Naturally occurring coumarin and sugar molecules have a diverse range of applications along with superior biocompatibility. Coumarin, a member of the benzopyrone family, exhibits a wide spectrum of ...medicinal properties, such as anti-coagulant, anti-bacterial, anti-tumor, anti-oxidant, anti-cancer, anti-inflammatory and anti-viral activities. The sugar moiety functions as the central scaffold for the synthesis of complex molecules, attributing to their excellent biocompatibility, well-defined stereochemistry, benign nature and outstanding aqueous solubility. When the coumarin moiety is conjugated with the sugar or nucleoside molecule, the resulting conjugates exhibit significant biological properties.
Due to the remarkable growth of such bioconjugates in the field of science over the last decade, owing to their future prospect as a potential bioactive core, an update to this area is very much needed. The present review focusses on the synthesis, characterization and the various therapeutic applications of coumarin conjugates, i.e., sugar and nucleoside coumarin conjugates along with their perspective for future research.
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•Sugar.•Coumarin.•Nucleoside.•Triazole.•Conjugates.
A novel class of phthalimides functionalized with privileged scaffolds was designed, synthesized and evaluated as potential inhibitors of plasmepsin 2 (Ki: 0.99 ± 0.1 μM for 6u) and plasmepsin 4 (Ki: ...3.3 ± 0.3 μM for 6t), enzymes found in the digestive vacuole of the plasmodium parasite and considered as crucial drug targets. Three compounds were identified as potential candidates for further development. The listed compounds were also assayed for their antimalarial efficacy against chloroquine (CQ) sensitive strain (3D7) of Plasmodium falciparum. Assay of twenty seven hydroxyethylamine derivatives revealed four (5e, 6j, 6o and 6s) as strongly active, which were further evaluated against CQ resistant strain (7GB) of P. falciparum. Compound 5e possessing the piperidinopiperidine moiety exhibited promising antimalarial activity with an IC50 of 1.16 ± 0.04 μM. Further, compounds 5e, 6j, 6o and 6s exhibited low cytotoxic effect on MCF-7 cell line. Compound 6s possessing C2 symmetry was identified as the least cytotoxic with significant antimalarial activity (IC50: 1.30 ± 0.03 μM). The combined presence of hydroxyethylamine and cyclic amines (piperazines and piperidines) was observed as crucial for the activity. The current studies suggest that hydroxyethylamine based molecules act as potent antimalarial agent and may be helpful in drug development.
Herein, we report the development of a diastereoselective and efficient route to construct sugar-derived pyrano3,2-cquinolones utilizing 1-C-formyl glycal and 4-hydroxy quinolone annulation. This ...methodology will open a route to synthesize nature inspired pyrano3,2-cquinolones. This is the first report for the stereoselective synthesis of sugar-derived pyrano3,2-cquinolones, where 100% stereoselectivity was observed. A total of sixteen compounds have been synthesized in excellent yields with 100% stereoselectivity. The molecular docking of the synthesized novel natural product analogues demonstrated their binding modes within the active site of type II topoisomerase. The results of the in-silico studies displayed more negative binding energies for the all the synthesized compounds in comparison to the natural product huajiosimuline A, indicating their affinity for the active pocket. Ten out of the sixteen novel synthesized compounds were found to have comparative or relatively more negative binding energy in comparison to the standard anti-cancer drug, doxorubicin. Additionally, the scalability and viability of this protocol was illustrated by the gram scale synthesis.
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•Design and synthesis of a small library of sixteen novel sugar-derived pyrano3,2-cquinolones.•This is the first report of 100% stereoselective synthesis of sugar-derived pyrano3,2-cquinolones.•The in silico molecular docking results displayed more negative binding energies for the all the synthesized compounds demonstrating their binding modes within the active site of topoisomerase II.•The protocol can be expected to find wide synthetic application because of its simplicity, mild reaction conditions, high efficiency, and high stereoselectivity.
Thiazolines and their derivatives hold significant importance in the field of medicinal chemistry due to their promising potential as pharmaceutical agents. These molecular entities serve as critical ...scaffolds within numerous natural products, including curacin A, thiangazole, and mirabazole, and play a vital role in a wide array of physiological reactions. Their pharmacological versatility encompasses anti-HIV, neurological, anti-cancer, and antibiotic activities. Over the course of recent decades, researchers have extensively explored and developed analogs of these compounds, uncovering compelling therapeutic properties such as antioxidant, anti-tumor, anti-microbial, and anti-inflammatory effects. Consequently, thiazoline-based compounds have emerged as noteworthy targets for synthetic endeavors. In this review, we provide a comprehensive summary of recent advancements in the synthesis of thiazolines and thiazoline-based derivatives, along with an exploration of their diverse potential applications across various scientific domains.
Thiazolines and their derivatives hold significant importance in the field of medicinal chemistry due to their promising potential as pharmaceutical agents.
Summary Background Lymphatic filariasis is targeted for elimination as a public health problem by 2020. The principal approach used by current programmes is annual mass drug administration with two ...pairs of drugs with a good safety profile. However, one dose of a triple-drug regimen (ivermectin, diethylcarbamazine, and albendazole) has been shown to clear the transmissible stage of the helminth completely in treated individuals. The aim of this study was to use modelling to assess the potential value of mass drug administration with the triple-drug regimen for accelerating elimination of lymphatic filariasis in different epidemiological settings. Methods We used three different transmission models to compare the number of rounds of mass drug administration needed to achieve a prevalence of microfilaraemia less than 1% with the triple-drug regimen and with current two-drug regimens. Findings In settings with a low baseline prevalence of lymphatic filariasis (5%), the triple-drug regimen reduced the number of rounds of mass drug administration needed to reach the target prevalence by one or two rounds, compared with the two-drug regimen. For areas with higher baseline prevalence (10–40%), the triple-drug regimen strikingly reduced the number of rounds of mass drug administration needed, by about four or five, but only at moderate-to-high levels of population coverage (>65%) and if systematic non-adherence to mass drug administration was low. Interpretation Simulation modelling suggests that the triple-drug regimen has potential to accelerate the elimination of lymphatic filariasis if high population coverage of mass drug administration can be achieved and if systematic non-adherence with mass drug administration is low. Future work will reassess these estimates in light of more clinical trial data and to understand the effect on an individual country's programme. Funding Bill & Melinda Gates Foundation.
Mathematical models of parasite transmission can help integrate a large body of information into a consistent framework, which can then be used for gaining mechanistic insights and making ...predictions. However, uncertainty, spatial variability and complexity, can hamper the use of such models for decision making in parasite management programs.
We have adapted a Bayesian melding framework for calibrating simulation models to address the need for robust modelling tools that can effectively support management of lymphatic filariasis (LF) elimination in diverse endemic settings. We applied this methodology to LF infection and vector biting data from sites across the major LF endemic regions in order to quantify model parameters, and generate reliable predictions of infection dynamics along with credible intervals for modelled output variables. We used the locally calibrated models to estimate breakpoint values for various indicators of parasite transmission, and simulate timelines to parasite extinction as a function of local variations in infection dynamics and breakpoints, and effects of various currently applied and proposed LF intervention strategies.
We demonstrate that as a result of parameter constraining by local data, breakpoint values for all the major indicators of LF transmission varied significantly between the sites investigated. Intervention simulations using the fitted models showed that as a result of heterogeneity in local transmission and extinction dynamics, timelines to parasite elimination in response to the current Mass Drug Administration (MDA) and various proposed MDA with vector control strategies also varied significantly between the study sites. Including vector control, however, markedly reduced the duration of interventions required to achieve elimination as well as decreased the risk of recrudescence following stopping of MDA.
We have demonstrated how a Bayesian data-model assimilation framework can enhance the use of transmission models for supporting reliable decision making in the management of LF elimination. Extending this framework for delivering predictions in settings either lacking or with only sparse data to inform the modelling process, however, will require development of procedures to estimate and use spatio-temporal variations in model parameters and inputs directly, and forms the next stage of the work reported here.
The current WHO-led initiative to eradicate the macroparasitic disease, lymphatic filariasis (LF), based on single-dose annual mass drug administration (MDA) represents one of the largest health ...programs devised to reduce the burden of tropical diseases. However, despite the advances made in instituting large-scale MDA programs in affected countries, a challenge to meeting the goal of global eradication is the heterogeneous transmission of LF across endemic regions, and the impact that such complexity may have on the effort required to interrupt transmission in all socioecological settings.
Here, we apply a Bayesian computer simulation procedure to fit transmission models of LF to field data assembled from 18 sites across the major LF endemic regions of Africa, Asia and Papua New Guinea, reflecting different ecological and vector characteristics, to investigate the impacts and implications of transmission heterogeneity and complexity on filarial infection dynamics, system robustness and control.
We find firstly that LF elimination thresholds varied significantly between the 18 study communities owing to site variations in transmission and initial ecological parameters. We highlight how this variation in thresholds lead to the need for applying variable durations of interventions across endemic communities for achieving LF elimination; however, a major new result is the finding that filarial population responses to interventions ultimately reflect outcomes of interplays between dynamics and the biological architectures and processes that generate robustness/fragility trade-offs in parasite transmission. Intervention simulations carried out in this study further show how understanding these factors is also key to the design of options that would effectively eliminate LF from all settings. In this regard, we find how including vector control into MDA programs may not only offer a countermeasure that will reliably increase system fragility globally across all settings and hence provide a control option robust to differential locality-specific transmission dynamics, but by simultaneously reducing transmission regime variability also permit more reliable macroscopic predictions of intervention effects.
Our results imply that a new approach, combining adaptive modelling of parasite transmission with the use of biological robustness as a design principle, is required if we are to both enhance understanding of complex parasitic infections and delineate options to facilitate their elimination effectively.
A solvent catalysed and metal catalyst-free Groebke-Blackburn-Bienayame three component reaction (GBB-3CR) has been developed for the synthesis of 2-(β-D-glycal-1-yl)-3-N-alkylamino-1-azaindolizines ...and 2-alkyl/aryl/heteroaryl-3-N-alkylamino-1-azaindolizines. The modified GBB reaction protocol is highly efficient, versatile, atom economic and has been performed in hexafluoroisopropanol (HFIP) without any added catalyst. The GBB-3CR showed high tolerance for a large no of substrates in term of aldehydes, differently substituted 2-aminopyridines and isocyanides without being affected by the presence of electron donating and electron withdrawing substituents at either aldehydes or 2-aminopyridines.
A microwave assisted, palladium-catalyzed regioselective halogenation of 3-phenyl-2
-benzo
1,4oxazin-2-ones has been demonstrated using inexpensive and readily available
-halosuccinimide. The ...reaction utilizes the nitrogen atom present in the heterocyclic ring as the directing group to afford regioselective halogenated products in good to moderate yields. The established protocol provides wide substrate scope, high functional group tolerance, and high atom and step economy. The reaction proved to be cost-effective and time-saving as it required only a few minutes for completion and is amenable to gram scale. The halogen atoms present in synthesized products provide further scope for post-functionalization. Several post-functionalized products have also been synthesised to demonstrate the high utility of the reaction in the field of drug discovery and late-stage functionalization.
A microwave‐assisted highly efficient intermolecular domino carbopalladation/CH functionalization sequence has been developed to access bis‐heteroaryl frameworks in a single operation. The reaction ...involves carbopalladation of the halogenated acrylamides or phenylpropiolamides by the Pd(0) catalysis, followed by the direct (hetero)arylation to give products with good to excellent yields. The synthetic utility of this method was also extended towards the application of the Ugi‐adduct as the starting material.
A selective method! Azoles have been used as nucleophiles to trap the σ‐alkyl/vinyl–palladium species for the synthesis of bis‐heteroaryl frameworks by a domino carbopalladation/CH functionalization strategy. This method exhibits remarkable selectivity, high functional group tolerance, and provides good to excellent product yields (see scheme).
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