: SARS-CoV-2 has fatally affected the whole world with millions of deaths. Amidst the dilemma of a breakthrough in vaccine development, hydroxychloroquine (HCQ) was looked upon as a prospective repurposed candidate. It has confronted numerous controversies in the past few months as a chemoprophylactic and treatment option for COVID-19. Recently, it has been withdrawn by the World Health Organization for its use in an ongoing pandemic. However, its benefit/risk ratio regarding its use in COVID-19 disease remains poorly justified. An extensive literature search was done using Scopus, PubMed, Google Scholar, www.cdc.gov, www.fda.gov, and who.int.: Toxicity vexations of HCQ; pharmaceutical perspectives on new advances in drug delivery approaches; computational modeling (PBPK and PD modeling) overtures; multipronged combination approaches for enhanced synergism with antiviral and anti-inflammatory agents; immuno-boosting effects. : Harnessing the multipronged pharmaceutical perspectives will optimistically help the researchers, scientists, biotech, and pharmaceutical companies to bring new horizons in the safe and efficacious utilization of HCQ alone or in combination with remdesivir and immunomodulatory molecules like bovine lactoferrin in a fight against COVID-19. Combinational therapies with free forms or nanomedicine based targeted approaches can act synergistically to boost host immunity and stop SARS-CoV-2 replication and invasion to impede the infection.
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