The omicron variant (B.529) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which emerged in late 2021, caused panic worldwide due to its contagiousness and multiple mutations in the spike protein compared to the Delta variant (B.617.2). There is currently no specific antiviral available to treat Coronavirus disease 2019 (COVID-19). However, studies on neutralizing monoclonal antibodies (mAb) developed to fight COVID-19 are growing and gaining traction. REGN-COV2 (Regeneron or imdevimab-casirivimab combination), which has been shown in recent studies to be less affected by Omicron's RBD (receptor binding domain) mutations among other mAb cocktails, plays an important role in adjuvant therapy against COVID-19. On the other hand, it is known that melatonin, which has antioxidant and immunomodulatory effects, can prevent a possible cytokine storm, and other severe symptoms that may develop in the event of viral invasion. Along with all these findings, we believe it is crucial to evaluate the use of melatonin with REGN-COV2, a cocktail of mAbs, as an adjuvant in the treatment and prevention of COVID-19, particularly in immunocompromised and elderly patients.

Aims: In this study, a series of new Mannich bases of 2(3H)-benzoxazolone derivatives containing substituted cyclic amine moieties with a potential to show cytotoxic activity have been prepared. In order to develop effective anticancer agents against various cancer cell lines, it is essential to study the structure activity relationship and the effect of different substituents on the activity of heterocyclic scaffolds which were known to have cytotoxic activities. Study Design: In silico and experimental design. Place and Duration of Study: Pharmaceutical Chemistry Department, Faculty of Pharmacy, Near East University, Nicosia, Cyprus, between January 2019- September 2020. Methodology: In this work, 2(3H)-benzoxazolone derivatives were prepared by Mannich reaction. The synthesis and structural characterization of the compounds were performed experimentally by FT-IR, 1H NMR, 13C NMR spectra and elemental analysis. In silico prediction of cell line cytotoxicity with PASS based CLC-Pred tool was performed to predict cytotoxicity of the compounds against different tumor cell lines. Results: In silico prediction results for the compounds showed that all benzoxazolone derivatives have cytotoxic activity against different cell lines and tumor types. It was clearly understood that the cytotoxicity of the compounds was affected by the substituents on their piperazine moieties and by the substituents on benzoxazolone core structure. Conclusion: In conclusion, newly synthesized Mannich bases of benzoxazolone derivatives were reported for the first time which may have a potential to show anticancer activities at different cancer cell lines. The efficiency of new compounds against cancer could be found via PASS based CLC-Pred database and could be further investigated by in vivo experimental cytotoxicity studies in the future to design new anticancer drug candidates.

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Background: 2(3H)-Benzoxazolone derivatives are preferential structural blocks in pharmacological probe designing with possibility of modifications at various positions on the core structure. Benzoxazolones showed various biological activities such as analgesics, anti-inflammatory and anti-cancer. Objective: In the present work, we have prepared new Mannich bases of 2(3H)-benzoxazolone derivatives and evaluated their cytotoxicities and proapoptotic properties in MCF-7 breast cancer cell line. Methods: The structures of these compounds were characterized by FT-IR, elemental analysis, 1H and 13C NMR. Cytotoxicities of all the target compounds were investigated by MTT assay. Apoptotic properties of compounds were evaluated by immunocytochemistry using antibodies against to caspase-3, cytochrome-c, FasL and TUNEL assay. Results: These two novel compounds, 1 and 2, both have the same piperazine substituent on the nitrogen atom of benzoxazolone and the main difference in the structures of these compounds is the presence of Cl substituent at the 5- position of the benzoxazolone ring. MTT results showed that compound 1 and 2 were effective in terms of reduction of cell viability at 100 µM and 50 µM concentration for 48 h, respectively. As a result of immunohistochemical staining, Fas L and caspase-3 immunoreactivities were significantly increased in MCF-7 cells after treated with compound 1. Additionally, caspase-3 and cytochrome-c immunoreactivities were also increased significantly in MCF-7 cells after treated with compound 2. The number of TUNEL positive cells was significantly higher in MCF-7 cells when compared with control group after treated with both compound 1 and 2. Conclusion: It could be concluded that N-substituted benzoxazolone derivatives increase potential anti-cancer effects and they could be promising novel therapeutic agents for chemotherapy.

The number of hospitalizations and fatalities brought on by COVID-19 has considerably grown since the World Health Organization proclaimed the disease as a global pandemic. New combination therapy is required to lessen the risk of COVID-19 progression during this time when the danger of transmission rises as new Omicron subvariants arise. In this situation, it is critical to boost the immune system to combat highly inflammatory conditions like the cytokine storm brought on by COVID-19. Furthermore, if administered early in COVID-19 illness, monoclonal antibodies (mAbs) that neutralize SARS-CoV-2 can minimize the chance of hospitalization. LY-CoV1404 (bebtelovimab) is one of these mAbs that has recently gained prominence due to its ability to effectively neutralize the SARS-CoV-2 virus and protect binding to spike proteins of several variants including B.1.1.529 (Omicron) and its subvariants (BA.1, BA.1.1, and BA.2) with various essential receptor binding domain (RBD) mutations. This brief review emphasizes the advantages of combining melatonin with bebtelovimab, which has been demonstrated to be the most effective SARS-CoV-2 neutralizing monoclonal antibody against the Omicron variant in the management of COVID-19. This study suggests that the combination therapy for Omicron subvariants is beneficial and could be regarded as adjuvant therapy for COVID-19 disease.