Heterocyclic Bases Research Articles

Synthesis and biological activity of aza and deaza analogues of purine nucleosides

Analogues and derivatives of nucleic acid components have been used as key drugs in different areas of medicine over the past decades. The replacement of one or more nitrogen atoms of the heterocyclic base with a CH group affords deazapurine nucleoside analogues, and the replacement of the methine group with a nitrogen atom gives azapurine derivatives. A combination of aza and deaza moieties in the purine base leads to aza(deaza)-modified bases. Some nucleoside analogues were found to exhibit pronounced anticancer and antiviral activity. The synthesis and evaluation of biological activity of aza- and deazapurine nucleoside analogues have attracted interest from researchers four decades ago. This review describes and integrates the studies concerning certain aspects of the synthesis and(or) activity of various representatives of this class of compounds. The structure–biological activity relationships are analyzed. The successful approaches to the design of aza- and deazapurine nucleoside analogues are considered. A comparison is given for the methods of chemical and enzymatic synthesis of these compounds.The bibliography includes 161 references.

Design, synthesis and biological evaluation of heterocyclic methyl substituted pyridine Schiff base transition metal complexes

In recent years heterocyclic Schiff base metal complexes attract more attention in biological application and also showing interesting co-ordination chemistry. In this research article a novel heterocyclic methyl-substituted pyridine Schiff base transition metal complexes of Fe(III), Co(III), Cu(II), and Ni(II) have been design and synthesized by reacting metal acetate or metal salts (FeCl3, CoOAc, CuOAc, NiOAc), with substituted heterocyclic ligand. All newly synthesized metalcomplexes were characterized by spectroscopic data and screened for elemental analysis, FT-IR, ESR, Magnetic susceptibility and TGA. The Electronic spectra and magnetic susceptibility measurements indicates that square planer and octahedral geometry of these complexes also suggest their structure in which (N, O) group acts as bidentate ligand. The thermal stability, decomposition rate and thermodynamic parameters of synthesized metal complexes were calculated by Freeman Carroll method. Also the biostatistical data of antimicrobial and anti-oxidant activities of synthesized metal complexes indicates moderate to good results.Graphic abstract

Evaluation of the Antiviral Potential of Modified Heterocyclic Base and 5'-Norcarbocyclic Nucleoside Analogs Against SARS-CoV-2.

The pandemic caused by the novel betacoronavirus SARS-CoV-2 has already claimed more than 3.5 million lives. Despite the development and use of anti-COVID-19 vaccines, the disease remains a major public health challenge throughout the world. Large-scale screening of the drugs already approved for the treatment of other viral, bacterial, and parasitic infections, as well as autoimmune, oncological, and other diseases is currently underway as part of their repurposing for development of effective therapeutic agents against SARS-CoV-2. In this work, we present the results of a phenotypic screening of libraries of modified heterocyclic bases and 5’-norcarbocyclic nucleoside analogs previously synthesized by us. We identified two leading compounds with apparent potential to inhibit SARS-CoV-2 replication and EC50 values in a range of 20–70 μM. The structures of these compounds can be further optimized to develop an antiviral drug.

De Novo Nucleic Acids: A Review of Synthetic Alternatives to DNA and RNA That Could Act as Bio-Information Storage Molecules.

Modern terran life uses several essential biopolymers like nucleic acids, proteins and polysaccharides. The nucleic acids, DNA and RNA are arguably life’s most important, acting as the stores and translators of genetic information contained in their base sequences, which ultimately manifest themselves in the amino acid sequences of proteins. But just what is it about their structures; an aromatic heterocyclic base appended to a (five-atom ring) sugar-phosphate backbone that enables them to carry out these functions with such high fidelity? In the past three decades, leading chemists have created in their laboratories synthetic analogues of nucleic acids which differ from their natural counterparts in three key areas as follows: (a) replacement of the phosphate moiety with an uncharged analogue, (b) replacement of the pentose sugars ribose and deoxyribose with alternative acyclic, pentose and hexose derivatives and, finally, (c) replacement of the two heterocyclic base pairs adenine/thymine and guanine/cytosine with non-standard analogues that obey the Watson–Crick pairing rules. This manuscript will examine in detail the physical and chemical properties of these synthetic nucleic acid analogues, in particular on their abilities to serve as conveyors of genetic information. If life exists elsewhere in the universe, will it also use DNA and RNA?

Spectral studies and crystal structures of molybdenum(VI) complexes containing pyridine or picoline as auxiliary ligands: interaction energy calculations and free radical scavenging studies

Three cis-MoO2 complexes [MoO2(CAB)(py)] (1), [MoO2(CAB)(3-pic)] (2) and [MoO2(CAB)(4-pic)] (3) which vary in the nature of the heterocyclic bases in the auxiliary coordination site derived from an ONO donor aroylhydrazone (H2CAB) have been synthesized and characterized by various physicochemical methods. The single-crystal X-ray diffraction studies reveal that the complexes adopt a distorted octahedral N2O4 coordination sphere around the Mo(VI) center in which the ONO donor atoms of hydrazone moiety and one oxido oxygen constitute the NO3 basal plane and the axial position by the other oxido oxygen and nitrogen atom of coordinated pyridine molecule in [MoO2(CAB)(py)] (1) or picoline molecule in [MoO2(CAB)(3-pic)] (2) and [MoO2(CAB)(4-pic)] (3). The hydrogen bonding interaction generates a two-dimensional supramolecular sheet-like architecture in [MoO2(CAB)(py)] (1) and [MoO2(CAB)(3-pic)] (2), whereas a three-dimensional network was observed in [MoO2(CAB)(4-pic)] (3). The interaction energy calculations reveal that the dispersion energy component dominates over other components and [MoO2(CAB)(3-pic)] (2) is found to be energetically more stable. Furthermore, the aroylhydrazone shows free radical scavenging activity, whereas the complexes are inactive.

Structural and spectral characterization of Cu(II) complexes of N(4)-substituted thiosemicarbazones derived from 2-hydroxyacetophenone: Crystal structure of a dinuclear Cu(II) complex

Copper(II) complexes of 2-hydroxyacetophenone-N(4)-cyclohexylthiosemicarbazone (H2L1) and 2-hydroxyacetophenone-N(4)-phenylthiosemicarbazone (H2L2) have been synthesized and characterized by different physicochemical techniques like magnetic studies and electronic, infrared and EPR spectral studies. [(CuL1)2] (1) is a dinuclear complex having four coordination around copper(II) with distorted square planar geometry. The two individual dinuclear complexes are interconnected through two bifurcated classical hydrogen bond interactions producing a sheet-like structure along b axis. [(CuL2)2]·1/2H2O (2) also has a dimeric structure. The thiosemicarbazones bind to the metal as dianionic ONS donor ligand in all the complexes, except in the complexes [Cu(HL1)Cl]·2H2O (3), [Cu(HL1)Br]·4H2O (4) and [Cu(HL1)NO3]·C2H5OH(H2O) (5), where the ligand moieties are coordinated as monoanionic (HL¯) ones. Complexes [CuL1dmbipy] (6), [CuL2dmbipy]·3H2O (7), [CuL2bipy]·H2O (8) and [CuL2phen]·2C2H5OH (9) are heterocyclic base adducts. The synthesis and characterization of monomeric and dimeric Cu(II) complexes with 2-hydroxyacetophenone-N(4)-cyclohexyl/phenyl substituted ONS donor ligands is described. It also reports the crystal structure of a novel binuclear Cu(II) complex with oxygen bridging and its interesting coordination. This compound [CuL1]2 is a rare example of copper(II)-thiosemicarbazone complex with oxygen bridging structure.

Anion exchange resins in phosphate form as versatile carriers for the reactions catalyzed by nucleoside phosphorylases.

In the present work, we suggested anion exchange resins in the phosphate form as a source of phosphate, one of the substrates of the phosphorolysis of uridine, thymidine, and 1-(β-ᴅ-arabinofuranosyl)uracil (Ara-U) catalyzed by recombinant E. coli uridine (UP) and thymidine (TP) phosphorylases. α-ᴅ-Pentofuranose-1-phosphates (PF-1Pis) obtained by phosphorolysis were used in the enzymatic synthesis of nucleosides. It was found that phosphorolysis of uridine, thymidine, and Ara-U in the presence of Dowex® 1X8 (phosphate; Dowex-nPi) proceeded smoothly in the presence of magnesium cations in water at 20–50 °C for 54–96 h giving rise to quantitative formation of the corresponding pyrimidine bases and PF-1Pis. The resulting PF-1Pis can be used in three routes: (1) preparation of barium salts of PF-1Pis, (2) synthesis of nucleosides by reacting the crude PF-1Pi with an heterocyclic base, and (3) synthesis of nucleosides by reacting the ionically bound PF-1Pi to the resin with an heterocyclic base. These three approaches were tested in the synthesis of nelarabine, kinetin riboside, and cladribine with good to excellent yields (52–93%).

Base-intercalated and base-wedged stacking elements in 3D-structure of RNA and RNA–protein complexes

Along with nucleobase pairing, base-base stacking interactions are one of the two main types of strong non-covalent interactions that define the unique secondary and tertiary structure of RNA. In this paper we studied two subfamilies of nucleobase-inserted stacking structures: (i) with any base intercalated between neighboring nucleotide residues (base-intercalated element, BIE, i + 1); (ii) with any base wedged into a hydrophobic cavity formed by heterocyclic bases of two nucleotides which are one nucleotide apart in sequence (base-wedged element, BWE, i + 2). We have exploited the growing database of natively folded RNA structures in Protein Data Bank to analyze the distribution and structural role of these motifs in RNA. We found that these structural elements initially found in yeast tRNAPhe are quite widespread among the tertiary structures of various RNAs. These motifs perform diverse roles in RNA 3D structure formation and its maintenance. They contribute to the folding of RNA bulges and loops and participate in long-range interactions of single-stranded stretches within RNA macromolecules. Furthermore, both base-intercalated and base-wedged motifs participate directly or indirectly in the formation of RNA functional centers, which interact with various ligands, antibiotics and proteins.

Ni(II) curcumin complexes for cellular imaging and photo-triggered in vitro anticancer activity

Nickel(II) complexes [Ni(cur)(L)2](OAc) (1-3) where L is N,N-donor heterocyclic bases namely 1,10-phenanthroline (phen in 1), dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq in 2), dipyrido[3,2-a:2′,3′-c]phenazine (dppz in 3) and Hcur is curcumin were prepared, fully characterized and light-induced in vitro anticancer activity studied. Three nickel(II) complexes containing acetylacetonato (Hacac) ligand, viz.[Ni(acac)(L)2](OAc) (4-6) where L is phen (in 4), dpq (in 5), dppz (in 6) were prepared and used as controls. Complex 4 was structurally characterized by single crystal X-ray diffraction technique, which revealed an octahedral NiN4O2 geometry around the metal centre. Complexes 1-3 showed an intense curcumin-based band at ∼440 nm in DMSO-Tris-HCl buffer (pH = 7.2) (1:4 v/v) which masks the nickel based d-d band. The curcumin comlexes (1-3) were redox inactive at the nickel centre, whereas the acetylacetonato complexes (4-6) displayed an irreversible voltammetric response at ∼1.00 V vs. Ag/AgCl reference electrode in DMF. The complexes bind to calf thymus DNA (ct-DNA) with considerable affinity and interacted with human serum albumin (HSA) with moderate affinity. The Ni(II) curcumin complexes display significant in vitro light-induced cytotoxicity in HeLa (human cervical carcinoma) and A549 (lung cancer cells) involving reactive oxygen species (ROS), with very low dark toxicity. The complexes were found to be much less toxic to immortalized lung epithelial normal cells (HPL1D). Confocal microscopic images using complex 2 and 3 showed that they primarily localize in the cytosol of A549 cells. The mechanism of cell death is mainly apoptosis in nature showing arrest of sub-G1 phase of cell cycle progression in A549 cells under visible light exposure and involves significant loss of mitochondrial membrane potential as observed from JC-1 assay.

NUCLEOSIDE ANALOGS WITH FLEXIMER NUCLEOBASE

This review article is devoted to the so-called fleximer nucleoside analogs, containing two or more planar moieties in the heterocyclic base, connected by a bond that permits rotation. Such analogs have been proposed as molecular probes for detecting enzyme–substrate interactions and studying the transcription and translation of nucleic acids, but subsequently have attracted the interest of researchers by their antiviral and antitumor activity. The methods used in the synthesis of such compounds, along with their structural features and also biological activity are considered in this review.

Gold Nanoparticles as Colorimetric Sensors for the Detection of DNA Bases and Related Compounds.

Results regarding interaction of colloidal gold solutions with nucleobases, including uracil (U), as well as its sulfur derivatives, 2-thiouracil (2TU) and 4-thiouracil (4TU), cytosine (C), adenine (A), and guanine (G), as well as urea and thiourea (TU), are reported. Anionic stabilized citrate gold nanoparticles (AuNPs) were synthesized by reducing the tetrachloroaurate (III) trihydrate with trisodium citrate. The surface plasmon resonance (SPR) band was used in the characterization of synthesized AuNPs, as well as transmission electron microscope (TEM) imaging, which was used in the characterization of dispersed and aggregated gold nanoparticles. Interactions of nucleobases with the gold surface was analyzed by following the plasmon absorbance band red shift of the AuNPs. The sulfur-containing compounds adsorbed to the nanoparticle surfaces by chemisorption-type interactions; with TU and 4TU, the process is accompanied by a sudden change in color; in contrast, 2TU forms stable functionalized gold nanoparticles. Urea and U do not adsorb to nanoparticle surfaces, but the other heterocyclic bases containing nitrogen interact effectively with the gold surface, causing the assembly of nanoparticles, even though the interparticle self-aggregation process was slower than that mediated by either TU or 4TU. The method is efficient in the colorimetric detection of nucleobases and derivatives at concentration levels on the order of 1 µM.

DNA binding, cleavage, apoptosis and cytotoxicity studies of three heteroleptic nickel complexes bearing β-diketones

In this work, three nickel(II) complexes, namely, [Ni(η2-NO3)(bta)(phen)] (I), [Ni(η2-NO3)(btc)(phen)] (II), and [Ni(η2-NO3)(btf)(phen)] (III) (bta = 4,4,4-trifluoro-1-phenyl-1,3-butanedione anion, btc = 1-(4-chlorophenyl)-4,4,4-trifluoro-1,3-butanedione anion, btf = 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione anion, phen = 1,10-phenanthroline) were prepared and fully characterized by magnetic susceptibility measurements, spectroscopic methods and single-crystal X-ray diffraction. The spectral and structural data confirm that the β-diketones anions coordinate via the oxygen atoms, whilst the heterocyclic base coordinates through the nitrogen atoms. A nitrate coordinated in bidentate mode completes the coordination sphere around the metal center. The anticancer activity of chelating ligands and their nickel complexes was evaluated against two tumor cell lines, MCF-7 (a hormone responsive cancer cell) and MDA-MB-231 (triple negative breast cancer cell). The complexes I and II were more active than cisplatin and interacted more effectively with DNA, with Kb values in the range of 103 –104 M−1. According to data from circular dichroism (CD) and fluorescence spectroscopy, these complexes appear to bind to the DNA groove and/or by electrostatic forces. Molecular docking followed by semiempirical simulations reinforce that they are capable of binding in the minor groove of the double helix of ct-DNA in an A-T rich region. DNA cleavage studies indicated that the complex II cleaves the plasmid DNA in the presence of H2O2. Subsequently, we found that I and II induce late apoptosis in MCF-7 cells.

Sofosbuvir Thio-analogues: Synthesis and Antiviral Evaluation of the First Novel Pyridine- and Pyrimidine-Based Thioglycoside Phosphoramidates.

The synthesis and antiviral screening of the first reported series of pyridine- and pyrimidine-based thioglycoside phosphoramidates are herein reported. They were prepared through two synthetic steps: The first step is via coupling of mercapto-derivatized heterocyclic bases with the appropriate α-bromo per-acetylated sugars. The second one is the hydrolysis of the acetate esters under basic conditions that were consequently conjugated with the phosphoramidating reagent to afford the desired thioglycoside protides. Eight compounds were evaluated for their antiviral activities against different viral cell lines, namely, adenovirus 7, HAV (hepatitis A) HM175, Coxsackievirus B4, and HSV-1 (herpes simplex virus type 1), in addition to the antiviral bioassay against ED-43/SG-Feo (VYG) replicon of HCV (hepatitis C virus) genotype 4a. Both compounds 5b and 11 showed notable antiviral activity against Coxsackie virus B4, reflected from the CC50 values of 17 and 20 μg/100 μL and IC50 values of 4.5 and 6.0 μg/100 μL, respectively. Same two compounds elicited remarkable activities toward herpes simplex virus type 1, represented by CC50 values of 17 and 16 μg/100 μL and IC50 values of 6.3 and 6.6 μg/100 μL, respectively. Combination of 11 with acyclovir elicited a notable synergistic activity in comparison with acyclovir alone, as inferred from herpes simplex polymerase enzyme inhibitory assay values of 2.64 and 4.78 μg/100 mL, respectively. Only compound 11 elicited a remarkable activity against HCV. Potential promising activities of compound 11 have been shown with respect to CC50, IC50, and enzyme assay inhibitory activities.

Synthesis, identification and structural of some transition metal complexes with New heterocyclic azo-schiff base ligand derived from 4-amino antipyrine

Synthesis, identification and structural of some transition metal complexes with New heterocyclic azo-schiff base ligand derived from 4-amino antipyrine

Nucleoside Analogs with Fleximer Nucleobase.

This review article is devoted to the so-called fleximer nucleoside analogs, containing two or more planar moieties in the heterocyclic base, connected by a bond that permits rotation. Such analogs have been proposed as molecular probes for detecting enzyme–substrate interactions and studying the transcription and translation of nucleic acids, but subsequently have attracted the interest of researchers by their antiviral and antitumor activity. The methods used in the synthesis of such compounds, along with their structural features and also biological activity are considered in this review.

Strained Conformations of Nucleosides in Active Sites of Nucleoside Phosphorylases.

Nucleoside phosphorylases catalyze the reversible phosphorolysis of nucleosides to heterocyclic bases, giving α-d-ribose-1-phosphate or α-d-2-deoxyribose-1-phosphate. These enzymes are involved in salvage pathways of nucleoside biosynthesis. The level of these enzymes is often elevated in tumors, which can be used as a marker for cancer diagnosis. This review presents the analysis of conformations of nucleosides and their analogues in complexes with nucleoside phosphorylases of the first (NP-1) family, which includes hexameric and trimeric purine nucleoside phosphorylases (EC 2.4.2.1), hexameric and trimeric 5′-deoxy-5′-methylthioadenosine phosphorylases (EC 2.4.2.28), and uridine phosphorylases (EC 2.4.2.3). Nucleosides adopt similar conformations in complexes, with these conformations being significantly different from those of free nucleosides. In complexes, pentofuranose rings of all nucleosides are at the W region of the pseudorotation cycle that corresponds to the energy barrier to the N↔S interconversion. In most of the complexes, the orientation of the bases with respect to the ribose is in the high-syn region in the immediate vicinity of the barrier to syn ↔ anti transitions. Such conformations of nucleosides in complexes are unfavorable when compared to free nucleosides and they are stabilized by interactions with the enzyme. The sulfate (or phosphate) ion in the active site of the complexes influences the conformation of the furanose ring. The binding of nucleosides in strained conformations is a characteristic feature of the enzyme–substrate complex formation for this enzyme group.

Samarium complexes with fluorinated β-diketone and heterocyclic Lewis bases as UV light converters

Four new heteroleptic asymmetric fluorinated β-diketone based [Sm(fod)3] adducts with organic ligands of different denticities (monodentate indazole and triphenylphosphine oxide (tppo), bidentate imidazolyl pyridine (impy) and tridentate 2,4,6-tris(2-pyridyl)-s-triazine (tptz)) have been synthesized and characterized in order to examine the suitability of organic co-ligands as a sensitizer for Sm(III) luminescence. The photoluminescence of the complexes is studied in chloroform and solid state. The dominance of the hypersensitive transition 4G5/2 → 6H9/2 reflects the asymmetry around the Sm (III) ion in the present complexes which is supported by the large values of intensity ratio (RSm). The stark splitting in magnetic dipole 4G5/2 → 6H7/2 transition in the cases of eight coordinate [Sm(fod)3(impy)] (3) and [Sm(fod)3(tppo)2] (4) complexes is similar. However, the splitting pattern of 3 and 4 is distinctively different from the nine- [Sm(fod)3(tptz)] (1) and seven-coordinate [Sm(fod)3(indazole)] (2) complexes. The intensity of the hypersensitive transition and stark splitting of magnetic dipole transition changes significantly upon change in the ligand environment around the Sm (III). The bright luminescence from these complexes reflects efficient energy transfer from the selected sensitizers to Sm (III) ion. It is worth mentioning that the lifetime for 4G5/2 → 6H9/2 transition of complex 3 in solid state is 269 μs which is higher than the lifetime of this transition noted for most of the tris(β-diketonate)Sm(III) reported so for. The emission colour from chloroform solution of [Sm(fod)3(tppo)2] (4) changes from parrot green to orange red upon change in excitation wavelengths. Of the selected sensitizers, the impy is most efficient since the emission from its complex is most intense.

Highly conjugative heterocyclic nitrogen base derivative and its metal complexes towards optoelectronic materials: Chemical architecture, synthesis, structural elucidation, catalytic, optoelectronic and pharmacological studies

The pharmacologically active structural architecture of highly conjugative heterocyclic structure core comprised of 1, 10-Phenanthroline derivatives with different metal acetates to arrive different complexes with molecular formulae of [M II L] where L = 1,10-Phenanthroline derivative. The structural features of synthesized compounds using elemental compositions, molar conductivity, magnetic properties as well spectral (UV–Vis., IR, NMR, ESR), thermal analysis and cyclic voltammetry protocols. On the basis of analytical and spectroscopic approaches demonstrated that an octahedral geometry for the Co(II), Zn(II), Cu(II) and Ni(II) chelates. The voltage–current output was utilized to conclude the threshold voltage (V on ) of synthesized metal complexes as emerging materials. The catalytic conversion of benzyl alcohol into benzaldehyde and to optimize the reaction situations were performed to attain enhanced turn over number. The prepared title chelates were accessed for antibacterial efficiency with B. subtilis, E. coli, S. aureus,) and fungi strains (A. flavus, C. albicans and A. niger ). The observed outcomes has indicated that the complexes showed greater antimicrobial efficiencies than ligand. Additionally, the SOD biomimetic activity of prepared metal complexes was measured and discussed. Antituberculosis efficiencies of 1,10-Phenanthroline derivative and its chelates was assessed against strain , M. tuberculosis H 37 Rv with the help of MABA assay protocol.

Syntheses and structural characterizations of six ionic inorganic-organic salts from heterocyclic aromatic bases and tetrachlorometallates of Zn, Cu and Cd

Six organic-inorganic hybrid salts, ([(HL1)2(CdCl4)(H2O)] (1) (L1 = 2-(imidazol-1-yl)-1-phenylethanone), [(HL2)2(ZnCl4)(H2O)] (2) (L2 = 6-bromobenzo[d]thiazol-2-amine), [(H2L3)2(CdCl4)2(CH3OH)] (3) (L3 = bis(N-imidazolyl)methane), [(H2L4)(ZnCl4)(H2O)2] (4) (L4 = bis(N-imidazolyl)butane), [(H2L5)2(CuCl4)2]·7H2O (5) (L5 = di(2-benzimidazol-1-ylethyl)ether) and [(H2L6)4(ZnCl4)4]·7H2O (6) (L6 = 1,2-bis(2-benzimidazolyl)-1,2-ethanediol)), were prepared and characterized by IR, XRD, EA and TG analyses. The aryl rings of the cations in all salts are essentially planar. XRD analysis indicated that all of the complexes are built from non-covalent bonds between the cations and the tetrachlorometallate anions. The lattice solvent (H2O/CH3OH) molecules also played crucial roles in structure extension of all salts. Extensive intermolecular interactions have been used in the self-assembly of motifs, ranging from strong X-H···Y (X = O, N; Y = Cl, O) H-bonds to weak CH···A (A = O, Cl, Br), CH2···A (A = O, Cl), O···O, Cl···O, Cl···S, Cl···π, Br···Cl, CH3···π and π···π associations. 3 D architectures are found in 1 and 3-6, but only a 2 D architecture appeared in 2. The arrangements of the anions and cations in the solid are governed not only by the size and symmetry of the cations, but also by the non-covalent bonds in the crystal structures.

An Expedient Synthesis of Flexible Nucleosides through Enzymatic Glycosylation of Proximal and Distal Fleximer Bases.

The structurally unique “fleximer” nucleosides were originally designed to investigate how flexibility in a nucleobase could potentially affect receptor–ligand recognition and function. Recently they have been shown to have low‐to‐sub‐micromolar levels of activity against a number of viruses, including coronaviruses, filoviruses, and flaviviruses. However, the synthesis of distal fleximers in particular has thus far been quite tedious and low yielding. As a potential solution to this issue, a series of proximal fleximer bases (flex‐bases) has been successfully coupled to both ribose and 2′‐deoxyribose sugars by using the N‐deoxyribosyltransferase II of Lactobacillus leichmannii (LlNDT) and Escherichia coli purine nucleoside phosphorylase (PNP). To explore the range of this facile approach, transglycosylation experiments on a thieno‐expanded tricyclic heterocyclic base, as well as several distal and proximal flex‐bases were performed to determine whether the corresponding fleximer nucleosides could be obtained in this fashion, thus potentially significantly shortening the route to these biologically significant compounds. The results of those studies are reported herein.