{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:09:16Z","timestamp":1790698156756,"version":"4.1.0"},"reference-count":63,"publisher":"American Chemical Society (ACS)","issue":"38","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Four series of 5-alkyl-6-benzyl-2-[(methylthio\/phenylthio)alkyl]thiopyrimidin-4(3H)-ones were systematically diversified at C2, C5, and C6 and evaluated as anti-HIV-1 agents. In MT-4 cells, these compounds displayed low-to-moderate cytotoxicity and subnanomolar-to-submicromolar inhibition of WT HIV-1, with potency governed by a balanced SAR. Ortho-dihalogenated C6-benzyl groups, particularly 2,6-F2 and 2,6-Cl2, were generally favored. In the 2,6-dihalobenzyl series, optimal activity required C5 methyl combined with para-substituted phenylthiomethyl groups at C2, whereas 3,5-Me2-benzyl analogues benefited from C5 isopropyl paired with methylthioethyl (24l) or unsubstituted phenylthiomethyl (24m) C2 side chains. The p-methoxyphenylthiomethyl thiothymine derivatives 21e (2,6-F2) and 23e (2,6-Cl2) emerged as lead inhibitors, showing high selectivity, potent activity against WT and clinically relevant HIV-1 variants, superior efficacy compared with nevirapine and efavirenz, dapivirine-like potency, and improved resistance tolerance relative to phenethyl-S-DABO bioisosteres. Together, biological and QSAR and docking data contribute to defining optimization strategies aimed at achieving durable anti-HIV-1 activity within the investigated chemotype and support further development of next-generation NNRTIs with improved efficacy against clinically relevant HIV-1 strains.<\/jats:p>","DOI":"10.1021\/acsomega.6c08020","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T15:02:37Z","timestamp":1789570957000},"page":"58141-58158","source":"Crossref","is-referenced-by-count":0,"title":["Systematic Structure\u2013Activity\nRelationship\nInvestigation on Novel 5-Alkyl-6-benzyl-2-{[(methylthio\/phenylthio)alkyl]thio}-pyrimidin-4(3\n                    <i>H<\/i>\n                    )-ones Endowed with Potent Anti-HIV-1 Activity"],"prefix":"10.1021","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8638-3214","authenticated-orcid":true,"given":"Gebremedhin 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