Compound A14 Research Articles

Novel Insecticidal Benzo[4,5]imidazo[1,2-b]pyrazole Derivatives Identified through Ring-Closure Scaffold Hopping on Fipronil.

A series of innovative benzo[4,5]imidazo[1,2-b]pyrazole scaffold containing compounds were rationally designed through a ring-closure scaffold hopping strategy and synthetized with an intermediate derivatization approach. Physicochemical properties analysis indicated the potential pesticide-likeness of the target compounds. The optimal target compound A14 showed relatively good insecticidal activity against P. xylostella, with an LC50 value of 37.58 mg/L, and demonstrated lower acute fish toxicity compared to fipronil. Docking binding mode analysis demonstrated that compound A14 bound to GABAR through a H-bond between the amide group and the residue of 6'Thr. The differences in binding modes between benzo[4,5]imidazo[1,2-b]pyrazole target compounds and fipronil may be a key factor for the reduced insecticidal activities. The elucidated binding mode and SAR profile lay a foundation for the further structural optimization of insecticidal benzo[4,5]imidazo[1,2-b]pyrazole derivatives.

Local Scaffold Diversity-Contributed Generator for Discovering Potential NLRP3 Inhibitors.

Deep generative models have become crucial tools in de novo drug design. In current models for multiobjective optimization in molecular generation, the scaffold diversity is limited when multiple constraints are introduced. To enhance scaffold diversity, we herein propose a local scaffold diversity-contributed generator (LSDC), which can be utilized to generate diverse lead compounds capable of satisfying multiple constraints. Compared to the state-of-the-art methods, molecules generated by LSDC exhibit greater diversity when applied to the generation of inhibitors targeting the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3). We present 12 molecules, some of which feature previously unreported scaffolds, and demonstrate their reasonable docking binding modes. Consequently, the modification of selected scaffolds and subsequent bioactivity evaluation lead to the discovery of two potent NLRP3 inhibitors, A22 and A14, with IC50 values of 38.1 nM and 44.43 nM, respectively. And the oral bioavailability of compound A14 is very high (F is 83.09% in mice). This work contributes to the discovery of novel NLRP3 inhibitors and provides a reference for integrating AI-based generation with wet experiments.

Design, synthesis, antifungal activity and molecular docking of novel pyrazole-4-carboxamides containing tertiary alcohol and difluoromethyl moiety as potential succinate dehydrogenase inhibitors.

Resistance problems with the long-term and frequent use of existing fungicides, and the lack of structure diversity of traditional pyrazole-4-carboxamide succinate dehydrogenase inhibitors, it is highly required to design and develop new fungicides to address the resistance issue. Different from previous pyrazole-4-carboxamide succinate dehydrogenase inhibitors by breaking the norm of difluoromethyl at the C-3 position of pyrazole and introducing a tertiary alcohol group at the C-3 position, 27 novel pyrazole-4-carboxamide derivatives were designed, synthesized and characterized by proton (1 H) nuclear magnetic resonance (NMR), carbon-13 (13 C) NMR, fluorine-19 (19 F) NMR and high-resolution electrospray ionization mass spectrometry (HR-ESI-MS). The crystal structures of compounds A14 and C5 were analyzed by single crystal X-ray diffraction. Their in vitro antifungal activities were evaluated against phytopathogen Fusarium graminearum, Botrytis cinerea, Phytophthora capsica, Sclerotinia sclerotiorum, Thanatephorus cucumeris. The results displayed that most of them exhibited significant antifungal activities against S. sclerotiorum at 50 mg/L, the half maximal effective concentration (EC50 ) data of A8 and A14 were 3.96 and 2.52 mg/L, respectively. Their in vivo antifungal activities were evaluated against Pseudoperonospora cubensis, Puccinia sorghi Schw, Colletotrichum gloeosporioides, F. graminearum, Erysiphe graminis, Thanatephorus cucumeris, the control efficacies of A6, B3, C3, and C6 against E. graminis reached 100% at a concentration of 400 mg/L. The molecular docking results showed that the binding mode of the target compounds containing tertiary alcohols were similar to that of fluxapyroxad in succinate dehydrogenase. In addition, tertiary alcohols were involved in the formation of hydrogen bonds. The excellent in vitro and in vivo inhibitory activities of novel pyrazole-4-carboxamide derivatives against succinate dehydrogenase were reported for the first time, and they could be used as the potential lead compounds. © 2023 Society of Chemical Industry.

Design and Synthesis of Novel Chalcone Derivatives: Anti-Breast Cancer Activity Evaluation and Docking Study.

Chalcone is a common simple fragment of natural products with anticancer activity. In a previous study, the research group discovered a series of chalcone derivatives with stronger anticancer activities. To find better anticancer drugs, novel chalcone derivatives A1-A14, B1-B14 have continuously been designed and synthesized. The antiproliferative activity of these compounds against breast cancer cells (MCF-7) was investigated by the Cell Counting Kit-8 (CCK-8) method with 5-fluorouracil (5-Fu) as the control drug. The results showed that compound A14 exhibited excellent antiproliferative ability compared to the control drug 5-Fu. Scratch experiments and cloning experiments further confirmed that compound A14 could inhibit the proliferation and colony formation activity of MCF-7 cells. In addition, molecular docking primarily explains the interaction between compound and protein. These results suggested that compound A14 could be a promising chalcone derivative for further anti-breast cancer research.

1,3,4-Oxadiazole Derivatives as Plant Activators for Controlling Plant Viral Diseases: Preparation and Assessment of the Effect of Auxiliaries.

Plant viral diseases cause the loss of millions of dollars to agriculture around the world annually. Therefore, the development of highly efficient, ultra-low-dosage agrochemicals is desirable for protecting the health of crops and ensuring food security. Herein, a series of 1,3,4-oxadiazole derivatives bearing an isopropanol amine moiety was prepared, and the inhibitory activity against tobacco mosaic virus (TMV) was assessed. Notably, compound A14 exhibited excellent anti-TMV protective activity with an EC50 value of 137.7 mg L-1, which was superior to that of ribavirin (590.0 mg L-1) and ningnanmycin (248.2 mg L-1). Moreover, the anti-TMV activity of some compounds could be further enhanced (by up to 5-30%) through supplementation with 0.1% auxiliaries. Biochemical assays suggested that compound A14 could suppress the biosynthesis of TMV and induce the plant's defense response. Given these merits, designed compounds had outstanding bioactivities and unusual action mechanisms and were promising candidates for controlling plant viral diseases.

Computational Bioactivity Analysis and Bioisosteric Investigation of the Approved Breast Cancer Drugs Proposed New Design Drug Compounds: Increased Bioactivity Coming with Silicon and Boron

Background: The breast cancer takes the first place among women cancer diagnosed worldwide. Objective: Based on the preferential multi-targeted approach on cancer therapy, we, in this study, aimed to design in silico drug candidates possessing multi-targeted bioactivity to cope with multi-drug resistance using the known drug structures, molecular modeling, and ADME parameters. Materials and Methods: We first evaluated the bioactivity score of the approved breast cancer drugs across the top-three drug targets GPCR, kinase, and nuclear receptors and calculated their physicochemical properties to see their drug-likeness profiles. Among 29 approved drugs, Aromasin and Capecitabine showed the broadest bioactivity across the targets listed. By using molecular modeling and bioisosteric modifications, and applying two filtering approaches, we investigated thirty-one analogues of Aromasin and Capecitabine. Results : Software prediction resulted in that the compounds A14, C4, and C13 replaced with B(OH)2 and/or Si(CH3)3 showed a broader spectrum of biological activity with a multi-targeted manner than even the approved analogs. Conclusion: The interesting point of these new design molecules is to have either silicon and/or boron incorporation. The increased bioactivity effect of Silicon and Boron incorporation is also seen in the recently approved drug list of FDA and in clinical trials ongoing. Our new design boron and silicon-based molecules appeared to be promising candidates for breast cancer treatment to be tested in vitro, in vivo, and in the clinic for further pharmacological investigations.

Exploring Aurone Derivatives as Potential Human Pancreatic Lipase Inhibitors through Molecular Docking and Molecular Dynamics Simulations.

Inhibition of human pancreatic lipase, a crucial enzyme in dietary fat digestion and absorption, is a potent therapeutic approach for obesity treatment. In this study, human pancreatic lipase inhibitory activity of aurone derivatives was explored by molecular modeling approaches. The target protein was human pancreatic lipase (PDB ID: 1LPB). The 3D structures of 82 published bioactive aurone derivatives were docked successfully into the protein catalytic active site, using AutoDock Vina 1.5.7.rc1. Of them, 62 compounds interacted with the key residues of catalytic trial Ser152-Asp176-His263. The top hit compound (A14), with a docking score of −10.6 kcal⋅mol−1, was subsequently submitted to molecular dynamics simulations, using GROMACS 2018.01. Molecular dynamics simulation results showed that A14 formed a stable complex with 1LPB protein via hydrogen bonds with important residues in regulating enzyme activity (Ser152 and Phe77). Compound A14 showed high potency for further studies, such as the synthesis, in vitro and in vivo tests for pancreatic lipase inhibitory activity.

Synthesis of Chalcone Derivatives: Inducing Apoptosis of HepG2 Cells via Regulating Reactive Oxygen Species and Mitochondrial Pathway.

Chalcone derivatives, as a hot research field, exhibit a variety of physiological bioactivities and target multiple biological receptors. Based on the skeleton of (E)-1,3-diphenyl-2-propene-1-one, 14 chalcone derivatives were designed and synthesized, and evaluated as the antitumor candidates agents against four human cancer cell lines (A549, Hela, HepG2, and HL-60) as well as one normal cell line (WI-38). Among the title compounds, compound a14 showed better inhibitory activity against HepG2 cells (IC50 = 38.33 µM) and had relatively weak cytotoxicity towards normal cells WI-38 (IC50 = 121.29 µM). In this study, apoptosis, cycle arrest, assessment of reactive oxygen species (ROS) level, and measurement of mitochondrial membrane potential were adopted to explore the inhibitory mechanism of a14 towards HepG2. Compound a14 could effectively block the division of HepG2 cell lines in the G2/M phase and robustly induced generation of ROS, demonstrating that the generation of ROS induced by a14 was the main reason for resulting in the apoptosis of HepG2 cells. Moreover, the mitochondrial membrane potential (MMP) of HepG2 cells treated with a14 was significantly decreased, which was closely related to the enhanced ROS level. Furthermore, based on Western blot experiment, cell apoptosis induced by a14 also involved the expression of B-cell lymphoma-2 (Bcl-2) family and Caspase 3 protein. In summary, compound a14 could contribute to the apoptosis of HepG2 cells through regulating ROS-mitochondrial pathway, which provides valuable hints for the discovery of novel anti-tumor drug candidates.

Discovery of 1,3,4-oxadiazol-2-one-containing benzamide derivatives targeting FtsZ as highly potent agents of killing a variety of MDR bacteria strains

The spread of infections caused by multidrug-resistant (MDR) pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA), has created a need for new antibiotics with novel mechanisms of action. The bacterial division protein FtsZ has been identified as a novel drug target that can be exploited clinically. As part of an ongoing effort to develop FtsZ-targeting antibacterial agents, we describe herein the design, synthesis and bioactivity of six series of novel 1,3,4-oxadiazol-2-one-containing, 1,2,4-triazol-3-one-containing and pyrazolin-5-one-containing benzamide derivatives. Among them, compound A14 was found to be the most potent antibacterial agent, much better than clinical drugs such as ciprofloxacin, linezolid and erythromycin against all the tested gram-positive strains, particularly methicillin-resistant, penicillin-resistant and clinical isolated S. aureus. Subsequent studies on biological activities and docking analyses proved that A14 functioned as an effective compound targeting FtsZ. Preliminary SAR indicated a general direction for further optimization of these novel analogues. Taken together, this research provides a promising chemotype for developing newer FtsZ-targeting bactericidal agents.

Design, Synthesis and Pharmacological Evaluation of Novel Hsp90N-terminal Inhibitors Without Induction of Heat Shock Response.

Heat shock protein 90 (Hsp90) is a potential oncogenic target. However, Hsp90 inhibitors in clinical trial induce heat shock response, resulting in drug resistance and inefficiency. In this study, we designed and synthesized a series of novel triazine derivatives (A1‐26, B1‐13, C1‐23) as Hsp90 inhibitors. Compound A14 directly bound to Hsp90 in a different manner from traditional Hsp90 inhibitors, and degraded client proteins, but did not induce the concomitant activation of Hsp72. Importantly, A14 exhibited the most potent anti‐proliferation ability by inducing autophagy, with the IC50 values of 0.1 μM and 0.4 μM in A549 and SK‐BR‐3 cell lines, respectively. The in vivo study demonstrated that A14 could induce autophagy and degrade Hsp90 client proteins in tumor tissues, and exhibit anti‐tumor activity in A549 lung cancer xenografts. Therefore, the compound A14 with potent antitumor activity and unique pharmacological characteristics is a novel Hsp90 inhibitor for developing anticancer agent without heat shock response.

Synthesis and Antibacterial Activity of Calycanthaceous Alkaloid Derivatives

A series of 45 calycanthaceous alkaloid derivatives with the tetrahydropyrroloindole core structure was synthesized from tryptophan in good yields. The synthesized compounds were evaluated against five strains of bacteria (Bacillus cereus, Bacillus subtilis, Staphylococcus aureus, Escherichia coil, Ralstonia solanacearum, and Pseudomonas aeruginosa). The bioassays indicated that among the synthesized compounds, compounds b3 and b4 exhibited a high degree of activity towards Gram positive B. subtilis. Compounds a14 and a18 displayed a high degree of activity towards R. solanacearum. These results will pave the way for further design, structural modification, and development of calycanthaceous alkaloids as antibacterial agents.

Design and optimization of N-acylhydrazone pyrimidine derivatives as E. coli PDHc E1 inhibitors: Structure-activity relationship analysis, biological evaluation and molecular docking study

By targeting the thiamin diphosphate (ThDP) binding site of Escherichia coli (E. coli) pyruvate dehydrogenase multienzyme complex E1 (PDHc E1), a series of novel ‘open-chain’ classes of ThDP analogs A, B, and C with N-acylhydrazone moieties was designed and synthesized to explore their activities against E. coli PHDc E1 in vitro and their inhibitory activity against microbial diseases were further evaluated in vivo. As a result, A1–23 exhibited moderate to potent inhibitory activities against E. coli PDHc E1 (IC50=0.15–23.55μM). The potent inhibitors A13, A14, A15, C2, had strong inhibitory activities with IC50 values of 0.60, 0.15, 0.39 and 0.34μM against E. coli PDHc E1 and with good enzyme-selective inhibition between microorganisms and mammals. Especially, the most powerful inhibitor A14 could 99.37% control Xanthimonas oryzae pv. Oryzae. Furthermore, the binding features of compound A14 within E. coli PDHc E1 were investigated to provide useful insights for the further construction of new inhibitor by molecular docking, site-directed mutagenesis, and enzymatic assays. The results indicated that A14 had most powerful inhibition against E. coli PDHc E1 due to the establishment of stronger interaction with Glu571, Met194, Glu522, Leu264 and Phe602 at active site of E.coli PDHc E1. It could be used as a lead compound for further optimization, and may have potential as a new microbicide.

Design, synthesis and inhibitory activity against human dihydroorotate dehydrogenase (hDHODH) of 1,3-benzoazole derivatives bearing amide units

A series of 1,3-benzoazole derivatives possessing amide moieties were designed, synthesized and evaluated as inhibitors against human dihydroorotate dehydrogenase (hDHODH). Compounds A11, A14 and A26 exhibited good to excellent activities against hDHODH at the concentration of 10μM. In particular, compound A14 displayed an IC50 value of 0.178μM with 2-fold preference over A771726. The result implied that a proper degree of steric size and electron density of the C-6 amide moiety was necessary to retain the inhibitory activity of the synthesized compounds.