Abstract: Jitobaom et al. BMC Pharmacology and Toxicology (2022) 23:41 https://doi.org/10.1186/s40360-022-00580-8 RESEARCH ARTICLE Open Access Synergistic anti‑SARS‑CoV‑2 activity of repurposed anti‑parasitic drug combinations Kunlakanya Jitobaom1, Chompunuch Boonarkart1, Suwimon Manopwisedjaroen2, Nuntaya Punyadee3,4, Suparerk Borwornpinyo5, Arunee Thitithanyanont2, Panisadee Avirutnan3,4 and Prasert Auewarakul1*    Abstract Background: COVID-19 pandemic has claimed millions of lives and devastated the health service system, livelihood, and economy in many countries worldwide. Despite the vaccination programs in many countries, the spread of the pandemic continues, and effective treatment is still urgently needed. Although some antiviral drugs have been shown to be effective, they are not widely available. Repurposing of anti-parasitic drugs with in vitro anti-SARS-CoV-2 activity is a promising approach being tested in many clinical trials. Combination of these drugs is a plausible way to enhance their effectiveness. Methods: The in vitro anti-SARS-CoV-2 activity of combinations of niclosamide, ivermectin and chloroquine were evaluated in Vero E6 and lung epithelial cells, Calu-3. Results: All the two-drug combinations showed higher potency resulting in up to 4-fold reduction in the half maximal inhibitory concentration ­(IC50) values compared to individual drugs. Among these combinations, niclosamideivermectin achieved the highest inhibitory level of over 99%. Combination synergy analysis showed niclosamideivermectin combination to have the best synergy score with a mean Loewe synergy score of 4.28 and a peak synergy score of 24.6 in Vero E6 cells and a mean Loewe synergy score of 3.82 and a peak synergy score of 10.86 in Calu-3 cells. Conclusions: The present study demonstrated the benefit of drug combinations on anti-SARS-CoV-2 activity. Niclosamide and ivermectin showed the best synergistic profile and should be further tested in clinical trials. Keywords: SARS-CoV-2, Repurposed drug, Anti-parasitic drugs, Niclosamide, Ivermectin, Chloroquine Background The spread of SARS-CoV-2 and the COVID-19 pandemic has swept through countries and continents causing catastrophic loss of lives, public health, livelihood, and economy. Up to March 2021, more than hundred million cases have been reported with over two million deaths [1]. The hope to get through the pandemic and resume normal life relies heavily on vaccine deployment, which will still take months or years in most less-developed countries *Correspondence: prasert.aue@mahidol.ac.th 1 Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand Full list of author information is available at the end of the article [2]. One of the reasons for the heavy loss of lives, hospital overload, and public panic is the lack of effective treatment. Remdesivir is now the only antiviral drug with emergency use authorization by US FDA [3]. The drug is, however, not yet widely available. Other FDA-approved drugs are anti-inflammatory targeting host inflammatory responses [4]. More drugs capable of inhibiting SARS-CoV-2 replication are urgently needed not only for treatment but also for reducing viral load and transmission [5]. Many repurposed anti-parasitic drugs have been shown to possess in vitro activity against SARS-CoV-2. In vitro screenings of FDA-approved drugs have identified a number of anti-parasitic drugs with anti-SARSCoV-2 activity and potential..