{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T15:11:32Z","timestamp":1788966692505,"version":"build-2803163510"},"reference-count":38,"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 Malaria remains a formidable global healthcare challenge due to emerging drug-resistant Plasmodium spp., underscoring the urgent need for novel antimalarial scaffolds. Thiolactomycin, a FAS-II inhibitor, is a promising lead for structural optimization. This study aims to design, synthesize, and evaluate a series of thiomorpholino and piperidino conjugates bearing a thiolactone moiety as target-specific antimalarial agents.<\/jats:p>\n <\/jats:sec>\n \n Experimental approach:<\/jats:title>\n \n A series of thiolactomycin-based conjugates was synthesized, including intermediate\n 7b<\/jats:bold>\n and conjugate\n 4g<\/jats:bold>\n . Antimalarial activity was evaluated\n in vitro<\/jats:italic>\n against the\n Plasmodium falciparum<\/jats:italic>\n D10 strain. To elucidate the mechanism, multi-target docking studies of\n 7b<\/jats:bold>\n and\n 4g<\/jats:bold>\n were performed against key FAS-II enzymes, followed by 200 ns explicit-solvent MD simulations and MM-PBSA binding free energy calculations targeting\n Pf<\/jats:italic>\n FabI.\n In silico<\/jats:italic>\n pharmacokinetics and drug-likeness profiling of potent molecules were also carried out.\n <\/jats:p>\n <\/jats:sec>\n \n Findings\/Results:<\/jats:title>\n \n Biological evaluation identified\n 7b<\/jats:bold>\n and\n 4g<\/jats:bold>\n as potent compounds with IC\n 50<\/jats:sub>\n values of 0.2 and 1.81 \u03bcM, respectively. However, the higher phenotypic potency of\n 7b<\/jats:bold>\n was accompanied by mutagenic liability (Ames positive) revealed by toxicological profiling. Conversely,\n 4g<\/jats:bold>\n exhibited superior binding affinity (-7.2 kcal\/mol) against\n Pf<\/jats:italic>\n FabI. MD simulations revealed an induced-fit stabilization of the\n 4g<\/jats:bold>\n -\n Pf<\/jats:italic>\n FabI complex and the complex achieved superior binding free energy (\u0394\n GTotal<\/jats:italic>\n = -22.14 kcal\/mol) compared to thiolactomycin.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion and implications:<\/jats:title>\n \n Conjugate\n 4g<\/jats:bold>\n was identified as a safer potent compound from the series. MD simulation of the\n 4g<\/jats:bold>\n -\n Pf<\/jats:italic>\n FabI complex revealed an induced fit stabilization involving persistent H-bonds that were absent in docking. These findings suggest\n 4g<\/jats:bold>\n as a promising molecule for further optimization.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.4103\/rps.rps_187_25","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T10:21:15Z","timestamp":1788949275000},"page":"582-604","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["Thiolactomycin-based morpholino and piperidino conjugates: synthesis, antimalarial evaluation, and PfFAS-II inhibition"],"prefix":"10.4103","volume":"21","author":[{"given":"Shaik","family":"Azeeza","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry and Pharmacology, CSIR- Indian Institute of Chemical Technology, Hyderabad 500007, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Shaheer","family":"Malik","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, Umm Al-Qura University, Makkah 21955, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qazi Mohammad Sajid","family":"Jamal","sequence":"additional","affiliation":[{"name":"Department of Health Informatics, College of Public Health and Health Informatics, Qassim University, Al Bukayriyah, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mufakham Ali","family":"Mohammad","sequence":"additional","affiliation":[{"name":"Research and Development Division, Saudi Chevron Phillips Company, Jubail Industrial City, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Munirah M.","family":"Al-Rooqi","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, Umm Al-Qura University, Makkah 21955, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saeed S.","family":"Samman","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, Taibah University, Madina, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaikh Thoukhir","family":"Basha","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry and Pharmacology, CSIR- Indian Institute of Chemical Technology, Hyderabad 500007, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdulrahman A.","family":"Alsimaree","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Science and Humanities, Shaqra University, Shaqra, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziad","family":"Moussa","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Science, United Arab Emirates University, P.O. 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