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Over the past two and a half years the world has seen a desperate scramble to find a treatment for SARS-CoV-2 and COVID. In that regard, nucleosides have long served as the cornerstone to antiviral treatments due to their resemblance to the naturally occurring nucleosides that are involved in numerous biological processes. Unlike other viruses however, it was found early on during the search for drugs to treat SARS-1 and later MERS, that the coronaviruses possess a unique repair enzyme, an exonuclease (ExoN)[3] which rendered nucleoside analogues useless, thus negating their use.[4] During the current outbreak however, as both well-known and new nucleoside analogues were investigated or reinvestigated as a possible cure for SARS-CoV-2, several novel and/or lesser-known mechanisms of action were uncovered. This review briefly describes these mechanisms.

C-nucleosides have intrigued biologists and medicinal chemists since their discovery in 1950's. In that regard, C-nucleosides and their synthetic analogues have resulted in promising leads in drug design. Concurrently, advances in chemical syntheses have contributed to structural diversity and drug discovery efforts. Convergent and modular approaches to synthesis have garnered much attention in this regard. Among them nucleophilic substitution at C1' has seen wide applications providing flexibility in synthesis, good yields, the ability to maneuver stereochemistry as well as to incorporate structural modifications. In this review, we describe recent reports on the modular synthesis of C-nucleosides with a focus on D-ribonolactone and sugar modifications that have resulted in potent lead molecules.

In an effort to study the effects of flexibility on enzyme recognition and activity, we have developed several different series of flexible nucleoside analogues in which the purine base is split into its respective imidazole and pyrimidine components. The focus of this particular study was to synthesize the truncated neplanocin A fleximers to investigate their potential anti-protozoan activities by inhibition of S-adenosylhomocysteine hydrolase (SAHase). The three fleximers tested displayed poor anti-trypanocidal activities, with EC50 values around 200 μM. Further studies of the corresponding ribose fleximers, most closely related to the natural nucleoside substrates, revealed low affinity for the known T. brucei nucleoside transporters P1 and P2, which may be the reason for the lack of trypanocidal activity observed.

Carbocyclic nucleosides have long played a role in antiviral, antiparasitic, and antibacterial therapies. Recent results from our laboratories from two structurally related scaffolds have shown promising activity against both Mycobacterium tuberculosis and several parasitic strains. As a result, a small structure activity relationship study was designed to further probe their activity and potential. Their synthesis and the results of the subsequent biological activity are reported herein.

Due to their ability to inhibit viral DNA or RNA replication, nucleoside analogues have been used for decades as potent antiviral therapeutics. However, one of the major limitations of nucleoside analogues is the development of antiviral resistance. In that regard, flexible nucleoside analogues known as “fleximers” have garnered attention over the years due to their ability to survey different amino acids in enzyme binding sites, thus overcoming the potential development of antiviral resistance. Acyclic fleximers have previously demonstrated antiviral activity against numerous viruses including Middle East Respiratory Syndrome coronavirus (MERS-CoV), Ebola virus (EBOV), and, most recently, flaviviruses such as Dengue (DENV) and Yellow Fever Virus (YFV). Due to these interesting results, a Structure Activity Relationship (SAR) study was pursued in order to analyze the effect of the pyrimidine functional group and acyl protecting group on antiviral activity, cytotoxicity, and conformation. The results of those studies are presented herein.

Pyrrolo[3,2-d]pyrimidines have been studied for many years as potential lead compounds for the development of antiproliferative agents. Much of the focus has been on modifications to the pyrimidine ring, with enzymatic recognition often modulated by C2 and C4 substituents. In contrast, this work focuses on the N5 of the pyrrole ring by means of a series of novel N5-substituted pyrrolo[3,2-d]pyrimidines. The compounds were screened against the NCI-60 Human Tumor Cell Line panel, and the results were analyzed using the COMPARE algorithm to elucidate potential mechanisms of action. COMPARE analysis returned strong correlation to known DNA alkylators and groove binders, corroborating the hypothesis that these pyrrolo[3,2-d]pyrimidines act as DNA or RNA alkylators. In addition, N5 substitution reduced the EC50 against CCRF-CEM leukemia cells by up to 7-fold, indicating that this position is of interest in the development of antiproliferative lead compounds based on the pyrrolo[3,2-d]pyrimidine scaffold.

A series of novel 5′-norcarbocyclic derivatives of 5-alkoxymethyl or 5-alkyltriazolyl-methyl uracil were synthesized and the activity of the compounds evaluated against both Gram-positive and Gram-negative bacteria. The growth of Mycobacterium smegmatis was completely inhibited by the most active compounds at a MIC99 of 67 μg/mL (mc2155) and a MIC99 of 6.7⁻67 μg/mL (VKPM Ac 1339). Several compounds also showed the ability to inhibit the growth of attenuated strains of Mycobacterium tuberculosis ATCC 25177 (MIC99 28⁻61 μg/mL) and Mycobacterium bovis ATCC 35737 (MIC99 50⁻60 μg/mL), as well as two virulent strains of M. tuberculosis; a laboratory strain H37Rv (MIC99 20⁻50 μg/mL) and a clinical strain with multiple drug resistance MS-115 (MIC99 20⁻50 μg/mL). Transmission electron microscopy (TEM) evaluation of M. tuberculosis H37Rv bacterial cells treated with one of the compounds demonstrated destruction of the bacterial cell wall, suggesting that the mechanism of action for these compounds may be related to their interactions with bacteria cell walls.