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Improved Synthesis of MDL 73811 - a Potent AdoMetDC Inhibitor and Anti-Trypanosomal Compound.

ABSTRACT: An improved synthesis of MDL 73811 - a potent AdoMetDC (S-adenosylmethionine decarboxylease) inhibitor and anti-trypanosomal compound with in vivo activity has been completed in four steps from commercially available 2',3'-O-isopropylideneadenosine. Utilization of Mitsunobu chemistry was crucial for the reliable and scalable introduction of the 5'-methylamine moiety, which was problematic using traditional activation/displacement chemistry as previously reported. All reactions in this synthesis were run on gram-scale resulting in a five-fold increase in yield over the original synthesis.

SUBMITTER: Brockway AJ

PROVIDER: S-EPMC4966539 | biostudies-other | 2016 Jul

REPOSITORIES: biostudies-other

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Improved Synthesis of MDL 73811 - a Potent AdoMetDC Inhibitor and Anti-Trypanosomal Compound.

Brockway Anthony J AJ Cosner Casey C CC Volkov Oleg A OA Phillips Margaret A MA De Brabander Jef K JK

Synthesis 20160701 13

An improved synthesis of MDL 73811 - a potent AdoMetDC (S-adenosylmethionine decarboxylease) inhibitor and anti-trypanosomal compound with in vivo activity has been completed in four steps from commercially available 2',3'-<i>O</i>-isopropylideneadenosine. Utilization of Mitsunobu chemistry was crucial for the reliable and scalable introduction of the 5'-methylamine moiety, which was problematic using traditional activation/displacement chemistry as previously reported. All reactions in this syn ...[more]

PMID: 27482123

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Project description:BackgroundInfluenza viruses are a major cause of morbidity and mortality around the world. More recently, a swine-origin influenza A (H1N1) virus that is spreading via human-to-human transmission has become a serious public concern. Although vaccination is the primary strategy for preventing infections, influenza antiviral drugs play an important role in a comprehensive approach to controlling illness and transmission. In addition, a search for influenza-inhibiting drugs is particularly important in the face of high rate of emergence of influenza strains resistant to several existing influenza antivirals.MethodsWe searched for novel anti-influenza inhibitors using a cell-based neutralization (inhibition of virus-induced cytopathic effect) assay. After screening 20,800 randomly selected compounds from a library from ChemDiv, Inc., we found that BPR1P0034 has sub-micromolar antiviral activity. The compound was resynthesized in five steps by conventional chemical techniques. Lead optimization and a structure-activity analysis were used to improve potency. Time-of-addition assay was performed to target an event in the virus life cycle.ResultsThe 50% effective inhibitory concentration (IC50) of BPR1P0034 was 0.42 +/- 0.11 microM, when measured with a plaque reduction assay. Viral protein and RNA synthesis of A/WSN/33 (H1N1) was inhibited by BPR1P0034 and the virus-induced cytopathic effects were thus significantly reduced. BPR1P0034 exhibited broad inhibition spectrum for influenza viruses but showed no antiviral effect for enteroviruses and echovirus 9. In a time-of-addition assay, in which the compound was added at different stages along the viral replication cycle (such as at adsorption or after adsorption), its antiviral activity was more efficient in cells treated with the test compound between 0 and 2 h, right after viral infection, implying that an early step of viral replication might be the target of the compound. These results suggest that BPR1P0034 targets the virus during viral uncoating or viral RNA importation into the nucleus.ConclusionsTo the best of our knowledge, BPR1P0034 is the first pyrazole-based anti-influenza compound ever identified and characterized from high throughput screening to show potent (sub-microM) antiviral activity. We conclude that BPR1P0034 has potential antiviral activity, which offers an opportunity for the development of a new anti-influenza virus agent.

Dataset Information

Improved Synthesis of MDL 73811 - a Potent AdoMetDC Inhibitor and Anti-Trypanosomal Compound.

Publications

Improved Synthesis of MDL 73811 - a Potent AdoMetDC Inhibitor and Anti-Trypanosomal Compound.

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