Series Of Compounds Research Articles

Discovery of Small Molecules that Bind to Son of Sevenless 2 (SOS2).

The Son of Sevenless (SOS) protein family includes two highly homologous proteins, SOS1 and SOS2, that act as guanine nucleotide exchange factors (GEFs) for RAS proteins. They catalyze the GDP-to-GTP exchange, resulting in an increase of the active GTP-bound form of RAS. Despite highly similar structures and expression patterns, SOS1 is generally accepted as the dominant RAS GEF for downstream signaling in pathological states. Nonetheless, SOS2 has been reported to critically impact the RAS-PI3K/AKT signaling axis, especially in KRAS-driven cancer cell lines and in the absence of SOS1. Hence, therapeutic targeting of SOS2 may be an attractive strategy to target RAS-driven malignancies. Herein, we report the discovery and initial optimization of a selective quinazoline-based compound series that binds with micromolar affinity to the catalytic site of SOS2. We also disclose an additional, previously unreported binding site on SOS2 occupied by a different small molecule class.

Design, Synthesis, and Pharmacological Evaluation of Nonsteroidal Tricyclic Ligands as Modulators of GABAA Receptors.

GABAA receptors (GABAARs) are the major elements of inhibitory neurotransmission in the central nervous system (CNS). They are established targets for regulation by endogenous brain neuroactive steroids (NASs) such as pregnanolone. However, the complexity of de novo synthesis of NAS derivatives has hindered attempts to circumvent the principal limitations of using endogenous NASs, including selectivity and limited oral bioavailability. In this study, we designed a series of tricyclic compounds, inspired by the structures of pregnanolone and pregnenolone sulfate, to explore novel nonsteroidal alternatives. Using patch clamp electrophysiology, we demonstrate that these compounds exhibit either positive or negative allosteric modulation of GABAARs. Specifically, we discover a positive allosteric modulator (PAM) and a series of tricyclic sulfate-based negative allosteric modulators (NAMs) all active at the micromolar level. This research has significantly broadened the chemical diversity of ligands targeting GABAARs offering potential for efficacious allosteric modulators while avoiding the complexity of NAS synthesis.

Bis(dialkylaminethiocarbonyl)disulfides Act as Electron Acceptors for EDA Complexes for the Synthesis of Dithiocarbamate Derivatives under Visible Light.

This study proposes a green and efficient atom- and step-economical method for converting hazardous CS2 to dithiocarbamate derivatives under visible light irradiation and catalyst-free conditions. By the construction of novel C-S and C-N bonds, a series of β-dicarbonyl compounds and amines are incorporated into the products. Under light, CS2 and amine first form bis(dialkylaminethiocarbonyl)disulfides, which then react with K2CO3-activated β-dicarbonyl compounds to form electron donor-acceptor (EDA) complexes and subsequently generate the target products. This study confirms for the first time that bis(dialkylaminethiocarbonyl)disulfides can act as electron acceptors to form an EDA complex with β-dicarbonyl compounds, which are then coupled to form the target product under light.

A Promising Strategy for Searching High Energy Density Materials Based on 2,4,5‐Trinitro‐Imidazole Functional Backbone

AbstractA series of high energy density compounds are designed by altering the triazole, tetrazine, oxadiazole rings and energetic groups (such as −CN, −N3, −NH2, −NHNH2, −NO2, −NHNO2, −C(NO2)3, −CH(NO2)2) into 2,4,5‐trinitro‐imidazole skeleton. Their structures are optimized by density functional theory (DFT) methods at B3LYP/6‐311G (d,p) method. Based on the optimized structures, the impact of different rings and energetic groups on their energy gaps, heats of formation, detonation performance and sensitivities are investigated. The results show that compound F4 possesses the highest values of heats of formation due to their high nitrogen content. However, compound F2 possesses the highest values of detonation pressure and detonation velocity which indicates that the detonation performance are determined by values of density rather than those of heats of formation. Taking both detonation performance and impact sensitivities into consideration, compounds B4, C4, F4, I4, J4 and J8 are screened as high energy density compounds due to their excellent detonation performance and acceptable sensitivities compared to those of RDX. Finally, the distribution of frontier molecular orbital, the electrostatic potential area distribution, thermodynamic properties and weak interactions of the screened compounds are fully investigated.

Copper-Catalyzed Radical Cascade Cyclization of N-Substituted Indole-3-Aldehydes with Aryl Alkenes: Access to Pyrrolo[1,2-a]indole Scaffolds.

Herein, we report a Cu-DTBP-catalyzed [3 + 2] cycloaddition reaction between 1-(2-oxo-2-phenylethyl)-1H-indole-3-aldehyde and arylalkene, using DMF as the solvent. Under relatively mild reaction conditions, a series of indole compounds were synthesized in moderate yields (up to 73%). This protocol features good functional group tolerance and high atom economy. In addition, we synthesized a total of 20 target compounds, providing a reliable and straightforward method to obtain structurally diverse pyrrolo[1,2-a]indole derivatives.

DESIGN, SYNTHESIS, AND EVALUATION OF ANTIBACTERIAL POTENTIAL OF HYDRAZONE-TETHERED PYRAZOLE-THIAZOLE DERIVATIVES

Objective: This study includes the investigation of the antimicrobial potential of a series of compounds designed by hybridization of thiazole, hydrazone and pyrazole systems identified as antimicrobial moieties in the literature. The aim was to filter the designed compounds with drugability parameters, synthesize the selected compounds and test their antibacterial potential in silico and in vitro. Material and Method: The drugability properties of synthesized compounds were determined by online scanners and the potential effects of selected compounds on E. coli and S. aureus strains were determined by disk diffusion method. Also, Autodock 4.2 software was used to determine the inhibitory potential of compounds against the dihydrofolate reductase (DHFR) enzyme. Result and Discussion: In our study, among the newly designed hydrazone-linked pyrazole-thiazole compounds, the compounds determined according to their drugability parameters (17a-c) were synthesized with high efficiency. Among the compounds tested for antibacterial activity, Compound 17c formed a zone diameter of 8 mm against E. coli strain and 9 mm against S. aureus strain at a concentration of 80 μg/ml. Also, compound 17c formed a zone diameter of 7 mm against E. coli strain and 8 mm against S. aureus strain at a concentration of 40 μg/ml. Furthermore, the ADMET profiles of the presented compounds indicate that they may have suitable drugability parameters as potential antibacterial agents.

Naphtho[1,2-b][1,4]diazepinedione-Based P2X4 Receptor Antagonists from Structure-Activity Relationship Studies toward PET Tracer Development.

The P2X4 receptor is implicated in various pathological conditions, including neuropathic pain and cancer. This study reports the development of 1,4-naphthodiazepinedione-based P2X4 receptor antagonists aimed at both therapeutic applications and potential use as PET tracers for imaging P2X4 receptor expression in cancer. Structure-activity relationship studies aided by docking studies and molecular dynamics simulations led to a series of compounds with potent P2X4 receptor antagonism, promising in vitro inhibition of interleukin-1β release in THP-1 cells and suitability for radiolabeling with fluorine-18. The most potent compounds were further evaluated for their physicochemical properties, metabolic stability, and in vivo biodistribution using PET imaging in mice. While these antagonists exhibited strong receptor binding and serum stability, rapid in vivo metabolism limited their potential as PET tracers, highlighting the need for further structural optimization. This study advances the understanding of P2X4 receptor antagonism and underscores the challenges in developing effective PET tracers for this target.

Synthesis, Antioxidant, and Antidiabetic Potential of Ferrocenylmethylnucleobase Compounds: In Vitro, In Silico Molecular Docking, DFT Calculation, and Molecular Dynamic Simulations

ABSTRACTThis study presents the synthesis and characterization of a novel series of ferrocenylmethylnucleobase compounds, namely, FcMeAd, FcMeCy, FcMeTh, and (FcMe)₂Ad with promising antioxidant and antidiabetic properties. Spectroscopic techniques confirmed their sandwich‐like geometry, with the nucleobase moiety coordinated to the ferrocene unit. Density functional theory (DFT) optimization revealed alignment with existing crystallographic data and indicated low frontier molecular orbital (FMO) energy gaps, suggesting facile intramolecular charge transfer and potential biological activity. The antidiabetic activity was evaluated in vitro through inhibition assays targeting α‐glucosidase and α‐amylase enzymes, which was supported by in silico molecular docking studies. Among the compounds, FcMeTh exhibited the highest antidiabetic and antioxidant properties due to the presence of carbonyl and amide functionalities, along with an electron‐donating methyl group. Molecular dynamics (MD) simulations confirmed high binding affinity and structural stability of the docked compounds, with strong interactions with the target enzymes, further validating the potential of these compounds as effective inhibitors. Pharmacokinetic and ADMET evaluations indicated their nontoxic, noncarcinogenic nature and suitability for oral administration. The combined in vitro and in silico findings, including the critical insights from MD simulations, suggest that these ferrocenylmethylnucleobase compounds, especially FcMeTh, possess enhanced antioxidant and antidiabetic properties. This highlights their potential as promising therapeutic agents for managing oxidative stress and Type 2 diabetes.

Photocatalytic Direct Borylation of Benzothiazole Heterocycles via a Triplet Activation Strategy.

Boron compounds are widely employed in organic chemistry, pharmaceuticals, and materials science. Among them, borylated heterocycles serve as versatile synthons for the construction of new C-C or C-heteroatom bonds via coupling or radical processes. Such methods for direct C-H borylation reactions are of high synthetic value to reduce the number of synthetic steps and the amount of waste and to improve efficiency. Despite significant advances, the borylation of heterocycles remains an ongoing challenge with great potential for applications in chemical synthesis. Herein, we describe a photocatalytic C-H borylation reaction of five-membered ring heterocycles by employing a stable N-heterocyclic carbene borane as the borylating reagent and a photoredox catalyst. Under green and mild conditions, C-H borylation was achieved on a series of benzo-fused five-membered heterocyclic compounds. Further studies demonstrate the utility of this approach for applications in pharmaceutical and agrochemical research.

Design, Synthesis, and Antibacterial Activity of Novel Sulfone Derivatives Containing a 1,2,4-Triazolo[4,3-a]Pyridine Moiety.

To develop antibacterial agents with a novel mechanism of action, a series of sulfone compounds containing a 1,2,4-triazolo[4,3-a]pyridine were designed and synthesized by progressive molecular structure optimization. The antibacterial activities of some derivatives against the four plant pathogens Xanthomonas oryzae pv. oryzae (Xoo), Xanthomonas oryzae pv. oryzicola (Xoc), Xanthomonas axonopodis pv. citri (Xac), and Pseudomonas syringae pv. actinidiae (Psa) were evaluated. Among them, compound K3 demonstrated significant antibacterial activities against Xoo, Xoc, and Xac, with EC50 values of 1.5, 1.7, and 4.9 mg/L, respectively. In the greenhouse, compound K3 exhibited a protective activity of 44.49% and a curative activity of 42.51% against rice bacterial leaf blight, which notably surpassed the traditional agents thiodiazole-copper (24.65% and 23.35%) and bismerthiazol (34.69% and 30.78%). Furthermore, compound K3 can inhibit the growth of pathogenic bacteria by inhibiting a variety of virulence factors (extracellular polysaccharides, biofilms, and motile and extracellular enzymes.). It also induced the production of reactive oxygen species (ROS) by the pathogens, leading to their death. Transcriptomic analysis revealed that K3 impacts rice biosynthesis, biofilm formation, and metabolic processes, enhancing the plant's self-defense biochemical processes and affecting carbohydrate transport and metabolism to resist pathogen invasion. Therefore, the inhibition of virulence factors as a strategy for controlling difficult-to-treat plant bacterial diseases presents a promising approach to the discovery of novel antibacterial candidates.

Studying the anti-inflammatory activity of a series of nitrogenous heterocyclic compounds and comparison of the obtained data with the results of quantum chemical calculations

Studying the anti-inflammatory activity of a series of nitrogenous heterocyclic compounds and comparison of the obtained data with the results of quantum chemical calculations

Synthesis and in vitro leishmanicidal activity of novel N-arylspermidine derivatives.

This work describes the synthesis and biological evaluation of hitherto unknown N-arylspermidine derivatives 3. Compounds 3 were efficiently prepared from cyclic amidines through a novel synthetic approach comprising alkylation with ω-halonitriles followed by reduction. The cyclic N-arylamidine directs the alkylation to the unsubstituted nitrogen and also provides the N-benzyl group present in the triamine after simultaneous reduction of the resulting quaternary salt 2 and the cyano group. The N-aryl spermidines were tested in Leishmania infantum promastigotes and also in the more challenging form intracellular amastigotes. The compounds toxicity was also assessed in two cell lines, THP-1 and HepG2. In silico physicochemical and ADME predictions were also carried out. Eight out of ten compounds displayed EC50 around 5µM against L. infantum intracellular amastigotes. Among them, derivatives 3c, 3d, and 3h showed potency in the low micromolar range with SI>5 and suitable predicted physicochemical ADME properties. The antileishmanial activity of the compounds would rely on the N-arylspermidine moiety, as assessed by evaluation of related substructures which were inactive. This first series of compounds, among which two derivatives (3b,h) displayed EC50 values comparable to Miltefosine, represent a good starting point for further studies and multiparametric optimization to obtain more potent and selective candidates for the treatment of this neglected tropical disease.

Synthesis, characterization, and biological profiling of novel benzotriazole-thio linked derivatives as promising anti-inflammatory, analgesic, and antibacterial agents

A series of new compounds, Substituted 2-((2H-benzo[d][1,2,3]triazol-2-yl)thio)-N'-(2-oxoindolin-3-ylidene)acetohydrazide (3a-3g), 2-((2H-benzo[d][1,2,3]triazol-2-yl)thio)-N-(2,4'-dioxospiro[indoline-3,2'-thiazolidin]-3'yl)acetamide (4a-4g), and 2'-(((2H-benzo[d][1,2,3]triazol-2-yl)thio)methyl)spiro[indoline-3,5'-thiazolo[4,3-b][1,3,4]oxadiazol]-2-one (5a-5g), were synthesized and checked for their anti-inflammatory, analgesic, and antibacterial activities. Compound 5d proved to be the most potent anti-inflammatory and antibacterial agent. The analgesic activity, however, was maximum in compound 5e. The structural integrity of the synthesized compounds was ascertained using elemental analysis, infrared spectroscopy (IR), and proton nuclear magnetic resonance spectroscopy (¹H NMR).

Antibacterial activity of the structurally novel C-2 amine-substituted analogues based on quinoxaline.

In the current study, we have designed and prepared a series of quinoxaline-based compounds, which were derived from o-phenylenediamine. Among them, compounds 5m-5p displayed good to moderate antibacterial activity with MICs of 4-16 μg mL-1 against S. aureus, 8-32 μg mL-1 against B. subtilis, 8-32 μg mL-1 against MRSA and 4-32 μg mL-1 against E. coli, respectively. Compound 5p, identified as a potent broad-spectrum antibacterial agent, demonstrated the strongest inhibitory effects against a range of bacterial strains and low cytotoxicity, thereby warranting further investigation. Compound 5p not only demonstrated the ability to disperse established bacterial biofilms but also induced a slower development of bacterial resistance compared to norfloxacin. Moreover, bactericidal time-kill kinetic studies revealed that at a high concentration of 3MIC, compound 5p was capable of directly killing MRSA cells. The subsequent postcontact effect (PCE) results showed that the growth rate of viable bacteria (MRSA) was greatly impacted and did not recover in less than 24 hours, even after antibacterial agent 5p was removed. The drug-like properties and ADME prediction exhibited that 5m-5p obeyed Lipinski's rule of five and therefore presumably maintained moderate to good bioavailability and human intestinal absorption rate when administered orally. Mechanistic investigations have elucidated that compound 5p exerted its antibacterial effect by compromising the structural integrity of bacterial cell membranes, resulting in the leakage of intracellular constituents and ultimately causing bacterial demise. Further studies in vivo have demonstrated that 5p exhibited potent antibacterial efficacy against MRSA in murine corneal infection models, particularly at elevated concentrations. The current dataset has also been meticulously analyzed to delineate the structure-activity relationships (SARs) of the synthesized compounds.

Introducing dibenzocyclooctatetraene into actinide chemistry: isolation of rare trivalent uranium sandwich complexes

The π-expanded dibenzocyclooctatetraene ligand was employed to access an unprecedented series of actinide sandwich compounds. The trivalent uranium complexes were studied by crystallography, spectroscopy, and computations.

Direct synthesis of enone-hydrazones under solvent free and additive free conditions.

A series of enone-hydrazones were synthesized through the reaction of enaminones with hydrazones under solvent-free, additive-free, and metal-catalyst-free conditions. The target products were obtained in high yields, with outstanding group tolerance, stereoselectivity, and chemical selectivity. In this work, a series of novel enaminone skeleton compounds were synthesized, and deuteration experiments showed that enone-hydrazones have different properties from traditional electron-deficient enketones.

C2O42--templated [Ln2Ni] heterometallic compounds for enhanced magnetocaloric effects at low fields.

In the history of magnetochemistry development, lanthanide-transition (3d-4f) heterometallic compounds have been considered an attractive candidate for magnetic refrigerants. Herein, a series of heterometallic compounds have been designed and templated by C2O42- anions, that is, {[Ln2Ni(L)(C2O4)2(H2O)2]·H2O}n [Ln = GdIII (abbr. Gd2Ni) = SmIII (abbr. Sm2Ni) = TbIII (abbr. Tb2Ni), H2C2O4 = oxalic acid; H4L = ethylene diamine tetraacetic acid]. The structural analysis reveals that Ln2Ni compounds feature a C2O42--templated wavy-shaped two-dimensional layer. Then, adjacent wavy-shaped layers are further aggregated by C2O42- anions, resulting in an innovative three-dimensional metal-organic framework. Magnetization analysis revealed that Gd2Ni exhibits a favorable -ΔSmaxm of 38.0 J kg-1 K-1 at 2.0 K for 7.0 T. In addition, the effect of weak ferromagnetic exchange interactions in Gd2Ni contributes to a decent magnetocaloric effect at low fields (-ΔSm = 25.1 J kg-1 K-1 at 2.0 T for 2.0 K and -ΔSm = 14.5 J kg-1 K-1 at 1.0 T for 2.0 K), outperforming most 3d-4f heterometallic compounds reported previously.

Active learning driven prioritisation of compounds from on-demand libraries targeting the SARS-CoV-2 main protease.

FEgrow is an open-source software package for building congeneric series of compounds in protein binding pockets. For a given ligand core and receptor structure, it employs hybrid machine learning/molecular mechanics potential energy functions to optimise the bioactive conformers of supplied linkers and functional groups. Here, we introduce significant new functionality to automate, parallelise and accelerate the building and scoring of compound suggestions, such that it can be used for automated de novo design. We interface the workflow with active learning to improve the efficiency of searching the combinatorial space of possible linkers and functional groups, make use of interactions formed by crystallographic fragments in scoring compound designs, and introduce the option to seed the chemical space with molecules available from on-demand chemical libraries. As a test case, we target the main protease (Mpro) of SARS-CoV-2, identifying several small molecules with high similarity to molecules discovered by the COVID moonshot effort, using only structural information from a fragment screen in a fully automated fashion. Finally, we order and test 19 compound designs, of which three show weak activity in a fluorescence-based Mpro assay, but work is needed to further optimise the prioritisation of compounds for purchase. The FEgrow package and full tutorials demonstrating the active learning workflow are available at https://github.com/cole-group/FEgrow.

Synthesis of Novel Benzothiazole-Profen Hybrid Amides as Potential NSAID Candidates.

Herein, we report the synthesis of a series of new compounds by combining 2-aminobenzothiazole with various profens. The compounds were characterized using techniques such as 1H- and 13C-NMR, FT-IR spectrometry, and high-resolution mass spectrometry (HRMS), with detailed HRMS analysis conducted for each molecule. Their biological activities were tested in vitro, revealing significant anti-inflammatory and antioxidant effects, comparable to those of standard reference compounds. Lipophilicity was experimentally determined through partition coefficient (RM) measurements. To understand their binding affinity, molecular docking studies were perfsormed to analyze interactions with human serum albumin (HSA). The stability of these predicted complexes was further evaluated through molecular dynamics simulations. The results highlight the compounds' promising biological activity and strong affinity for HSA. The new hybrid molecule between 2-ABT and ketoprofen 3b demonstrates significant promise based on the experimental data and is further supported by in silico calculations. Compound 3b exhibits the best hydrogen peroxide scavenging activity among the tested compounds, with an IC50 of 60.24 μg/mL. Furthermore, 3b also displays superior anti-inflammatory activity, with an IC50 of 54.64 μg/mL, making it more effective than the standard ibuprofen (76.05 μg/mL).

Design, synthesis and antimicrobial activity evaluation of novel Marinoquinoline derivatives against phytopathogenic bacteria.

Plant diseases caused by plant pathogens pose a great threat to biodiversity and food security, and the problem of drug resistance caused by traditional antibiotics and fungicides is becoming more and more serious. It is urgent to develop new antibacterial molecules with low toxicity and high efficiency. Marinoquinoline A is an alkaloid isolated from marine actinomycetes and has a variety of pharmacological activities. In this study, a series of compounds were designed and synthesized by fragment fusion strategy inspired by Marinoquinoline, and their antibacterial activities were evaluated, and the structure-activity relationship was discussed. Among these derivatives, ZM-9 showed the most significant antibacterial activity against Xanthomonas oryzae (Xoo) with MIC of 1.56 μg mL-1, while ZN-8 showed the best antibacterial activity against Xanthomonas axonopodis pv. Citri (Xac) with MIC of 0.78 μg mL-1, both of which were better than Thiodiazole copper. The results of in vivo antibacterial activity test showed that 200 μg mL-1 ZM-9 and ZN-8 had significant control effects on rice and citrus. The biochemical experiments showed that ZM-9 and ZN-8 could inhibit the secretion of extracellular polysaccharides, destroy the biofilm integrity of the pathogens, increase permeability, and cause oxidative stress damage. In summary, most of the chemical entities inspired by Marinoquinoline have shown good antibacterial activity. In particular, compounds ZM-9 and ZN-8 can be used as lead compounds for further structural optimization to develop new antibacterial agents. © 2024 Society of Chemical Industry.