Structure-activity Relationship Research Articles

Quinoline- and pyrimidine-based allosteric modulators of the sarco/endoplasmic reticulum calcium ATPase.

Small-molecule allosteric activators of the enzyme sarco/endoplasmic reticulum calcium ATPase (SERCA) hold promise as novel experimental tools to manipulate intracellular calcium concentrations and as therapeutic agents to treat medical conditions associated with elevated cytosolic calcium levels. Here, we synthesized and characterized 20 analogs of the known allosteric SERCA activator CDN1163 and tested their ability to stimulate SERCA activity. The structures of the compounds varied in the alkyl group of the parent scaffold's ether moiety as well as in the composition of the nitrogenous aromatic ring system. The most active compounds exhibited potencies in the sub-micromolar range while increasing enzyme activity by more than 25%. The observed structure-activity relationships indicated that bulky alkyl groups in the ether moiety along with a quinoline ring methyl substituent were beneficial for activity. Replacement of the quinoline by a pyrimidine ring system reduced activity. To conceive a potential mechanism of action, we generated a molecular model of the transition state of SERCA when undergoing the rate-limiting step of its catalytic cycle. Subsequent blind docking with CDN1163 identified a high-affinity binding site close to the enzyme's ATP binding pocket, suggesting that the activators may accelerate SERCA's catalytic cycle by aiding in ATP binding and positioning.

Synthetic studies on the tetrasubstituted D-ring of cystobactamids lead to potent terephthalic acid antibiotics

Novel scaffolds for broad-spectrum antibiotics are rare and in strong demand because of the increase in antimicrobial resistance. The cystobactamids, discovered from myxobacterial sources, have a unique hexapeptidic scaffold with five arylamides and possess potent, resistance-breaking properties. This study investigates the role of the central D-ring pharmacophore in cystobactamids, a para-aminobenzoic acid (PABA) moiety that is additionally substituted by hydroxy and isopropoxy functions. We varied the two oxygenated substituents and replaced both amide connectors with bioisosteres. Synthetic routes were developed that included metal-mediated aromatic functionalization or heterocycle formations, leading to 19 novel analogues. The antibiotic efficacy of all analogues was determined against bacteria from the ESKAPE pathogen panel. While the replacement and the repositioning of hydroxy and isopropoxy substituents was not advantageous, exchanging PABA by terephthalic acid amides led to the highly potent analogue 42 with broad-spectrum activity, insensitivity towards AlbD-mediated degradation and promising pharmacokinetic properties in mice. The study highlights the steep structure-activity relationships in the tetrasubstituted D-ring and a surprisingly favorable reversion of the amide connecting C and D.

Trace Iron-Modified CeO₂-supported Core-shell CoO@Co Catalyst for Selective Conversion of Furfural to 1,5-Pentanediol.

In the conversion of furfural using non-noble metal catalysts, preferential cleavage of the C2-O bond followed by hydrogenation of the C=C bond facilitates selective access to valuable 1,5-pentanediol (1,5-Ped). Herein, we developed CeO₂ loaded core-shell CoO@Co nanoparticle catalysts. Adjusting Co loading, Fe doping, and reduction temperature improved reaction efficiency. 7Co-0.2Fe/CeO₂ catalysts reduced at 500 °C demonstrated optimal performance. 1,5-Ped produced at 54.76 mmol/g(Co)/h, representing the top activity levels among the reported catalysts. H₂-TPR, XRD, HAADF-STEM, FT-IR, XPS, and XANES were employed to investigate the catalyst structure-activity relationship. Co²⁺ cleaves furan ring C-O bond, Co⁰ promotes double-bond hydrogenation. The CoO@Co structure favors the desired 1,5-Ped production route. Trace Fe species optimize the Co²⁺/Co⁰ ratio, enhance the substrate adsorption, and inhibit the furan ring saturation. These findings emphasize the importance of fine-tuning catalyst structure and composition for selectivity improvement.

Water-Driven Stacking Structure Transformation of Ultrathin Ru Nanosheets for Efficient Hydrogen Evolution Reaction.

Ultrathin crystalline materials are a class of popular materials that can potentially exhibit fascinating physical and chemical properties dictated by their unique stacking freedom. However, it is challenging to achieve the controllable synthesis over their stacking structure for ultrathin crystalline materials. Herein, water is employed as a key regulatory factor to realize phase engineering in ultrathin nanosheets (NSs), thereby altering stacking faults to achieve distinct stacking arrangements. Ruthenium (Ru) NSs with consistent specific surface areas but different stacking manners are fabricated through the systematic regulation of water. Based on this, it is demonstrated that the hydrogen evolution reaction (HER) performance can be significantly influenced by their stacking structures. Further in-depth investigations reveal that the distinct stacking structures of Ru NSs, featuring a limited area of side facets, will influence the energy barrier of sluggish Volmer step in HER. Ru NSs with ABC stacking exhibit an accelerated Volmer process with outstanding catalytic activity, demonstrating a remarkably low overpotential (25mV at 10mAcm-2) and Tafel slope (29mVdec-1) than most of the reported HER catalysts. The work will advance the understanding of controllable synthesis methods and illuminate the structure-activity relationships in ultrathin crystalline nanomaterials.

Catalytic CO2 Desorption from MEA Solution of Al-FeOOH Composite Catalysts’ Desorption Performance, Structure–Activity Relationship, and New Mechanism

In order to reduce the massive heat duty of amine-based CO2 capture technology, an AlOOH/FeOOH composite catalyst (AF-M/N) was synthesized to speed up the CO2 desorption rates and reduce the heat duty of an aqueous MEA solution. The catalysis of AF-M/M from 1/9 to 9/1 was investigated comprehensively, with characterization of the catalytic desorption with heat duty and desorption factors. Results indicated the special composite catalyst (AF-1/9) possessed optimized catalysis with a relative heat duty of 78.7% and a desorption factor of 0.0037 × 10−3 (mol CO2/L2 kJ min) and relative desorption factor of 194.7%. The structure–activity correlations indicated that the mesopore surface area (MSA), which reached 329 m2/g, and Brϕnsted/Lewis acid ratio (B/L ratio) of 0.11 were the most important factors for enhancing catalysis. Furthermore, molecular simulations were conducted for the catalytic carbamate breakdown mechanism, focusing on the “isomerization” of “carbamate acid” vs. “Zwitterion” as the key step. From the DFT study, the isomerization was most likely to proceed with H2O as catalyst via intermolecular proton transfer instead of intramolecular proton transfer, with an activation energy Ea of 85.9 kJ/mol. With the aid of AlOOH the isomerization was further facilitated due to stabilized Zwitterion, and the Ea decreased to 69.2 kJ/mol. The results not only synthesized a new heterogeneous catalyst but also revealed the map of “isomerization” on a molecular level. Such a discovery indicates that water-assisted proton transfer is advantageous for catalytic carbamate breakdown.

Optimizing Materials to Boost the Valorization of CO2: Tuning Cobalt-Cobalt Interactions on In2O3-Based Photothermal Catalysts.

The valorization of CO2 is an important challenge within the current panorama, since this molecule is probably the main contributor to climate change. In this study, the synthesis of materials based on a nanostructured batonnet-type indium oxide is carried out. In them, different amounts of Co are introduced, varying between 2 and 8% mol. It is verified that the most active sample in the transformation of carbon dioxide to carbon monoxide contains 6 mol %. of Co. This sample's activity under dual excitation exceeds the thermal counterpart by more than 30%. After carrying out a complete physical and chemical characterization with the help of X-ray absorption spectroscopy and other techniques, it is shown that catalysts with amounts of cobalt equal to or below 4 mol % contain isolated single-atom species, while those with higher amounts of metal display a Co-Co interaction which triggers the evolution of the samples under reaction conditions. The optimum control of this Co-Co interaction and the nature of the final cobalt-containing species determine dual photothermal catalytic properties. This work establishes a structure-activity relationship to interpret the catalytic behavior of highly dispersed subnanometric cobalt species, and thus an avenue to optimize the photothermal valorization of carbon dioxide.

Comparative evaluation and QSAR modeling of developmental neurotoxicity of novel brominated flame retardants in zebrafish

The novel brominated flame retardants (NBFRs) have received wide concerns due to their ubiquitous occurrence in the environment and their potential risks to ecosystems and human health. However, the toxicity data of NBFRs are still lacking, especially their toxicity comparison data, and toxicity predictions for untested NBFRs are extremely limited. In this study, eight commonly used NBFRs and decabromodiphenyl ether (BDE209) were selected to compare their toxicity at concentrations between 0.03 and 3.69 μM, by exposing zebrafish embryos until 120 h post-fertilization (hpf) and evaluating 18 toxicity indicators including basic development indicators and a series of behavioral indicators. The toxicity potency of the tested compounds ranked by the total number of significantly affected endpoints were pentabromobenzene (PBB) ≈ 2,4,6-tribromophenol (TBP) > BDE209 ≈ bis(2-ethylhexyl) tetrabromophthalate (TBPH) > pentabromotoluene (PBT) ≈ 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (EHTBB) > 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE) > hexabromobenzene (HBB) > decabromodiphenyl ethane (DBDPE). Almost all the tested compounds affected the locomotor behavior of zebrafish larvae, suggesting that the refined behavioral indicators were sensitive endpoints. Furthermore, the quantitative structure-activity relationship (QSAR) model we developed suggested that molecular surface area (MSA) might be the critical factor for determining the developmental neurotoxicity of NBFRs to zebrafish larvae, except for congeners with larger molecules (e.g. DBDPE, BTBPE). These findings would contribute to elucidating the toxicity differences among various NBFRs and provide important references for their toxicity prediction.

Uncovering structure-activity relationships in Brønsted acidic deep eutectic solvents for extractive and oxidative desulfurization

Modeling the structure-activity relationships (SARs) of deep eutectic solvents (DESs) is crucial for upgrading their catalytic performance in targeted reactions. Herein, a series of Brønsted acidic DESs are developed for the SARs research at molecular and atomic levels. Experimental and theoretical results suggest that the catalytic activity increases with the decreasing distances between O atom of active sites in DESs and S atom in sulfur compounds, and the R2 between EODS efficiency and the valid distances of O···S is above 0.9. Such geometric configuration can be optimized by altering the composition of DESs, which in turn substantially triggers the reaction acceleration between active intermediates and substrates. The resulting DES (TEAC/2BSA) achieved deep desulfurization for various sulfur compounds based on the optimal valid distances of O···S. This work contributes to a deep understanding of the reaction mechanism and enables the effective screening of task-specific DESs.

Molecular modeling aided design, synthesis, and activity evaluation of N-arylindole derivatives as GPR52 agonists

G protein-coupled receptor 52 (GPR52) is considered to be a promising target to improve the symptoms of psychiatric disorders and its agonists are expected to treat schizophrenia without traditional side effects. Several research institutions have reported some small molecule GPR52 agonists, which can be the starting point for rational drug development. In this study, a series of N-arylindole derivatives were designed and synthesized based on 3g according to classical pharmacochemical methods and computer aided drug design (CADD). The designed compounds exhibited good to excellent activities and the structure-activity relationship (SAR) study was explored. The results show that the connection mode between the hydrophilic head (Part I) and the indole ring (Part II) plays an important role in the GPR52 agonist activity. Among these compounds, compounds 16 and 21 have good GPR52 agonist activity (EC50 = 93 nM and 75 nM) and can inhibit hyperactive behavior in mice induced by MK-801 (EC50 =7.94 mg/kg and 6.64 mg/kg). These designed small molecules will provide new options for the development of novel GPR52 agonists.

Targeting the cyclin-dependent kinase family in anticancer drug discovery: From computational to experimental studies

Uncontrolled cell proliferation, primarily regulated by cyclin-dependent kinases (CDKs), is a critical driver of cancer progression, with dysregulation of CDKs contributing to various cancer types. CDKs have emerged as well-established targets for cancer therapy; however, traditional drug development methods have often proven to be time-consuming, challenging, and expensive. Recent advancements in CDK inhibitors (CDKIs) have shown immense clinical potential but many first-generation CDKIs face issues of non-selectivity and significant toxicity, limiting their clinical approval. To address these challenges, innovative computational approaches, particularly pharmacophore modeling, have the potential to streamline drug discovery. These methods can guide the selection of small molecules through target-specific structure-activity relationship (SAR) models and chemotypes screening across databases, thereby accelerating the identification of effective CDKIs. This review paper summarizes the latest developments on CDK inhibitors, highlights their structural features, and the methodologies (key databases & software tools) that can provide further suggestions for future drug development.

Therapeutic Contribution of Tau-Binding Thiazoloflavonoid Hybrid Derivatives Against Glioblastoma Using Pharmacological Approach in 3D Spheroids.

Growing evidence has unveiled the pathological significance of Tau in many cancers, including the most aggressive and lethal brain tumor glioblastoma multiform (GBM). In this regard, we have recently examined the structure-activity relationship of a new series of seventeen 2-aminothiazole-fused to flavonoid hybrid compounds (TZF) on Tau-overexpressing GBM cells. Here, we evaluated the anticancer activities of the two lead compounds 2 and 9 using multi-cellular spheroids (MCSs) which represent an easy 3D human cell model to mimic GBM organization, physical constraints and drug penetration. The two compounds reduced cell evasion from spheroids up to three times, especially for Tau-expressing cells. As a first step towards a therapeutic approach, we quantified the effects of these compounds on MCS growth using two complementary protocols: single and repeated treatments. A single injection with compound 9 slowed down the growth of MCSs formed with U87 shCTRL cells by 40% at 10 µM. More interestingly, multiple treatment with compound 9 slowed the growth of U87 shCTRL spheroids by 40% at a concentration of 5 µM, supporting the increased bioavailability of compound 9 within MCSs. In conclusion, compound 9 deserves particular attention as promising candidate for specifically targeting Tau-expressing cancers such as GBM.

Combining in-situ quadrupole mass spectrometer analyses: Study on the structure–activity relationship and lubrication mechanisms of ammonium phosphate ionic liquids

Since the lubrication performances of ionic liquids are closely linked to their unique structures, four protic ionic liquids (PILs), [N44HH][DEHP], [N444H][DEHP], [N448H][DEHP] and [N4412H][DEHP], are designed to investigate the effect of cationic structures on the lubrication behaviors and lubrication mechanisms. Vacuum tribological tests were carried out to minimize the impact of the atmospheric environment. The structure–activity relationships and lubrication mechanisms of PILs were emphatically examined by in-situ quadrupole mass spectrometer (Q-MS) and XPS analyses. Results demonstrated that all four PILs exhibited outstanding lubrication performance under a vacuum condition. Unusually, extended alkyl chain cationic structures resulted in a changed lubrication mechanism, leading to a slight decrease in performance. In-situ Q-MS analyses and XPS further revealed that the length of the alkyl chain in cations influenced the strength of intermolecular forces in PILs, leading to changes in their lubrication performance and mechanisms.

Structure-activity relationship between crystal plane and pyrite-driven autotrophic denitrification efficacy: Electron transfer and metagenome-based microbial mechanism

Pyrite-driven autotrophic denitrification (PAD) has been recognized as a promising treatment technology for nitrate removal. Although the occurrence of PAD has been found in recent years, there is a knowledge gap about effects of crystal plane of pyrite on the performance and mechanism of PAD system. Here, this study investigated the effects of crystal planes ({100}, {111} and {210}) of single-crystal pyrite on denitrification performance, electron transfer, and microbial mechanism in PAD system. The removal efficiency of nitrate in B-{210} reached 100%, which was 1.67-fold and 2.86-fold higher than that of B-{100} and B-{111}, respectively. X-ray photoelectron spectroscopy and electrochemical results indicated that Fe-S bonds of pyrite with {210} crystal plane were more susceptible to breakage by Fe3+ oxidation assault, and leaching microbially available Fe2+ and sulfur intermediates to drive autotrophic denitrification. Metagenomic results suggested that community of functional pyrite-driven denitrifiers varied in response to crystal plane, and abundances of N-S transformation and EET-related microbes and genes in B-{210} notably up-regulated compared to B-{100} and B-{111}. In addition, this work proposed a dual-mode for electron transfer pathway during pyrite oxidation and nitrogen transformation in PAD system. In B-{210}, Fe(II)- and sulfur-driven denitrifiers obtained electron after pyrite oxidation-dissolution, and the enrichment of pyrite-oxidizing bacteria in B-{210} could enhance the electron transfer from pyrite through electron shuttles. This work highlighted that stronger surface reactivity and electron shuttle effect in B-{210} enhanced electron transfer, leading to favorable PAD performance in B-{210}. Overall, this study provides novel insights into the structure-activity relationship between the crystal plane structure of pyrite and denitrification activity in PAD system.

Modulating structure of Ce-UiO-66 by introducing fluorinated terephthalic acid for enhanced removal efficiency of antibiotics: Insights into degradation kinetics and pathways

In this work, the 2-fluoroterephthalic acid with asymmetric structure and high electronegative F species was introduced in the assembly of Ce-UiO-66 catalysts to increase the defect density and enlarge pore structure for enhancement in removal efficiency of sulfamethoxazole. Owing to the strong coordination ability from high electronegative F species of 2-fluoroterephthalic acid with Ce-oxo nodes, the designed CUF exhibited improved interfacial properties (accelerated electron transfer rate, available active sites and enhanced interaction with PMS), which was favorable for the exploration and accessibility of active sites with sulfamethoxazole and PMS to decrease the adsorption barrier and accelerate PMS activation. As a result, the CUF catalysts exhibited higher adsorption capacity (173.4 mg/g) than that of CUH (117.8 mg/g), the enhanced degradation efficiency of sulfamethoxazole with a rate constant higher than 2.3 times CUH, good elimination (>95 %) of methylene blue, tetracycline and ibuprofen. In addition, the CUF/PMS system possessed satisfactory stability in wide solution pH, recycling and real water and good potential application in continuous wastewater treatment based on the designed dynamic catalytic reactor. This work provided deep insight into the design of catalysts with high adsorption performance and degradation efficiency based on the structure–activity relationship.

Manipulating the d- and p-Band centers of amorphous alloys by variable composition for robust oxygen evolution reaction

Amorphous electrocatalysts display several unique advantages in electricity-driven water splitting compared to their crystalline analogs, but understanding their structure–activity relationships remains a major challenge. Herein, we show that the d- and p-electronic states of amorphous Ni-Fe-B can be subtly manipulated by varying the Ni and Fe contents. The optimal Ni-Fe-B alloy exhibits a high performance in the oxygen evolution reaction (OER), as supported by its impressive stability (no clear degradation after 100 h) and considerably lower overpotential compared to those of its crystalline analogs. Based on theoretical calculations, different Ni and Fe contents can cause significant shifts in the d-band levels of Ni and Fe and the p-band level of B, thus altering the OER activity. Additionally, the energy difference between the d- and p-band centers (ΔEad-p) may be an effective index for use in reflecting the structure–activity relationship of an amorphous Ni-Fe-B alloy in the OER. An amorphous Ni-Fe-B alloy with a smaller ΔEad-p displays a higher intrinsic activity. This study supplies a unique direction for use in constructing the structure–activity relationships of amorphous electrocatalysts by revealing the role of ΔEad-p, which promotes fundamental research and the practical application of amorphous electrocatalysts.

Fabrication of polydopamine doped helical/chiral porous carbon fiber (HPCFs@PDA) and N-doped carbon layers (HPCFs@NCLs) for their application as wave absorber with ultrawide EAB

A new class of wave absorbing materials HPCFst@PDA and HPCFst@NCLs (where HPCFs describes helical/chiral porous carbon fiber, t refers to carbonization 700, 800 °C, PDA ascribed to poly (dopamine), and NCLs corresponds to nitrogen doped carbon layers) with helical/chiral, hierarchical, multi-layered structural morphology containing different heterostructures was triumphantly constructed through single-step carbonization of HPCFst. The HPCFst biomass fiber was go through self-polymerization of dopamine and we get HPCFs700@PDA, HPCFs800@PDA as an intermediate product. Finally, the PDA doped HPCFs biomass (HPCFs700@PDA, HPCFs800@PDA) was effectively transformed into NCLs from inside toward outside (HPCFs700@NCLs, HPCFs800@NCLs) through carbonization. Notably, HPCFs exhibit helical/chiral, hierarchical porous morphology with hetero-interfaces (such as dipole interfaces) that improve dielectric loss, while PDA and NCLs ameliorate wave absorber conductivity, through generation of polarization centers, heterointerfaces and resulting in considerable dielectric loss. Moreover, HPCFs with such unique structural morphology provide additional loss mechanism through cross-polarization that improve dissipation/attenuation of microwave. The microwave absorption mechanism of HPCFst@PDA(1–3), HPCFst@NCLs(1–3) (where 1, 2, 3 refer to filler content 27.50, 30.00, 32.50%wt PDA derived absorber and 20.00, 22.50, 25.00%wt NCLs filler) and their structure active relationship are further elucidated. Evidently, HPCFs700@PDA2 gained reflection loss (RL) of −51.60 dB at 13.60 GHz, across the broad spectrum of frequencies (EAB, RL ≤ −10 dB) covers 6.70 GHz (11.30–18.00 GHz) at 2.70 mm thickness. The EAB ameliorate to the value of 7.20 GHz (10.70–18.00 GHz) at thickness of 2.80 mm. While HPCFs700@NCLs2 RL was improved to −63.00 dB at 2.40 mm thickness with EAB 5.10 GHz (11.40–16.50) at 13.30 GHz frequency. Likewise, HPCFs800@PDA2 RL elevates to the value of −53.40 dB with adequate EAB covering 12.80–18.00 GHz (5.20 GHz) at higher values of 14.40 GHz and 2.10 mm thickness. For HPCFs800@NCLs2, the RL is as high as −65.40 dB at 9.90 GHz, with an effective thickness of 3.20 mm covering 7.50–11.20 GHz (3.20 GHz) EAB. At matching thickness of 2.00 mm the EAB covers 13.80–18.00 (4.20 GHz). Their top-notch microwave absorption capabilities with widened EAB at lower matching thickness demonstrate potentially promising prospects of HPCFst@PDA and HPCFst@NCLs as wave absorbing materials.

Identification of new structure of indol-3-acetyl-arylsulfonohydrazide as potent α-glucosidase and α-amylase inhibitors and molecular docking

Herein this work, indole analogs (1-16) were synthesized by treating 2-(1H-indol-3-yl)acetohydrazide with various aryl sulfonyl chloride in pyridine as solvent and screened for α-amylase and α-glucosidase inhibitory activity under positive control of standard drug acarbose (IC50 = 12.80 ± 0.10 μM /12.90 ± 0.10 μM. All analogs of the series appeared with excellent to good inhibitory activity as compared to standard drug. The inhibitory activity range for α-amylase is 0.70 ± 0.01 μM to 19.40 ± 0.40 μM, while for α-glucosidase inhibitory activity is 1.20 ± 0.10 μM to 20.40 ± 0.40 μM respectively. Most of the analogs appeared with excellent inhibitory activity, and some analogs like 5, 6, 7, 8, 9, 10,13 and 14 for both enzymes displayed many folds better inhibitory activity than standard drug acarbose. The influences of substituents on inhibitory activity were superficially resonated via structure activity relationship. Docking studies were established to confirm the binding interaction between analogs and active sites of enzymes.

Structure activity relationships of antischistosomal N-phenylbenzamides by incorporation of electron-withdrawing functionalities

For the adult Schistosoma mansoni flatworm pathogen, we report further structure activity relationships (SAR) of 19 N-phenylbenzamide analogs. Our previous SAR studies, designed by selecting representative substituents from the Craig plot, identified 9 and 11 which possessed electron-withdrawing groups that benefited potency. This study sought to enhance the potency of this chemotype by incorporating other electron-withdrawing functionalities not studied previously and to overcome the potential pharmacokinetic liabilities associated with the high lipophilicity of frontrunner compounds. Compared to the most potent compound, 9 (EC50 = 80 nM), from our previous work, the most potent compounds in the current study (32 (EC50 = 1.17 µM), 34 (EC50 = 1.64 µM) and 38 (EC50 = 1.16 µM)) were less active although they retained single digit micromolar potency. Furthermore, compound 38 generated a CC50 value of > 20 µM in counter toxicity screens using HEK 293 cells, translating to a wide selectivity index of > 17.

Design, synthesis, and evaluation of some benzimidazole analogs as AMPK agonists

AMP-activated protein kinase is a crucial regulator of cellular metabolism with potential therapeutic implications in various diseases. In this study, the benzimidazole scaffold was chosen for investigation with EX-229 as the lead compound. Modifications were made to the terminal carboxyl group, and the methylindole moiety was replaced with phenylpyrrolidinone to synthesize and assess the AMP-activated protein kinase-activating properties of 13 benzimidazole derivatives. In vitro studies have shown that most of the synthesized compounds have significant excitatory effects on AMP-activated protein kinase. Particularly, A11 demonstrated the most potent activity with an EC50 value of 39 nM. Combining activity data and molecular docking analysis revealed the necessity of end-molecule hydrogen bond donors for LYS29, and the importance of an appropriate torsion angle at the pyrrolidinone position to facilitate the formation of a crucial hydrogen bond with LYS31. These discoveries offer preliminary insights into the interaction of small-molecule drugs with the AMP-activated protein kinase protein and establish a foundation for the future development of AMP-activated protein kinase activators guided by structure–activity relationships.

Azole Derivatives: Cutting‐Edge Agents in Cancer Therapy

AbstractMonocyclic 5‐membered heterocycles including imidazoles, thiazoles, oxazoles, and their related compounds have gained significant attention in medicinal chemistry because of their potent anticancerous activity. These small heterocyclic molecules possess versatile properties, including biological activity, absorption, distribution, metabolism, excretion, and chemical diversity that give them immense potential as anticancer agents. It is also a fact that inherent characteristic of azoles to combine with many biological molecules through hydrogen bond, stacking, and hydrophobic interaction makes them effective against almost all cancer types. In the present paper the author discusses the way which is connected with chemical structure of monocyclic azoles and their anticancer activity namely the ability of these compounds to intercalate with DNA, to inhibit some enzymes and to interfere cellular signaling pathways. Interestingly, several azole derivatives have been seen to be effective in preclinical efficacy studies as well as in clinical trials and are considered to be potent in overcoming the problem of resistance and side effects of the common anticancer agents. As the synthetic chemistry progresses, the structural system of the azoles has diversified and development in the pharmacology has become more specific. This has helped in enhancing the formation of new molecules in the azole class with improved selectivity and efficacy. Furthermore, the comprehensive review explains how computational chemistry and structure‐activity relationship (SAR) approaches are applied to the design of future‐generation azole compounds. In light of these facts, this article is designed to give a broad overview of the current state of monocyclic azole‐based anticancer agents in an attempt to further assert its therapeutic promise and spur further attempts at infusing the said agents into the cancer therapeutics fray. The discoveries made in this study may allow the development the radical different therapeutic approaches, which could lead to improved and targeted treatment of cancer.