Novel 1,2,4-triazole and Purine Acyclic Cyclopropane Nucleoside Analogues: Synthesis, Antiviral and Cytostatic Activity Evaluations

Abstract

Evaluation of their affinity for herpes simplex type 1 (HSV-1) and varicella-zoster virus-encoded thymidine kinases (VZV TK) also showed that none of the compounds was able to significantly inhibit 1 µM deoxythymidine phosphorylation by HSV-1 and VZV TK at 500 µM concentrations. The in vitro cytostatic activity evaluation results indicated a weak antiproliferative activity for all tested compounds. Only 6-pyrrolylpurine derivative bearing a carboxylic group substituted cyclopropane ring produced a rather slight inhibitory effect at higher micromolar concentrations on a breast carcinoma cell line (MCF-7) and no cytotoxic effect on human normal fibroblasts (WI 38). Conclusions: The lack of antiherpetic activity may be due to poor, if any, recognition of the compounds by virus-induced nucleoside kinases as an alternative substrate to become metabolically activated.The discovery of the acyclic guanosine analogue acyclovir (ACV; Figure 1) as a selective anti-herpes simplex virus (HSV) agent [1] initiated investigation of new acyclic nucleoside analogues with better antiviral activity properties than ACV. These efforts resulted in the discovery of new broad-spectrum antiviral agents: ganciclovir (GCV; Figure 1) [2][3][4] and penciclovir (PCV; Figure 1) [5,6]. In addition, the crystal structure of HSV-1-encoded thymidine kinase (TK), a key enzyme for activation of antiherpetic nucleosides, in complex with GCV, revealed the importance of the two hydroxyl groups of GCV mimicking the 3′-and 5′-hydroxyl groups of the 2′-deoxyribose moiety in natural nucleosides for substrate recognition [7].Based on these findings, (1′S, 2′R)-9-{[1′,2′-bis(hydroxymethyl)cycloprop-1-yl]methyl}guanine (A-5021; Figure 2) was developed as a nucleoside analogue that potently inhibits the replication of several herpes viruses including HSV type-1 (HSV-1) and HSV type-2 (HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV) and human herpesvirus type 6 (HHV-6). Though the sugar moiety of A-5021 has a cyclopropane ring, its overall feature is considered to be acyclic due to the flexible methylenic spacer. The antiviral activity of A-5021 is superior over ACV against HSV-1, HSV-2, . The racemic 9-{[1′,2′-bis(hydroxymethyl)cycloprop-1-yl] methyl}guanine and especially its 1′S, 2′R enantiomer

Recent Advances in 1,2,4‐Triazole Scaffolds as Antiviral Agents

“…A-5021 exhibited potent activity against HSV-1, HSV-2, and VZV that was superior to the clinically acyclovir drug, as well as a potent inhibitor of Epstein-Barr virus, which was equipotent to the acyclovir. [55] Wittine et al prepared a series of molecules containing 3substituted 1,2,4-triazole moiety linked via ethylene spacer to lactone or lactam functionality to yield 1,3-disubstituted 1,2,4triazole l-ascorbic acid (29)(30)(31)(32)(33) and imino-ascorbic acid (33) derivatives ( Figure 9). Their inhibition of the hepatitis C virus replication in the Huh 5-2 replicon system was assessed.…”

“…[105] In 2012, Muratore et al identified small molecule compounds capable of inhibiting the growth of influenza A and B viruses in cultured cells effectively and specifically by targeting a viral RNA-dependent RNA polymerase assembly interface. They have developed ELISA to measure interactions between PA and PB1 by the use of the synthesized PB1 1-15 À Tat peptide (PTP), which has a C-terminal sequence, from the HIV Tat protein (amino acids [47][48][49][50][51][52][53][54][55][56][57][58][59]. The known PAÀ PB1 interaction inhibitor was tested by increasing concentrations of synthetically PB1-derived peptide (amino acids 1-15) fused to the translocating domain of HIV Tat protein (PB1 1-15 -Tat peptide).…”

Chemistry of 1, 2, 4-Triazole: A Review Article

“…Wingrove et al put forward a hypothesis that the activity of loreclezole (30) (second-generation antiepileptic drug) is dependent on the interaction between the triazole moiety and the amide group of asparagine (Asn-289), which is located on the β2 subunit of the GABAA receptor [94]. [98].…”

Testing the sensitivities of noncognate inhibitors to varicella zoster virus thymidine kinase: implications for postherpetic neuralgia therapy with existing agents

“…To date, however, only very few compounds (mainly acyclic guanosine analogs) have been reported to show inhibitory activity towards VZV TK [5,6]. In contrast, a large number of antiviral agents have been successfully developed that target the TKs of other members of the herpesvirus family, especially herpes simplex virus type 1 (HSV-1).…”