In December 2019, several cases of pneumonia of unknown etiology were reported in Wuhan, China. The outbreak, which was reported to have commenced in late December 2019 in China, was soon worldwide, with increased cases and deaths [1]. The causative agent of the outbreak earned the name SARS-CoV-2 after being identified as a beta coronavirus whose genomic sequence was closely aligned to severe acute respiratory syndrome coronavirus (SARS-CoV), earlier identified in 2003 [1,2,3]. SARS-CoV-2 has been identified as the seventh coronavirus known to infect humans [4]; SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2 have been reported to be severe, while human coronavirus (HCov)-HKU1, HCov-NL63, HCoV-OC43, and HCoV-229E are mild [5]. As of 5:52 pm CEST, 11 October 2021, the WHO had identified 237,383,711 confirmed cases of COVID-19, including 4,842,716 deaths globally [6].

SARS-CoV-2, including the recently reported severe variant B.1.617.2 [7,8], attacks the respiratory tract with symptoms ranging from breathing difficulties, sore throat, high fever, diarrhea, and cough to multiple organ failure and ultimately death [9]. This can occur when the spike protein (Spro), which possesses an S1 domain and an S2 subunit, binds to angiotensin-converting enzyme-2 (ACE-2) receptors on the surface of the host alveoli to allow for entry [10]. Thus, studies have identified the Spro as a drug target to prevent interaction with ACE-2, thereby inhibiting the entry of the virus [11,12]. Furthermore, with the aid of RNA-dependent RNA polymerase (RdRp), the viral RNA translation results in the synthesis of proteins responsible for synthesizing new virions from single-stranded RNA, which makes RdRp a primary drug target to prevent viral growth and replication [13,14]. Overall, viral studies have shown that viral proteases are typical targets for anti-viral drug development [15,16]. Hence, the main protease (Mpro) of SARS-CoV-2, which plays a role in viral replication, could be a potential therapeutic target [17,18].

In this study, computational tools are utilized instead of the traditional methods of developing and discovering new therapeutic agents. The latter is more involved, requires rigorous scientific procedures, and may be time-consuming. However, the bioinformatics approach is viable for designing and developing new drugs of biomedical interest as it predicts the binding affinities and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties of test compounds to protein receptors and domains [19,20].

Heterocyclic compounds play an essential role in drug discovery and development; hence, great work has gone into developing simple and environmentally friendly methods for their high yielding production [21]. For example, compounds derived from azetidine have shown to have a diverse range of pharmacological activities, such as anticancer [22], antibacterial [23,24], antimicrobial [25], antischizophrenic [26], antimalarial [27,28], antiobesity [29,30], anti-viral [31], antioxidant [31], and dopamine antagonist [32] activity, amongst others. They are also reported to be tRNA-synthetase inhibitors, signal transducers and activators of transcription-3 (STAT-3) inhibitors, and vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors [31,33,34,35]. Other heterocyclics, such as cyclic amidine and guanidine also possess biological potency [36,37]. Heterocyclic skeletons of promising pharmacological importance usually contain nitrogen, sulphur, and oxygen as they represent a major proportion of the bioactive heterocyclic compounds and marketed drugs [21]. Azetidine, amidine, and gunanine rings are nitrogen-containing heterocyclic organic compounds with different synthetic strategies and pharmaceutical importance [31,32,37,38]. As a result, pharmaceutical companies incorporate these compounds into the design, formulation, development, and synthesis of drugs. Specifically, the antiproliferative properties of azetidine derivatives have prompted their use and production in anti-viral research [31,39,40]. Their anti-viral activities are aided by their ability to inhibit proteins essential to the viral life cycle [41,42]. Some of these heterocyclic drugs with anti-viral activities have been approved by the FDA. In 2018, the FDA approved baricitinib, a heterocyclic derivative of azeitidine, to treat patients with rheumatoid arthritis [31]. Recently, baricitinib was found to engender early stabilization of the respiratory functions and reduce rehospitalization and the mortality rate resulting from COVID-19 at a daily high dose [43]. Barticinib combined with other drugs has been found to control the virus. Treatment of the virus with baricitinib plus hydroxychloroquine was associated with recovery in 11 of 15 patients [44]. Treatment with baricitinib plus dexamethasone resulted in the reduced mortality of COVID-19 drugs [45]. Moreover, Baricitinib plus remdesivir was reported to be superior to remdesivir alone as it reduces recovery time and accelerates improvement in clinical status among patients with COVID-19, notably among those receiving high-flow oxygen or noninvasive ventilation [46].