Compounds 4g Research Articles

Synthesis, molecular modelling and antibacterial activity of 4-aryl-thiosemicarbazides

Abstract N-Substituted phenyl/cyclohexyl-2-(pyridine-4-carbonyl) hydrazine-1-carbothioamides (2a–r) were synthesized, characterized by spectral and analytical data. The compounds were evaluated for antibacterial activity by the disc diffusion method. Most of the compounds showed activity against Gram-positive bacteria. Compound 2h with 4-Sulfapyrimidine phenyl substitution was found to be the most promising candidate, active against Gram-positive and methicillin-resistant Staphylococcus aureus (MRSA) strains with minimum inhibitory concentration (MIC) of (2–7 μg/mL). From the docking study, we predicted that compounds (2r, 2g, 2h, 2o, 2p and 2e) possess better antibacterial activity by having a good binding affinity with target protein and they could be used as potential drugs as antimicrobials. Amongst all the docked compounds, the compound 2h presented near binding affinity & interaction docking score with DNA gyrase enzymes with reference to ciprofloxacin.

Discovery of 6,7-dihydro-5H-pyrrolo[3,4-d] pyrimidine derivatives as a new class of ATR inhibitors

Ataxia telangiectasia and Rad3-related (ATR) kinase is a key regulating protein within the DNA damage response (DDR), responsible for sensing replication stress (RS), and has been considered as a potential target for cancer therapy. Herein, we report the discovery of a series of 6,7-dihydro-5H-pyrrolo[3,4-d]-pyrimidine derivatives as a new class of ATR inhibitors. Among them, compound 5g exhibits an IC50 value of 0.007 μM against ATR kinase. In vitro, 5g displays good anti-tumor activity and could significantly reduce the phosphorylation level of ATR and its downstream signaling protein. Overall, this study provides a promising lead compound for subsequent drug discovery targeting ATR kinase.

Synthesis, antiproliferative activity, molecular docking studies of hydrazone functionalised thioparabanic acid and rhodanine analogues

Twenty new samples of hydrazone functionalized thioparabanic acid and rhodanine analogues were prepared by reacting a mixture of acyl methylene substituted rhodanine and hydantoin compounds with hydrazine and acyl hydrazine derivatives in good yields (53–89%). The cytotoxic effect of newly synthesized compounds 3a–g, 4a–m was evaluated on the human colon cancer cell line (DLD-1) and human liver cancer cell line (HepG2) by comparison with cisplatin as a positive control drug. Two of the molecules (3f [2-hydroxy-N'-((Z)-1-(5-oxo-2-thioxoimidazolidin-4-ylidene)propan-2-ylidene)benzohydrazide], 3g [(5Z)-5-(2-(2-(3,4-dimethylphenyl)hydrazono)propylidene)-2-thioxoimidazolidin-4-one]) showed significant inhibition on cancer cells. Particularly, one of the molecules (3f) was found to be more effective than cisplatine with IC50 values of 4.71 µM and 2.79 µM for DLD-1, HepG2, respectively. Selectivity of the most active five compounds was screened against a healthy human cell line (Wl-38). Compounds 3g and 4l, which are, respectively, thioparabanic acid and rhodanine derivatives, demonstrated good selectivity, and it was observed that the toxic effect of these compounds was more on colon and liver cancer cells than on normal lung cells. The molecular docking evaluations for active 3f and 3g molecules on the liver and colon cancer were conducted to support the obtained experimental results with the in silico AutoDock Vina program and the results were shown to support each other.

Design and synthesis of novel pyrazolopyrimidine-based derivatives as reversible BTK inhibitors with potent antiproliferative activity in mantle cell lymphoma

Development of Bruton’s tyrosine kinase (BTK) inhibitors is of great value and significance in the treatment of B-cell malignancies and autoimmune diseases. Herein, a novel class of pyrazolopyrimidine-based BTK inhibitors were designed and evaluated in mantle cell lymphoma (MCL) cell lines. We demonstrated that target compounds had made great progress in improvement of antiproliferative activity compared to lead compound. Compounds 13c, 13g, 13h, 13l, 13n and 13o demonstrated effectively antiproliferative activity in MCL cells lines with single-digit micromolar potency. Furthermore, compound 13l specifically disturbed mitochondrial membrane potential and increased reactive oxygen species level in Z138 cells in a dose-dependent manner. 13l induced cell apoptosis through the caspase 3- mediated apoptotic pathway in Z138 cells. Overall, this study provides valuable lead compounds for developing antitumor agents. Graphical abstract

Design and synthesis of new 2-oxoquinoxalinyl-1,2,4-triazoles as antitumor VEGFR-2 inhibitors

VEGFR-2 is a tyrosine kinase receptor for VEGFs that play a central role in tumor angiogenesis. The inhibition of the tyrosine kinase domain of VEGFR-2 has become an attractive therapeutic strategy in recent years for inhibiting tumor growth. In this study, a series of novel 2-oxoquinoxalinyl-1,2,4-triazoles were designed and synthesized as potential antitumor agents and VEGFR-2 inhibitors. Eight compounds in this series showed high growth inhibition against MCF-7 with GI50 ranging from 1.6 to 8.06 µM compared to staurosporine (GI50 = 8.39 µM) and sorafenib (GI50 = 11.20 µM). In addition, the results of the in vitro tyrosine kinase inhibition of VEGFR-2 revealed that most of the compounds possessed IC50 values in the sub-micromolar range. Compound 6g (IC50 = 0.037 µM) showed more potent VEGFR-2 inhibitory activity than sorafenib (IC50 = 0.045 µM). Furthermore, docking studies of the compounds with tyrosine kinase domain of VEGFR-2 (PDB ID: 4ASD) were performed. According to the results, 6g exhibited hydrogen bonding interactions with Glu885, Asp1046 and Cys919 amino acids in a similar way to sorafenib. Finally, physicochemical predictions of target compounds were examined in silico. The results revealed that all the compounds possessed promising drug-likeness profile.

Synthesis, Biological Evaluation, 2D-QSAR, and Molecular Simulation Studies of Dihydropyrimidinone Derivatives as Alkaline Phosphatase Inhibitors.

The presence of alkaline phosphatases has been observed in several species and has been known to play a crucial role in various biological functions. Higher expressions of alkaline phosphatase have been found in several multifactorial disorders and cancer patients, which has led it to be an interesting target for drug discovery. A strong structural similarity exists between intestinal alkaline phosphatases (IAPs) and tissue-nonspecific alkaline phosphatases (TNAPs), which has led to the discovery of only a few selective inhibitors. Therefore, a series of 22 derivatives of 6-(chloromethyl)-4-(4-hydroxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1) and ethyl 6-(chloromethyl)-4-(2-hydroxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (2) were synthesized to evaluate the anticancer potential of these compounds against breast cancer. The compounds were characterized through spectral and elemental analyses. The inhibitory effect of dihydropyrimidinone derivatives on alkaline phosphatases was evaluated using the calf alkaline phosphatase assay. The antioxidant activity of these compounds was performed to study the radical scavenging effect. In silico molecular docking and molecular dynamic simulations were performed to elucidate the binding mode of active compounds. Moreover, the two-dimensional qualitative-structure–activity relationship (2D-QSAR) was performed to study the structural requirements for enzyme inhibition. The calf alkaline phosphatase inhibitory assay revealed significant inhibition of the enzyme by compound 4d with IC50 1.27 μM at 0.1 mM concentration as compared to standard KH2PO4 having IC50 2.80 μM. The compounds 4f, 4e, and 4i also showed very good inhibition with IC50 values of 2.502, 2.943, and 2.132 μM, respectively, at the same concentration. The antioxidant assay revealed efficient radical scavenging activity of compounds 4f, 4e, and 4g at 100 μg/mL with IC50 values of 0.48, 0.61, and 0.75 μg/mL, respectively. The molecular docking and simulation studies revealed efficient binding of active compounds in the active binding site of the target enzyme. The final QSAR equation revealed good predictivity and statistical validation having R2 = 0.958 and Q2 = 0.903, respectively, for the generated model. The compound 4d showed the highest inhibitory activity with stable binding modes acting as a future lead for identifying alkaline phosphatase inhibitors. The molecular simulations suggested the stable binding of this compound, and the QSAR studies revealed the importance of autocorrelated descriptors in the inhibition of alkaline phosphatase. The investigated compounds may serve as potential pharmacophores for potent and selective alkaline phosphatase inhibitors. We intend to further investigate the biological activities of these compounds as alkaline phosphatase inhibitors.

Synthesis and antitumor activity of novel silibinin and 2,3-dehydrosilybin derivatives with carbamate groups.

A novel series of silibinin and 2,3-dehydrosilybin derivatives bearing carbamate groups were designed, synthesized and their in vitro anticancer activities were screened against human cancer cell lines including MCF-7, NCI-H1299, HepG2 and HT29 by CCK-8 assay. The results showed that most of the compounds significantly suppressed the proliferation of tested cancer cells. Among them, compounds 2h, 3h and 3f demonstrated markedly higher antiproliferative activity on MCF-7 cells with IC50 values of 2.08, 5.54 and 6.84 µM, respectively. Compounds 3e, 3g and 2g displayed better cytotoxic activity against NCI-H1299 cells with IC50 values of 8.07, 8.45 and 9.09 µM, respectively. Compounds 3g, 3c and 3h exhibited a promising inhibitory effect against HepG2 cells with IC50 values of 8.88, 9.47 and 9.99 µM, respectively. Compounds 3e, 2e and 3c revealed effective biological potency on HT29 cells with IC50 values of 6.27, 9.13 and 9.32 µM, respectively. In addition, the outcomes of the docking studies between compounds 2f, 2h, 3e, 3g and Hsp90 receptor (PDB ID: 4AWO) suggest the possible mechanism of inhibition against MCF-7 cell lines. Graphical abstract

Synthesis and evaluation of 6-Fluoro benzothiazole substituted quinazolinones

The present work was hypothesized to synthesize Benzothiazole substituted diethyl amino Quinazolinone derivatives and evaluate their antimicrobial activity. Quinazolinones were synthesized from condensation of 2-amino benzothiazole, anthranilic acid and acetic anhydride further followed by condensation with formaldehyde and diethyl amine. Antimicrobial activity was evaluated by agar disc diffusion using organisms and anti-inflammatory and antioxidant activies were studied using albumin denaturation and hydrogen peroxide radical scavenging methods. The structures of the synthesized Quinazolinone derivatives were confirmed by spectral analysis, such as IR, H-NMR and among the derivatives screened, the compounds 4d, 4f 4g, 4h have appreciable antimicrobial activity compared to standards. The compounds (4a-4h) have least anti-inflammatory activity while compound 4g have significant antioxidant activity as that of positive control.

Benzothiazole sulfonate derivatives bearing azomethine: Synthesis, characterization, enzyme inhibition, and molecular docking study

Enzyme inhibition is one of the most applied ways to find new diagnostic facilities for the prevention and treatment of many health problems. Tyrosinase and pancreatic lipase inhibitions have been used for the treatment of skin pigmentation problems and obesity, respectively. This study mainly focused to evaluate the enzyme inhibitions of the newly synthesized sulfonate derivatives (3a-3i) for tyrosinase and pancreatic lipase. The structural characterizations of the 2-(((5-methylbenzo[d]thiazol-2-yl)imino)methyl)phenyl sulfonate derivatives were performed by 1H NMR, 13C NMR, and HR-MS analyses. According to the in vitro enzyme inhibition methods, compound 3e had the highest tyrosinase inhibitory activity (46.9 ± 3.6 µM IC50 value). On the other hand, the effective pancreatic lipase inhibitory activities of the compounds 3f, 3e, and 3g were determined from their low IC50 values 58.3 ± 6.7 µM, 59.5 ± 13.8 µM, and 64.8 ± 6.3 µM, respectively. Molecular docking studies were also conducted for the synthesized compounds with tyrosinase and pancreatic lipase enzymes separately. Finally, the ADME studies were carried out to determine the pharmacokinetics, drug similarities, and medicinal properties of the target compounds..

Bioefficacy evaluation of ferrocenyl chalcones against Meloidogyne incognita and Sclerotium rolfsii infestation in tomato

The present study reports, bioefficacy evaluation of effective compounds against Meloidogyne incognita and Sclerotium rolfsii in pot cultured tomato. The identified five most effective compounds, i.e. (2E)-1-(4-Methylphenyl)-3-ferrocenyl-prop-2-en-1-one (6g), (2E)-1-(4-Methoxyphenyl)-3-ferrocenyl-prop-2-en-1-one (6h), (2E)-1-(3-Bromophenyl)-3-ferrocenyl-prop-2-en-1-one (6j), (2E)-1-(2,4-Dichlorophenyl)-3-ferrocenyl-prop-2-en-1-one (6k) and (2E)-1-(3,5-Dichloro-2-hydroxyphenyl)-3-ferrocenyl-prop-2-en-1-one (6p) along with Carbofuran 3G as positive control were tested at 20, 40 and 80 ppm by soil drenching and root dipping methods. The study revealed that all plant growth parameters were positively influenced by these compounds. The presence of an electron releasing group positively influenced the efficacy, and the activity was highest in compounds 6g and 6h at 80 ppm. Based on in vitro results against S. rolfsii, (2E)-1-Ferrocenyl-3-(4-bromophenyl)-prop-2-en-1-one (3b), (2E)-1-Ferrocenyl-3-(2,6-dichlorophenyl)-prop-2-en-1-one (3o) and (2E)-1-(5-Chloro-2-hydroxyphenyl)-3-ferrocenyl-prop-2-en-1-one (6o) along with Tebuconazole 25.9% EC and Hexaconazole 5% SC as positive control were evaluated. The shoot length was found to be highest (24.50 cm) in plants treated with 3b followed by 3o and 6o at 1000 ppm. The percent disease incidence was significantly decreased as compared to control. The percent disease incidence was found to be minimum in plants treated with 3b at 1000 ppm. However, root dipping was not as effective as soil drenching. Therefore, ferrocenyl chalcone derivatives proved to be of great fungicidal and nematicidal potential opening new opportunities for expanding their effectiveness as new pest control agents.

Synthesis, crystallographic study, molecular docking, ADMET, DFT and biological evaluation of new series of aurone derivatives as anti-leishmanial agents

A new series of aurone derivatives (4a-l) was synthesized and their structures were established on the basis of IR, NMR, mass spectra and elemental analysis. In addition, the identity of the representative compound 4g was successfully characterized with the aid of X-ray crystallography. All the synthesised compounds were docked in the binding pocket of Leishmania L-arginine amidinohydrolase enzyme (PDB ID: 5HJA). Docking score and molecular interaction studies revealed a good picture of compounds’ affinity and fitting inside the binding pocket of enzyme. In silico ADME, toxicity and DFT studies were also performed for the compound 4g, having highest docking score. The compound did not violate Lipinski's rule of five. Results showed good intestinal absorption and human serum binding. Compound was also found non-carcinogenic in acute and chronic rat and mice model studies, predicted using Maestro 9.6 software. All the derivatives were tested for anti-leishmanial activity against Leishmania donovani (L. donovani) promastigotes. Compound 4g exhibited more than 90 percent inhibition (IC50 4.97 ± 0.856 µM) in L. donovani promastigotes inhibition assay and was further evaluated for axenic amastigote study, changes in the cellular morphology and cytotoxicity. Compound 4g demonstrated better anti-leishmanial activity and lesser cytotoxicity as compared to standard drug miltefosine.

Bis-(N-aminoethylethanolamine)-Copper(II) nanocatalysis (AEEA-Cu(II)-NPs) meditated to synthesis a series of 2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide derivatives: Characterization of theoretical, computational and evaluation of molecular docking, and cytotoxicity activities

In this work, bis-(N-aminoethylethanolamine)-Copper (II) nano (AEEA-Cu(II)-NPs) catalysis was synthesized and used as a catalyst in Biginelli reactions. Synthesized nanocatalysis was characterized by UV, FT-IR, XRD, SEM, and particle size distribution analysis. The title compounds of thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide derivatives (1a-1o) were synthesized via Biginelli method, the reaction was carry out via AEEA-Cu(II)-NPs catalysis. Synthesized compounds (1a-1o) were characterized by FT-IR, 1H NMR, 13C NMR, mass spectrometry, and elemental analysis. The spectral data of compound 1a was confirmed by the comparison of both experimental and theoretical values. GC-EI-MS analysis of the characteristic protonation pathways for GC-EI-MS fragmentation of synthetic 2-thioxo-pyrimidine-5-carboxamide derivatives is reported. Computing methods of compound 1a was studied such as optimize the geometry, frontier molecular orbital analysis (HOMO-LUMO), and molecular electrostatic potential (MESP). In cytotoxicity screening, compounds were tested against. Cell lines 2HepG2 (liver), MCF-7 (breast), and HeLa (cervical) cancer cell lines. Molecular docking was used to determine the inter and intramolecular interactions. In order to determine the most effective pyrimidine derivatives (1f and 1 g) for the protein 4FM9, and Autodock Vina 1.1.2 software was used in conjunction with the binding mode of fluorouracil as a reference compound. The compounds 1f and 1g were extremely effective against HepG2 cells compared to fluorouracil. During docking studies, 1f showed a higher attraction for the 4FM9 protein (−6.5 kcal/mol) than fluorouracil (−5.4 kcal/mol). The compounds 1f, and 1g showed impressive inhibitory properties in cytotoxic screening as compared to the reference compound. Due to the docking studies and cytotoxicity screening results, the new compounds look promising as therapeutic agents.

Synthesis and characterization of novel combretastatin analogues of 1,1-diaryl vinyl sulfones, with antiproliferative potential via in-silico and in-vitro studies

Novel 1,1-diaryl vinyl-sulfones analogues of combretastatin CA-4 were synthesized via Suzuki–Miyaura coupling method and screened for in-vitro antiproliferative activity against four human cancer cell lines: MDA-MB 231(breast cancer), HeLa (cervical cancer), A549 (lung cancer), and IMR-32 (neuroblast cancer), along with a normal cell line HEK-293 (human embryonic kidney cell) by employing 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. The compounds synthesised had better cytotoxicity against the A549 and IMR-32 cell lines compared to HeLa and MDA-MB-231 cell lines. The synthesized compounds also showed significant activity on MDA-MB-231 cancer cell line with IC50 of 9.85–23.94 µM, and on HeLa cancer cell line with IC50 of 8.39–11.70 µM relative to doxorubicin having IC50 values 0.89 and 1.68 µM respectively for MDA-MB-231 and HeLa cell lines. All the synthesized compounds were not toxic to the growth of normal cells, HEK-293. They appear to have a higher binding affinity for the target protein, tubulin, PDB ID = 5LYJ (beta chain), relative to the reference compounds, CA4 (− 7.1 kcal/mol) and doxorubicin (− 7.2 kcal/mol) except for 4E, 4M, 4N and 4O. The high binding affinity for beta-tubulin did not translate into enhanced cytotoxicity but the compounds (4G, 4I, 4J, 4M, 4N, and 4R, all having halogen substituents) that have a higher cell permeability (as predicted in-silico) demonstrated an optimum cytotoxicity against the tested cell lines in an almost uniform manner for all tested cell lines. The in-silico study provided insight into the role that cell permeability plays in enhancing the cytotoxicity of this class of compounds and as potential antiproliferative agents.

Piroxicam Analogs: Design, Synthesis, Docking Study and Biological Evaluation as Promising Anti-HIV-1 Agents.

In this study, we describe the synthesis, docking study and biological evaluation of 1,2-benzothiazines 1,1-dioxide derivatives. Taking the well-known drug, Piroxicam as a lead compound, we designed and synthesized two series of 1,2-benzothiazines 1,1-dioxide derivatives to assay their ability in inhibition of HIV-1 replication in cell culture. Most of the new compounds were active in the cell-based anti-HIV-1 assay with EC50 < 50 μM. Among them, compound 7g was found to be the most active molecule.Docking study using 3OYA pdb code on the most active molecule 7g with EC50 values of 10 μM showed a similar binding mode to the HIV integrase inhibitors. Since all the compounds showed no remarkable cytotoxicity (CC50> 500 μM), the designed scaffold is promising structure for the development of new anti-HIV-1 agents.

Synthesis, in-vivo anti-diabetic &amp; anticancer activities and molecular modelling studies of tetrahydrobenzo[d]thiazole tethered nicotinohydrazide derivatives

A series of thirty new thiazole-pyridine derivatives were synthesized by reaction of 4,4,7,7-tetra-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine with 6-chloronicotinate followed by condensing with benzaldehydes and screened for their anti-diabetic activity by in vivo housing Swiss albino mice. All synthesized compounds resulted in reducing the glucose level when compared with reference standard drug glibenclamide. In specific, compound 7 exhibited significant activity in terms of fasting blood glucose level reduction. In addition, the in-silico binding studies of the potential compounds 11f and 11g with human PPAR-γ protein complexed with Retinoid X Receptor (RXR) alpha Nuclear Receptor showed good interactions when compared to the standard drug Rosiglitazone. The newly synthesized drugs may be potential anti-diabetic drugs with possible specific actions.

Potential Fluorinated Anti-MRSA Thiazolidinone Derivatives with Antibacterial, Antitubercular Activity and Molecular Docking Studies.

MRSA infection is one of the alarming diseases in the current scenario. Identifying newer molecules to treat MRSA infection is of urgent need. In the present study, we have designed fluorinated thiazolidinone derivatives with various aryl/heteroaryl units at 5th position of the thiazolidinone core as promising anti-MRSA agents. All the compounds were screened for antibacterial activity against four bacterial strains. Among the tested compounds, the halogenated compounds with simple arylidene ring, (5Z)-5-[(3-chloro-2-fluorophenyl)methylidene]-2-[(1,3-thiazol-2-yl)amino]-1,3-thiazol-4(5H)-one (4b), (5Z)-5-[(4-chloro-2-fluorophenyl)methylidene]-2-[(1,3-thiazol-2-yl)amino]-1,3-thiazol-4(5H)-one (4c), (5Z)-5-[(3-fluoro-4-methylphenyl)methylidene]-2-[(1,3-thiazol-2-yl)amino]-1,3-thiazol-4(5H)-one (4f) and (5Z)-5-[(3,5-difluorophenyl)methylidene]-2-[(1,3-thiazol-2-yl)amino]-1,3-thiazol-4(5H)-one (4g) showed excellent activity with MIC 3.125-6.25 μg/mL against S. aureus and P. aeruginosa organism. Furthermore, these potent compounds were screened against MRSA strains, ESKAPE panel organism, and H37Rv mycobacterium strain. Compounds 4c (MIC 0.39 μg/mL), and 4f (MIC 0.39 and 0.79 μg/mL) displayed promising activity against MRSA strains (ATCC and clinical isolates, respectively). The most potent compounds, 4c and 4f eradicated the growth of bacterial colonies in a time-kill assay indicated that these are bactericidal in nature. The preliminary toxicity study of the potent molecules revealed that these compounds are non-hemolytic in nature as they did not induce lysis in human RBCs. In addition, the molecular docking and dynamics studies of compounds 4b, 4c, 4f and 4g were carried out on MurB protein of S. aureus (PDB code: 1HSK). Docking results demonstrated remarkable hydrogen bonding interaction with key amino acids ARG310, ASN83, GLY79 and π-π interactions with TYR149 which confirm the mode of action of the molecules.

Design, Synthesis, and Biological Activity of Chalcone Analogs Containing 4-Phenylquinolin and Benzohydrazide.

A series of chalcone derivatives (3a-3m) containing 4-phenylquinoline and benzohydrazide were designed and synthesized, and their anti-inflammatory, analgesic, and antidepressant activities were evaluated. Using the classic antidepressant model, except for compounds 3a and 3d, 11 compounds all showed certain antidepressant activity at a dose of 100 mg/kg, among which compounds 3f, 3h, and 3m showed good antidepressant activity (inhibition rate, respectively 63.0 %, 73.2 %, and 76.4 %), which was equivalent to the positive control fluoxetine (inhibition rate of 70.0 %). Secondly, the inhibitory activity of these compounds on mouse MAOA was evaluated. At 10 mM, compounds 3f and 3j showed a certain selective inhibitory effect on mouse MAOA , while compounds 3b, 3d, 3g, 3i, and 3m had a good inhibitory effect on mouse MAOA (inhibition rate is 42.3-71.4 %). The mouse ear edema model was used to evaluate the anti-inflammatory activity of compounds 3a-3m. At 30 mg/kg, compounds 3b, 3c, 3e, 3f, 3g, and 3m showed certain anti-inflammatory effects (inhibition rate of 51.5-99.9 %), which was equivalent to the positive control indomethacin (inhibition rate of 69.7 %). Results of the acetic acid-induced abdominal writhing test showed that, at 30 mg/kg, excepted for compounds 3a, 3b and 3d, all the other 10 compounds can show certain analgesic activity (inhibition rate 67-99.9 %). The use of Auto dock Vina (simina) to simulate molecular target docking shows that the development of quinoline and benzohydrazide groups is of great significance to MAOA inhibitors.

Structural Optimization and Structure-Activity Relationship Studies of 6,6-Dimethyl-4-(phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one Derivatives as A New Class of Potent Inhibitors of Pan-Trk and Their Drug-Resistant Mutants.

Tropomyosin receptor kinases (TrkA, TrkB, and TrkC) are attractive therapeutic targets for multiple cancers. Two first-generation small-molecule Trks inhibitors, larotrectinib and entrectinib, have just been approved to use clinically. However, the drug-resistance mutations of Trks have already emerged, which calls for new-generation Trks inhibitors. Herein, we report the structural optimization and structure-activity relationship studies of 6,6-dimethyl-4-(phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one derivatives as a new class of pan-Trk inhibitors. The prioritized compound 11g exhibited low nanomolar IC50 values against TrkA, TrkB, and TrkC and various drug-resistant mutants. It also showed good kinase selectivity. 11g displayed excellent in vitro antitumor activity and strongly suppressed Trk-mediated signaling pathways in intact cells. In in vivo studies, compound 11g exhibited good antitumor activity in BaF3-TEL-TrkA and BaF3-TEL-TrkCG623R allograft mouse models without exhibiting apparent toxicity. Collectively, 11g could be a promising lead compound for drug discovery targeting Trks and deserves further investigation.

Discovery of Novel Triazolothiadiazines as Fungicidal Leads Targeting Pyruvate Kinase

Pyruvate kinase (PK) was discovered as a potent new target for novel fungicide development. A series of novel triazolothiadiazine derivatives were rationally designed and synthesized by a ring expansion strategy and computer-aided pesticide design using the 3D structure of Rhizoctonia solani PK (RsPK) obtained by homology modeling as a receptor and our previously discovered lead YZK-C22 as a ligand. The in vitro bioassay results indicated that compounds 4g, 6h, 6m, 6n, 6o, and 6p exhibited good activity against R. solani with the EC50 values falling between 10.99 and 72.76 μM. Especially, 6m showed similar potency to YZK-C22 (10.99 vs 11.97 μM of the EC50 value, respectively). The in vivo bioassay results suggested that 6m against R. solani at a concentration of 200 μg/mL displayed a numerically higher inhibition than YZK-C22 (70 vs 60%, respectively). A field experiment validated that 6m at an application rate of 120 g ai/ha showed comparable efficacy against R. solani to thifluzamide at an application rate of 80 g ai/ha (77.80 vs 84.5%, respectively). Enzymatic inhibition suggested that the potency of 6m was about twofold lower than that of YZK-C22 (67.30 vs 32.64 μM of IC50, respectively). Fluorescence quenching studies validated that RsPK was quenched by both 6m and YZK-C22, implying that they both might act at the same target site of PK. A possible binding conformation of 6m in the RsPK active site was depicted by molecular docking. Our studies suggest that 6m could be a fungicidal lead targeting PK.

Synthesis and anticancer activity of [1,2,4] triazole [4,3-b] [1,2,4,5] tetrazine derivatives

A series of [1,2,4] triazole [4,3-b] [1,2,4,5] tetrazine derivatives were synthesized, and they were screened for their anticancer activity against human lung cancer (A549), mouse normal hepatocytes (AML12), human colorectal adenocarcinoma (CaCo2), human gastric cancer (EGC), human hepatocellular carcinoma (HEPG2) and human colon carcinoma (HT-29) cell lines. Among them, compound 4g (8-((6-(3,5-Dimethyl-1H-pyrazol-1-yl)-[1,2,4] triazolo[4,3-b][1,2,4,5]tetrazin-3-ylthio)methyl)quinoline) performed well, and its IC50 value against human colon carcinoma (HT-29) cell was 12.69 ± 7.14 µM.