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The Zika virus (ZIKV) infections remains a global health threat. However, no approved drug for treating ZIKV infection. We previously found TZY12-9, a 5ʹ-amino NI analog, that showed anti-ZIKV activity without chemical phosphorylation. Here, a series of 5ʹ-amino NI analogs were synthesized and evaluated. The compound XSJ2-46 exhibited potent in vitro activity without requiring chemical phosphorylation, favorable pharmacokinetic and acute toxicity profiles. Preliminary mechanisms of anti-ZIKV activity of XSJ2-46 were investigated via a series of ZIKV non-structural protein inhibition assays and host cell RNA-seq. XSJ2-46 acted at the replication stage of viral infection cycle, and exhibited reasonable inhibition of RNA-dependent RNA polymerases (RdRp) with an IC 50 value of 8.78 μM, while not affecting MTase. RNA-seq analysis also revealed differential expression genes involved in cytokine and cytokine receptor pathway in ZIKV-infected U87 cells treated with XSJ2-46. Importantly, treatment with XSJ2-46 (10 mg/kg/day) significantly enhanced survival protection (70% survival) in ZIKV-infected ICR mice. Additionally, XSJ2-46 administration resulted in a significant decrease in serum levels of ZIKV viral RNA in the IFNα/β receptor-deficient (Ifnar −/− ) A129 mouse model. Therefore, the remarkable in vitro and in vivo anti-ZIKV activity of compound XSJ2-46 highlights the promising research direction of utilizing the 5ʹ-amino NI structure skeleton for developing antiviral NIs. [Display omitted] • 5ʹ-amino adenosine derivatives exhibited significant in vitro anti-ZIKV activity. • Compound XSJ2-46 gave potent in vitro activity, with an IC 50 value of 2.15 μM. • XSJ2-46 (10 mg/kg/day) showed a 70% survival rate in a ZIKV-infected mice model. • XSJ2-46 significantly reduced serum levels of ZIKV viral RNA in the mice model. [ABSTRACT FROM AUTHOR]

Abstract: We herein report the application of the phosphorodiamidate phosphate prodrug approach to a series of thirteen nucleoside analogs with antiviral or anticancer activity. Twenty-five symmetrical phosphorodiamidates were synthesized, bearing esterified l-Alanine (and in one case d-Alanine) in the prodrug moiety, each as single stereoisomer. The presence of an achiral phosphorus represents a potential advantage over the phosphoramidate ProTide approach, where diastereoisomeric mixtures are routinely obtained, and different biological profiles may be expected from the diastereoisomers. Optimization of the synthetic pathway allowed us to identify two general methods depending on the particular nucleoside analogs. All the compounds were biologically evaluated in antiviral and anticancer assays and several showed improvement of activity compared to their parent nucleosides, as in the case of ddA, d4T, abacavir and acyclovir against HIV-1 and/or HIV-2. The biological results were supported by metabolism studies with carboxypeptidase Y monitored by 31P NMR to investigate their bioactivation. This work further validates the phosphorodiamidate approach as a monophosphate prodrug motif with broad application in the antiviral and anticancer fields. [Copyright &y& Elsevier]

Zika virus (ZIKV) is a mosquito-borne flavivirus and outbreaks of ZIKV have been reported in Africa, Americas and other parts of the world lately. The ZIKV epidemic has received extensive attention due to its ability to cause serious medical consequences and complications such as microcephaly and Guillain-Barre syndrome in recent years. Up to now, there are no specific treatments or vaccines available for ZIKV infection, which highlights the urgent need for developing new therapies. In this work, we designed and synthesized a series of novel 6-methyl-7-acetylenenyl-7-deazapurine nucleoside analogs as potential inhibitors of ZIKV replication. The biological activities against ZIKV replication were evaluated and the structure-activity relationship (SAR) was also studied. Among the compounds evaluated, nucleoside analog 38 (EC 50 = 2.8 ± 0.8 μM, EC 90 = 6.8 ± 2.3 μM) showed the most potent anti-ZIKV activity with low cytotoxicity (CC 50 = 54.1 ± 6.9 μM) in an A549 based cellular model. The inhibitory activity of 38 was about 5 times more potent than the positive control NITD008. Notably, 38 showed similar inhibition potency against different ZIKV strains (ZG-01 and MR766) in a variety of host cell types including SNB19, A549, Huh7, Vero. In addition, 38 (K d = 1.87 μM) has a stronger affinity to ZIKV RNA-dependent RNA polymerase (RdRp) protein than NITD008 (K d = 3.43 μM) in the non-phosphorylation assay. These results indicated that compound 38 may serve as a promising candidate in future anti-ZIKV drug discovery. [Display omitted] • A series of novel 2′-methyl-2′-fluoro-6-methyl-7-alkynyl-7-deazapurine ribonucleoside analogs were designed and synthesized, and some of them exhibited potent anti-ZIKV activity. •Compound 38 is about 5 times more potent than NITD008 in cellular based ZIKV replication assays. •Compound 38 showed similar inhibition potency against different ZIKV strains (ZG-01 and MR766) in a variety of host cell types (including SNB19, A549, Huh7, Vero). •Compound 38 (K d = 1.87 μM) has a stronger affinity to ZIKV RdRp protein than NITD008 (K d = 3.43 μM) in non-phosphorylation. [ABSTRACT FROM AUTHOR]

Abstract: The synthesis of a series of α-l-2′-deoxythreofuranosyl nucleosides featuring the nucleobases A, T, C and U is described in seven steps from 1,2-O-isopropyledene-α-l-threose, involving a Vorbrüggen coupling and a Barton-McCombie deoxygenation protocol as the key steps. All analogues, including a phosphoramidate nucleoside phosphate prodrug of the T analogue, were evaluated against a broad panel of different viruses but found inactive, while also lacking notable cellular toxicity. The thymidine analogue showed inhibition to mitochondrial thymidine kinase-2 (TK-2), herpes simplex virus type 1 (HSV-1) TK, varicella-zoster virus (VZV) TK and Mycobacterium tuberculosis thymidylate kinase. [Copyright &y& Elsevier]

Emerging and re-emerging viruses periodically cause outbreaks and epidemics all over the world, eventually leading to global events such as the current pandemic of the novel SARS-CoV-2 coronavirus infection COVID-19. Therefore, an urgent need for novel antivirals is crystal clear. Here we present the synthesis and evaluation of an antiviral activity of phenoxazine-based nucleoside analogs divided into three groups: (1) 8-alkoxy-substituted, (2) acyclic, and (3) carbocyclic. The antiviral activity was assessed against a structurally and phylogenetically diverse panel of RNA and DNA viruses from 25 species. Four compounds (11a-c , 12c) inhibited 4 DNA/RNA viruses with EC 50 ≤ 20 μM. Toxicity of the compounds for the cell lines used for virus cultivation was negligible in most cases. In addition, previously reported and newly synthesized phenoxazine derivatives were evaluated against SARS-CoV-2, and some of them showed promising inhibition of reproduction with EC 50 values in low micromolar range, although accompanied by commensurate cytotoxicity. [Display omitted] • 8-Alkoxy-substituted, acyclic and carbocyclic phenoxazine derivatives were synthesized. • The activity was assessed against a broad panel of RNA/DNA viruses from 25 species. • Four compounds (11a-c , 12c) inhibited 4 DNA/RNA viruses with EC 50 ≤ 20 μM. • Three of them exhibited submicromolar activity against VZV. • The compounds did not show pronounced cytotoxicity against all the studied cell lines. [ABSTRACT FROM AUTHOR]