Dataset Information

Synthesis, structure-activity relationship and antiviral activity of 3'-N,N-dimethylamino-2',3'-dideoxythymidine and its prodrugs.

ABSTRACT: A probable NRTI molecule, viz. 3'-N,N-dimethylamino-2',3'-dideoxythymidine (4) and its 5'-O-carboxyl ester prodrugs - 5'-(N-alpha-BOC-L-phenylalanyl)-3'-N,N-dimethylamino-2',3'-dideoxythymidine (5), 5'-L-phenylalanyl-3'-N,N-dimethylamino-2',3'-dideoxythymidine (6) and 5'-decanoyl-3'-N,N-dimethylamino-2',3'-dideoxythymidine (7) have been synthesized and screened against HIV, HSV-1 and 2, parainfluenza-3, vesicular stomatitis and several other viruses. The compound 6 showed good antiviral activity with EC(50) value 0.03 microM (SI=8) against VSV in Hela and HEL cell lines. However, the lead compound 4 and its derivatives 5, 6 and 7 showed no remarkable activity against HIV-1 and other viruses. Molecular docking studies with HIV-1 RT using DS 2.5 and pymol softwares have shown marked differences in the interaction patterns between the lead compound 4 and AZT.

SUBMITTER: Singh RK

PROVIDER: S-EPMC7127469 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Synthesis, structure-activity relationship and antiviral activity of 3'-N,N-dimethylamino-2',3'-dideoxythymidine and its prodrugs.

Singh Ramendra K RK Yadav Dipti D Rai Diwakar D Kumari Garima G Pannecouque C C De Clercq Erik E

European journal of medicinal chemistry 20100520 9

A probable NRTI molecule, viz. 3'-N,N-dimethylamino-2',3'-dideoxythymidine (4) and its 5'-O-carboxyl ester prodrugs - 5'-(N-alpha-BOC-L-phenylalanyl)-3'-N,N-dimethylamino-2',3'-dideoxythymidine (5), 5'-L-phenylalanyl-3'-N,N-dimethylamino-2',3'-dideoxythymidine (6) and 5'-decanoyl-3'-N,N-dimethylamino-2',3'-dideoxythymidine (7) have been synthesized and screened against HIV, HSV-1 and 2, parainfluenza-3, vesicular stomatitis and several other viruses. The compound 6 showed good antiviral activity ...[more]

PMID: 20538384

Similar Datasets

Project description:The double-stranded DNA (dsDNA) viruses represented by adenovirus and monkeypox virus, have attracted widespread attention due to their high infectivity. In 2022, the global outbreak of mpox (or monkeypox) has led to the declaration of a Public Health Emergency of International Concern. However, to date therapeutics approved for dsDNA virus infections remain limited and there are still no available treatments for some of these diseases. The development of new therapies for treating dsDNA infection is in urgent need. In this study, we designed and synthesized a series of novel disulfide-incorporated lipid conjugates of cidofovir (CDV) as potential candidates against dsDNA viruses including vaccinia virus (VACV) and adenovirus (AdV) 5. The structure-activity relationship analyses revealed that the optimum linker moiety was C2H4 and the optimum aliphatic chain length was 18 or 20 atoms. Among the synthesized conjugates, 1c exhibited more potency against VACV (IC50 = 0.0960 μM in Vero cells; IC50 = 0.0790 μM in A549 cells) and AdV5 (IC50 = 0.1572 μM in A549 cells) than brincidofovir (BCV). The transmission electron microscopy (TEM) images revealed that the conjugates could form micelles in phosphate buffer. The stability studies in the GSH environment demonstrated that the formation of micelles in phosphate buffer might protect the disulfide bond from glutathione (GSH) reduction. The dominant means of the synthetic conjugates to liberate the parent drug CDV was by enzymatic hydrolysis. Furthermore, the synthetic conjugates remained sufficiently stable in simulated gastric fluid (SGF), simulated intestinal fluid (SIF), and pooled human plasma, which indicated the possibility for oral administration. These results indicated 1c may be a broad-spectrum antiviral candidate against dsDNA viruses with potential oral administration. Moreover, modification of the aliphatic chain attached to the nucleoside phosphonate group was involved as an efficient prodrug strategy for the development of potent antiviral candidates.

Project description:Topical microbicides, used by women to prevent the transmission of HIV and other sexually transmitted infections are urgently required. Dendrimers are highly branched nanoparticles being developed as microbicides. However, the anti-HIV and HSV structure-activity relationship of dendrimers comprising benzyhydryl amide cores and lysine branches, and a comprehensive analysis of their broad-spectrum anti-HIV activity and mechanism of action have not been published.Dendrimers with optimized activity against HIV-1 and HSV-2 were identified with respect to the number of lysine branches (generations) and surface groups. Antiviral activity was determined in cell culture assays. Time-of-addition assays were performed to determine dendrimer mechanism of action. In vivo toxicity and HSV-2 inhibitory activity were evaluated in the mouse HSV-2 susceptibility model. Surface groups imparting the most potent inhibitory activity against HIV-1 and HSV-2 were naphthalene disulfonic acid (DNAA) and 3,5-disulfobenzoic acid exhibiting the greatest anionic charge and hydrophobicity of the seven surface groups tested. Their anti-HIV-1 activity did not appreciably increase beyond a second-generation dendrimer while dendrimers larger than two generations were required for potent anti-HSV-2 activity. Second (SPL7115) and fourth generation (SPL7013) DNAA dendrimers demonstrated broad-spectrum anti-HIV activity. However, SPL7013 was more active against HSV and blocking HIV-1 envelope mediated cell-to-cell fusion. SPL7013 and SPL7115 inhibited viral entry with similar potency against CXCR4-(X4) and CCR5-using (R5) HIV-1 strains. SPL7013 was not toxic and provided at least 12 h protection against HSV-2 in the mouse vagina.Dendrimers can be engineered with optimized potency against HIV and HSV representing a unique platform for the controlled synthesis of chemically defined multivalent agents as viral entry inhibitors. SPL7013 is formulated as VivaGel(R) and is currently in clinical development to provide protection against HIV and HSV. SPL7013 could also be combined with other microbicides.

Dataset Information

Synthesis, structure-activity relationship and antiviral activity of 3'-N,N-dimethylamino-2',3'-dideoxythymidine and its prodrugs.

Publications

Synthesis, structure-activity relationship and antiviral activity of 3'-N,N-dimethylamino-2',3'-dideoxythymidine and its prodrugs.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets