Through the SARS-CoV-2 pandemic, it has become clear that the development of antivirals is essential for the health and wellbeing of the population. In this study, novel active site protease inhibitors against SARS-CoV-2 were tested for their inhibitory activity against the viral 3-Chymotrypsin like protease through the means of FRET based enzymatic assays. Additionally, Compound 104 targeting the NS2B-NS3 protease was tested against Zika virus through yield reduction assays as a means to assess whether these assays are suitable for the assessment of peptide hybrid compounds in Zika virus.Novel compounds against SARS-CoV-2 were screened and five of the selected six active compounds were found to inhibit the viral protease at a half-maximal inhibitory concentration (IC50) of below 0.075 µM.In Zika virus, the yield reduction assay was assessed and it was found that under the conditions tested, this assay is not suitable for the assessment of peptide hybrid compounds in Zika virus.The active novel compounds against SARS-CoV-2 should be taken for further assessment in cell based assays as the next step of development. Compound 104 should be assessed under different experimental conditions to identify whether different conditions can make this assay suitable for the intended use.