Base Analogues Research Articles

Green synthesis of Tacrine modified Schiff bases as anti-Alzheimer Agents: An effective strategy validated through in-silico and in-vitro analysis

A variety of Tacrine-modified Schiff base analogues were developed via solvent free (green) method and structurally elucidated using 1HNMR, FTIR and UV–Vis analysis. High product yield was obtained from the synthesised molecules, which were produced efficiently at room temperature without the need of a solvent. The developed molecules were subsequently assessed for their potential to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). These molecules revealed effective inhibition of AChE and BChE enzymes with IC50 values varying from 0.1 ± 0.02 to 0.3 ± 0.03 μM and 0.065 ± 0.01 to 0.3 ± 0.03 μM respectively. Compared to the standard Tacrine which has IC50 values of 0.35 ± 0.02 μM for AChE and 0.1 ± 0.01 μM for BChE. Notably, compound 3f showed strong inhibition among others for both the enzymes. The structure–activity relationship of derivatives synthesized were verified and established through molecular docking studies. Theoretical ADME studies also predicted excellent drug-likeness for all the synthesized molecules. Antioxidant activities were also assessed because elevated oxidative stress levels are linked with cognitive loss in Alzheimer's disease (AD). These findings suggest that the lead compound is potentially an effective inhibitor for the therapeutic management of AD.

Exploring nitro-Tröger’s bases for ct-DNA and HSA sensing: An experimental and theoretical study

In this study, we present Tröger’s base analogs synthesized through condensation between p-formaldehyde and methyl-nitro-anilines in good yields. Tröger’s bases exhibit absorption peaks around 350 nm attributed to allowed ππ* electronic transitions. The fluorescence emission at 380 nm showed no correlation with the position of the nitro group. Spectroscopic analyses employing UV–Vis absorption, steady-state fluorescence emission, and molecular docking calculations revealed that these Tröger’s bases interact effectively with ct-DNA and human serum albumin (HSA). These findings suggest that this class of compounds might serve as promising optical sensors for biomacromolecules.

Analogical reasoning during hypothesis generation: the effects of object and domain similarities on access and transfer

In two experiments on analogical hypothesis generation, we factorially manipulated the presence of domain and object similarities between a base situation and a target phenomenon, and assessed their effects on the transfer of the source’s explanatory structure before and after an indication to use the base analog as a source for analogical explanations. The absence of any kind of surface similarity led to very low rates of spontaneous transfer. In both experiments, however, either kind of surface similarity sufficed to enhance the spontaneous transfer of the base explanation during the formulation of plausible hypotheses for the target. The transfer advantage of object and domain similarity cannot be attributed to the effect of these variables on post-access processes, since experimental conditions did not differ with regard to the ability to transfer the base explanation upon explicit request. The effect of domain similarity on spontaneous analogical explanation constitutes a relevant finding, especially given the lack of attention received by this dimension of similarity in behavioural studies and computer simulations of analogical retrieval.

Synthesis, biological and computational evaluation of benzoxazole hybrid analogs as potential anti-Alzheimer's agents.

Aim: Current study aims exploration of bis-benzoxazole bearing bis-Schiff base scaffolds (1-16) as anti-Alzheimer's agents.Materials & methods: 2-aminophenol is used as starting materials which react with different reagents in different step to give us bis-benzoxazole bearing bis-Schiff base analogs. NMR and HREI-MS techniques were used for characterization. All derivatives demonstrated varied range of activities with IC50 values 1.10±0.40-24.50±0.90μM against acetylcholinesterase (AChE) and 1.90±0.70-28.60±0.60μM against butyrylcholinesterase (BuChE) in contrast to donepezil. In both cases, analog-3 was found most potent. Molecular docking explored modes of interactions between scaffolds and receptor sites of targeted enzymes.Conclusion: This study offering promising approach for optimization and development of potent inhibitors of cholinesterase enzymes.

Insights into the role of potent thiadiazole based Schiff base derivatives in targeting type-II diabetes: A combine in-vitro and in-silico approaches

A novel series of varied substituted thiadiazole based Schiff base analogues (1–21) were designed and characterized using NMR (13C, 1H) and HREI-mass spectrometry, and secerned against the enzymes responsible for hyperglycemia i-e α-amylase and α-glucosidase. Newly designed analogues demonstrated distinct inhibitory activities having IC50= 1.10 ± 0.50 to 21.40 ± 0.20 µM (for alpha-amylase) and 2.50 ± 0.05 to 21.40 ± 0.10 µM (for alpha-glucosidase) in contrast to acarbose a well-known marketed drug (IC50 = 3.16 ± 0.22 & 4.8 ± 0.21 µM for α-amylase and α-glucosidase, respectively). Compound (20) with tri-fluoromethyl at para position of aromatic ring revealed as lead candidate among the members of synthesized series, having effective inhibitory activity against enzymes α-amylase and α-glucosidase. The excellent activity of compound (20) might be due to involvement of fluoro atom interacting via H-bonding with the active sites of enzymes α-amylase and α-glucosidase being targeted. Furthermore, for exploration of binding interactions of potent drugs, molecular docking was performed. For investigation of drug likeness and toxicity, ADME analysis was also conducted.

Current Market Potential and Prospects of Copper-based Pyridine Derivatives: A Review.

Nicotine, minodronic acid, nicotinamide (niacin), zolpidem, zolimidine, and other pyridine-based chemicals play vital roles in medicine and biology. Pyridinecontaining drugs are widely available on the market to treat a wide range of human ailments. As a result of these advances, pyridine research is continually expanding, and there are now higher expectations for how it may aid in the treatment of numerous ailments. This evaluation incorporates data acquired from sources, like PubMed, to provide a thorough summary of the approved drugs and bioactivity data for compounds containing pyridine. Most of the reactions discussed in this article will provide readers with a deeper understanding of various pyridine-related examples, which is necessary for the creation of copper catalysis-based synthetic processes that are more accessible, secure, environmentally friendly, and practical, and that also have higher accuracy and selectivity. This paper also discusses significant innovations in the multi-component copper-catalyzed synthesis of N-heterocycles (pyridine), with the aim of developing precise, cost-effective, and environmentally friendly oxygenation and oxidation synthetic methods for the future synthesis of additional novel pyridine base analogs. Therefore, the review article will serve as a novel platform for researchers investigating copperbased pyridine compounds.

Metabolic RNA labeling in non-engineered cells following spontaneous uptake of fluorescent nucleoside phosphate analogues.

RNA and its building blocks play central roles in biology and have become increasingly important as therapeutic agents and targets. Hence, probing and understanding their dynamics in cells is important. Fluorescence microscopy offers live-cell spatiotemporal monitoring but requires labels. We present two fluorescent adenine analogue nucleoside phosphates which show spontaneous uptake and accumulation in cultured human cells, likely via nucleoside transporters, and show their potential utilization as cellular RNA labels. Upon uptake, one nucleotide analogue, 2CNqAXP, localizes to the cytosol and the nucleus. We show that it could then be incorporated into de novo synthesized cellular RNA, i.e.it was possible to achieve metabolic fluorescence RNA labeling without using genetic engineering to enhance incorporation, uptake-promoting strategies, or post-labeling through bio-orthogonal chemistries. By contrast, another nucleotide analogue, pAXP, only accumulated outside of the nucleus and was rapidly excreted. Consequently, this analogue did not incorporate into RNA. This difference in subcellular accumulation and retention results from a minor change in nucleobase chemical structure. This demonstrates the importance of careful design of nucleoside-based drugs, e.g. antivirals to direct their subcellular localization, and shows the potential of fine-tuning fluorescent base analogue structures to enhance the understanding of the function of such drugs.

Exploration for the opioidergic, GABAergic and histaminergic potentials of synthesized Schiff’s base derivatives: An in-vivo approach

Herein, five Schiff’s base analogs (designated as AK1 to AK5) were synthesized and screened for their analgesic and anti-inflammatory efficacies. All compounds exhibited analgesic activity at selected doses from 45.31 % to 75.75 %, while the standard drug diclofenac sodium produced result as 86.33 %. Compounds AK1, AK3, AK4 and AK5 were found significantly P<0.001 effective at a dose of 25 mg/kg body weight (b.w). Similarly, in tail immersion test the produced percentage activity were in range from 40.19 % to 62.35 %. in which the compounds AK1, AK2, AK4 and AK5 were significantly P<0.01 effective at dose 12.5 mg/kg b.w, while at this dose significance level of efficacy of AK3 was P<0.05. Similarly, at administering doses of 25 mg/kg b.w all compounds were effective with significance level P<0.001, n = 8. Administration of the synthesized Schiff’s bases at the tested doses significantly reduced paw edema as compared to control. Results of paw edema at 3rd hour was significant P<0.001. AK4 and AK5 were subjected to mechanistic approaches by GABAergic, opiodergic and histaminergic pathways. In GABAergic pathway bicuculline caused a partial reversal of writhings responses indicating the involvement of GABA receptors and therefore the tested compounds may have act through GABAergic pathway. The naloxone caused a mild reversal in the tail immersion test and indicated that some other mechanisms are additionally involved in mode of action of these compounds. Additionally a mild response was observed while studying its action involving histaminergic pathway.

Synthesis, antimicrobial evaluation, and molecular docking studies of Mannich base analogs derived from 2,3-dihydro-1,3,4-oxadiazole-2(3H)-thione scaffold

Synthesis, antimicrobial evaluation, and molecular docking studies of Mannich base analogs derived from 2,3-dihydro-1,3,4-oxadiazole-2(3H)-thione scaffold

Enantiopurification by Co-Crystallization within Cyclodextrin Metal–Organic Framework

Tröger’s base analogs (TBAs) and their derivatives are versatile, Λ-shaped, tetracyclic chiral building blocks utilized in numerous fields of research. Although various methods for the enantiopurification of TBAs have been demonstrated in the literature, none has achieved it with the use of metal–organic frameworks (MOFs). This investigation introduces a convenient and scalable method to obtain enantiopure TBAs with the formation and digestion of a chiral MOF composed of fully recoverable and non-hazardous starting materials, namely, cyclodextrin-based metal–organic framework (CD-MOF).

Synthesis, Characterization, Molecular Docking Studies and Biological Evaluation of Thiazole Schiff Base Analogs

In this work, potentially safe few Schiff base compounds containing a thiazole moiety were synthesized and characterized. Three thiazole derivatives (2a-c) were successfully synthesized through a two-step reaction involving substituted benzaldehyde, thiosemicarbazide and 1,3-dichloroacetone. The elucidation of the synthesized compounds was accomplished by using spectral studies. Antimicrobial activities demonstrated that some compounds exhibited moderate effectiveness against microbes, compared to the standard antibiotic’s ceftriaxone and amphotericin B, using the disc diffusion technique. In the DPPH free radical scavenging assay, all compounds displayed promising antioxidant effectiveness. Moreover, the molecular docking studies showed that thiazole Schiff base analogs effectively bind to potential receptor binding sites.

Establishment and application of a rapid molecular diagnostic platform for the isothermal visual amplification of group B Streptococcus based on recombinase polymerase.

With growing concerns about Group B streptococcal (GBS) infections and their adverse effects on perinatal pregnancies, including infection, premature delivery, neonatal septicemia, and meningitis, it is urgent to promote GBS screening at all pregnancy stages. The purpose of this study is to establish a device-independent, fast, sensitive, and visual GBS detection method. Taking advantage of the characteristics of the recombinase polymerase isothermal amplification (RPA), the activity of the nfo nuclease cleavage base analog (tetrahydrofuran, THF) site, and the advantages of visual reading of the lateral flow chromatography strip (LFS), a GBS detection method was developed. This method focused on the conservative region of the Christie-Atkins-Munch-Petersen factor encoded by the cfb gene, a virulence gene specific to GBS. Two forward primers, two biotin-labeled reverse primers, and one fluorescein isothiocyanate (FITC)-labeled and C3spacer-blocked probe were designed. The study involved optimizing the primer pair and probe combination, determining the optimal reaction temperature and time, evaluating specificity, analyzing detection limits, and testing the method on 87 vaginal swabs from perinatal pregnant women. The results showed that the visual detection method of GBS-RPA-LFS, using the cfb-F1/R2/P1 primer probe, could detect GBS within 15 min at the temperature ranging from 39°C to 42°C. Furthermore, the method specifically amplified only GBS, without cross-reacting with pathogens like Lactobacillus iners, Lactobacillus crispatus, Candida albicans, Listeria monocytogenes, Yersinia enterocolitica, Klebsiella Pneumoniae, Enterobacter cloacae, Citrobacter freundii, Vibrio alginolyticus, Vibrio parahaemolyticus, Salmonella typhimurium, Staphylococcus aureus, Pseudomonas aeruginosa, or Trichomonas vaginalis. It could detect a minimum of 100 copies per reaction. In clinical 98 samples of vaginal swabs from pregnant women, the agreement rate between the GBS-RPA-LFS method and TaqMan real-time fluorescence quantification method was 95.92%. In conclusion, this study successfully established a combined RPA and LFS GBS in situ detection platform, with short reaction time, high sensitivity, high specificity, portability, and device independence, providing a feasible strategy for clinical GBS screening.

Synthesis and Photophysical Characterization of a pH-Sensitive Quadracyclic Uridine (qU) Analogue.

Fluorescent base analogues (FBAs) have become useful tools for applications in biophysical chemistry, chemical biology, live-cell imaging, and RNA therapeutics. Herein, two synthetic routes towards a novel FBA of uracil named qU (quadracyclic uracil/uridine) are described. The qU nucleobase bears a tetracyclic fused ring system and is designed to allow for specific Watson-Crick base pairing with adenine. We find that qU absorbs light in the visible region of the spectrum and emits brightly with a quantum yield of 27 % and a dual-band character in a wide pH range. With evidence, among other things, from fluorescence lifetime measurements we suggest that this dual emission feature results from an excited-state proton transfer (ESPT) process. Furthermore, we find that both absorption and emission of qU are highly sensitive to pH. The high brightness in combination with excitation in the visible and pH responsiveness makes qU an interesting native-like nucleic acid label in spectroscopy and microscopy applications in, for example, the field of mRNA and antisense oligonucleotide (ASO) therapeutics.

Exploring overlooked growth-promoting mechanisms by plant-associated bacteria

Abstract Agriculture-oriented microbiome studies try to develop microbiota beneficial to their plant hosts. This positive goal extends to the soil quality driving plant growth and disease resistance. In research aimed at identifying the causes of this beneficial action, a common interpretation is that microbes will synthesize metabolites useful to their hosts. This view assumes that important microbial metabolites are exported for use by their hosts. Yet, this seems unlikely for essential metabolites, without a counterpart imported from the plants, as the corresponding syntheses would often involve the consumption of resources without explicit benefit to the microbes. Illustrating this function with the example of Bacilli of the Subtilis clade, we emphasize here that the most direct access to the contents of microbial cells is through cell lysis, a phenomenon often linked to the process of sporulation. This process also releases macromolecules that are digested in the environment, releasing key metabolites such as queuine, an important base analog present in the anticodon of some transfer RNAs. This overlooked importance of cell lysis could also be a major cause of the ubiquitous presence of bacteriophages in microbiota.

The role of DNA damage in neural stem cells ageing.

Neural stem cells (NSCs) are pluripotent stem cells with the potential to differentiate into a variety of nerve cells. NSCs are susceptible to both intracellular and extracellular insults, thus causing DNA damage. Extracellular insults include ultraviolet, ionizing radiation, base analogs, modifiers, alkyl agents and others, while intracellular factors include Reactive oxygen species (ROS) radicals produced by mitochondria, mismatches that occur during DNA replication, deamination of bases, loss of bases, and more. When encountered with DNA damage, cells typically employ three coping strategies: DNA repair, damage tolerance, and apoptosis. NSCs, like many other stem cells, have the ability to divide, differentiate, and repair DNA damage to prevent mutations from being passed down to the next generation. However, when DNA damage accumulates over time, it will lead to a series of alterations in the metabolism of cells, which will cause cellular ageing. The ageing and exhaustion of neural stem cell will have serious effects on the body, such as neurodegenerative diseases. The purpose of this review is to examine the processes by which DNA damage leads to NSCs ageing and the mechanisms of DNA repair in NSCs.

Exploring the conformational dynamics of the SARS-CoV-2 SL4 hairpin by combining optical tweezers and base analogues.

The parasitic nature of the SARS-CoV-2 virus demands selective packaging of its RNA genome (gRNA) from the abundance of other nucleic acids present in infected cells. Despite increasing evidence that stem-loop 4 (SL4) of the gRNA 5' UTR is involved in the initiation of this process by binding the nucleocapsid (N) protein, little is known about its conformational dynamics. Here, we unravel the stability, dynamics and (un)folding pathways of SL4 using optical tweezers and a base analogue, tCO, that provides a local and subtle increase in base stacking without perturbing hydrogen bonding. We find that SL4 (un)folds mainly in a single step or through an intermediate, encompassing nucleotides from the central U bulge to the hairpin loop. Due to an upper-stem CU mismatch, SL4 is prone to misfold, the extent of which can be tuned by incorporating tCO at different positions. Our study contributes to a better understanding of SARS-CoV-2 packaging and the design of drugs targeting SL4. We also highlight the generalizability of using base analogues in optical tweezers experiments for probing intramolecular states and conformational transitions of various nucleic acids at the level of single molecules and with base-pair resolution.

Solid-state synthesis of polyfunctionalized 2-pyridones and conjugated dienes.

Functionalized 2-pyridones are important biologically active compounds, DNA base analogues and synthetic intermediates. Herein, we report a simple, green, solid-state synthesis of differently substituted 2-pyridones. It starts from commercially available amines and activated alkynes, uses silica gel (15%Cs2CO3/SiO2) as the solid phase and a reaction vial as the only equipment. If necessary, heating is performed in a laboratory oven. Since most reactions are completed within a few hours, no additional energy consumption is required. The syntheses do not require solvents and other reagents and are easily monitored by standard analytical techniques. The atom economy is high, since all atoms of reactants are present in the products and EtOH is the only by-product. The syntheses produce polyfunctionalized conjugated dienes as the only intermediates, which are also important building blocks.

Fluorescent molecular rotors detect O6-methylguanine dynamics and repair in duplex DNA.

Alkylation at the O6 position of guanine is a common and highly mutagenic form of DNA damage. Direct repair of O6-alkylguanines by the "suicide" enzyme O6-methylguanine DNA methyltransferase (MGMT, AGT, AGAT) maintains genome stability and inhibits carcinogenesis. In this study, a fluorescent analogue of thymidine containing trans-stilbene (tsT) is quenched by O6-methylguanine residues in the opposite strand of DNA by molecular dynamics that propagate through the duplex with as much as ∼9 Å of separation. Increased fluorescence of tsT or the cytosine analogue tsC resulting from MGMT-mediated DNA repair were distinguishable from non-covalent DNA-protein binding following protease digest. To our knowledge, this is the first study utilizing molecular rotor base analogues to detect DNA damage and repair activities in duplex DNA.

Ultrasensitive detection of a responsive fluorescent thymidine analogue in DNA via pulse-shaped two-photon excitation.

Fluorescent base analogues (FBAs) are versatile nucleic acid labels that can replace a native nucleobase, while maintaining base pairing and secondary structure. Following the recent demonstration that free FBAs can be detected at the single-molecule level, the next goal is to achieve this level of detection sensitivity in oligonucleotides. Due to the short-wavelength absorption of most FBAs, multiphoton microscopy has emerged as a promising approach to single-molecule detection. We report the multiphoton-induced fluorescence of 5-(5-(4-methoxyphenyl)thiophen-2-yl)-6-aza-uridine (MeOthaU), a polarity-sensitive fluorescent thymidine analogue, as a nucleoside, and in two single-stranded deoxyribo-oligonucleotides, with and without their complementary strands. Ensemble steady-state and time-resolved measurements in dioxane, following one-photon and two-photon excitation, reveals both strongly and weakly emissive species, assigned as rotamers, while in Tris buffer there are additional non-emissive states, which are attributed to tautomeric forms populated in aqueous environments. The two-photon (2P) brightness for MeOthaU is highest as the free nucleoside in dioxane (10 GM) and lowest as the free nucleoside in Tris buffer (0.05 GM). The species-averaged 2P brightness values in DNA are higher for the single strands (0.66 and 0.82 GM for sequence context AXA and AXT, respectively, where X is MeOthaU) than in the duplex (0.31 and 0.25 GM for AXA and AXT, respectively). Using 2P microscopy with pulse-shaped broadband excitation, we were able to detect single- and double-stranded oligos with a molecular brightness of 0.8-0.9 kHz per molecule. This allowed the detection of as few as 7 DNA molecules in the focus, making it the brightest responsive FBA in an oligonucleotide reported to date.

Synthesis, biological evaluation and molecular docking study of indazole based schiff base analogues as new anti-diabetic inhibitors

Indazole-based Schiff base analogues (1–27) were synthesized by a three-step reaction pathway starting from 1-methyl-1H-indazole-3-carboxylic acid as the basic compound. The structure of the new indazoles was characterized and confirmed by mass spectral analyses as well as NMR spectroscopic data. All synthesized analogues were screened for their in vitro α-glucosidase and α-amylase inhibitory activities. All analogues of the series exhibited good inhibitory potentials, with IC50 values ranging from 0.40 ± 0.01 to 16.20 ± 0.30 µM for α-glucosidase and 0.70 ± 0.01 to 17.40 ± 0.30 µM for α-amylase as compared to the standard drug acarbose (IC50 = 12.90 ± 0.10 and 12.80 ± 0.10 µM, respectively). The most effective analogue of the series is analogue 22 having 3‑hydroxyl groups with an IC50 value of 0.40 ± 0.01 µM and 0.70 ± 0.01 µM for α-glucosidase and α-amylase, respectively. Structure-activity relationship was carried out, which mainly depends upon the nature, number, position, and electron donating/withdrawing effect of the substituent(s) attached to the phenyl ring. To investigate the binding interaction of the potent analogue with the active site of an enzyme, molecular docking studies were carried out.