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The first acyclonucleosides based on the benzothiadiazine dioxide system were synthesized following the silylation procedure. Several acyclic moieties, including acetoxyethoxymethyl, benzyloxymethyl, and propargyloxymethyl groups, were introduced. Two synthetic strategies were designed to selectively obtain the N-1 or N-3 derivatives. Lipase-mediated deacylation was used for the deprotection of the acyclonucleosides. Some of the benzothiadiazine dioxide acyclonucleosides, in particular 16, proved active against human cytomegalovirus (CMV) at concentrations slightly higher than that found for ganciclovir [50% inhibitory concentration (IC50) = 3. 5-3.7 micrograms/mL, cytotoxicity (CC50) >/= 40 micrograms/mL, MCC = 20 micrograms/mL]. Additionally, compound 16 inhibited the replication of human immunodeficiency virus type 1 (HIV-1) and HIV-2 in CEM cells at concentrations that were 5-fold lower than its cytotoxic concentration.

Abstract Several 2′,3′-dideoxynucleosides have proven to be effective against HIV-1 in cell culture. The 2′,3-unsaturated analogues dideoxycytidinene (D4C) and dideoxythymidinene (D4T) are among the most potent and selective inhibitors of HIV-1 replication in vitro. However, 2′,3′-didehydro-2′,3′-dideoxynucleosides are relatively unstable. A chlorine substituent at the 2′-position increases the stability, and, therefore, some 2′-chloro-2′,3′-didehydro-2′,3′-dideoxynucleosides were synthesized and evaluated for anti-HIV-1 activity.

The emerging challenge of HIV-1 drug resistance urgently demands the development of next-generation HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Herein, we designed and synthesized two series of novel 2,4,6-trisubstituted pyrimidines that target a previously insufficiently explored binding site at the interface between the p66 and p51 subunits of HIV-1 reverse transcriptase (RT). After iterative structural optimization, <b>15k</b> turned out to exhibit potent antiviral activity to wild-type and mutant HIV-1 strains, with EC₅₀ values ranging from 0.0046 to 0.033 μM and relatively low cytotoxicity (CC₅₀ = 26.64 μM). Molecular modeling revealed that <b>15k</b> adopts a unique "Y-shaped" conformation within the NNRTI-binding pocket (NNIBP), forming novel hydrogen bonds with E138 and K101 at the p51-p66 interface─a key factor contributing to its potent resistance profile. Moreover, <b>15k</b> exhibits favorable <i>in vivo</i> metabolic (<i>T</i>_1/2 = 2.12 h) and safety profiles. In summary, newly discovered <b>15k</b> represents a promising anti-HIV-1 drug candidate for further development.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

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