01:40Z","timestamp":1772607700000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Membrane-targeted schiff base derivatives overcome MRSA resistance through phosphatidylglycerol binding and ROS-mediated killing"],"prefix":"10.3389","volume":"14","author":[{"given":"Yaguang","family":"Liu","sequence":"first","affiliation":[{"name":"The Second Hospital of QinHuangDao, Pharmacy Department","place":["QinHuangDao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianzhi","family":"Hu","sequence":"additional","affiliation":[{"name":"The Second Hospital of QinHuangDao, Pharmacy Department","place":["QinHuangDao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binbin","family":"Liu","sequence":"additional","affiliation":[{"name":"The Second Hospital of QinHuangDao, Pharmacy Department","place":["QinHuangDao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Qu","sequence":"additional","affiliation":[{"name":"The Second Hospital of QinHuangDao, Pharmacy Department","place":["QinHuangDao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1521","DOI":"10.1080\/14756366.2021.1924698","article-title":"Synthesis, potential antitumor activity, cell cycle analysis, and multitarget mechanisms of novel hydrazones incorporating a 4-methylsulfonylbenzene scaffold: a molecular docking study","volume":"36","author":"Abdel-Aziz","year":"2021","journal-title":"J. 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