Compounds 9k Research Articles

Design and synthesis of new 1,2,4-oxadiazole/quinazoline-4-one hybrids with antiproliferative activity as multitargeted inhibitors.

The combination of BRAF and tyrosine kinase (TK) inhibitors has been demonstrated to be highly effective in inhibiting tumor development and is an approach for overcoming resistance in clinical trials. Accordingly, a novel series of 1,2,4-oxadiazole/quinazoline-4-one hybrids was developed as antiproliferative multitargeted inhibitors. The structures of the newly synthesized compounds 9a-o were validated using IR, NMR, MS, and elemental techniques. 9a-o were tested as antiproliferative agents. The results showed that the majority of the tested compounds showed significant antiproliferative action with 9b, 9c, 9h, 9k, and 9l being the most potent. Compounds 9b, 9c, 9h, 9k, and 9l were tested as EGFR and BRAFV600E inhibitors. These in vitro tests revealed that compounds 9b, 9c, and 9h are strong antiproliferative agents that may act as dual EGFR/BRAFV600E inhibitors. 9b, 9c, and 9h were further investigated for their inhibitory effect on mutant EGFR (EGFRT790M), and the results showed that the tested compounds had considerable inhibitory action. Cell cycle study and apoptosis detection demonstrated that compound 9b exhibits cell cycle arrest at the G2/M transition. Molecular docking simulations reveal the binding mechanism of the most active antiproliferative agents.

Novel hybrid motifs of 4-nitroimidazole-piperazinyl tagged 1,2,3-triazoles: Synthesis, crystal structure, anticancer evaluations, and molecular docking study

4-((4-(1-benzyl-2-methyl-4-nitro-1H-imidazole-5-yl)piperazine-1-yl)methyl)-1-substituted-1H-1,2,3-triazole motifs are designed and synthesized via click chemistry. The reaction of 1-(N1-benzyl- 2-methyl-4-nitro-1H-imidazole- 5-yl)-4-(prop-2-yn-1-yl) piperazine 5 as new scaffold with diverse primary azides to selectively produce 1,4-disubstituted-1,2,3-triazoles 9a–k, 10a–c and 11a–q. Physicochemical methods: when 1H NMR, 13C NMR, and HRMS are utilized to fully characterize all synthesized compounds. X-ray structural determination and analysis for compound 9a is also performed. The newly designed chromophores are assessed for their anti-proliferative potency against three selected human cancer cell lines (MCF-7, HepG2, and PC3), and one normal cell line (Dermal/Fibroblast). Compounds 9g and 9k have shown potent activities against the MCF-7 cell line with IC50 values of (2.00 ± 0.03 μM) and (5.00 ± 0.01 μM) respectively. ADMET studies and Molecular docking investigations are performed on the most active hybrid nitroimidazole derivatives 9g and 9k with 4-hydroxytamoxifen (4-OHT) at the human estrogen receptor alpha (hER) during binding active sites to study the ligand–protein interactions and free binding energies at atomic levels. The triazole ring in the 9g derivative forms a hydrogen bond with Asp58 with distance 3.2 Å. And it is found that polar contact with His231 amino acid residue.In silico assessment of the compounds showed very good pharmacokinetic properties based on their physicochemical values, also the ADMET criteria of the most active hybrid systems are within the acceptable range.

Biochemical and in silico inhibition of bovine and human carbonic anhydrase-II by 1H-1,2,3-triazole analogs.

A series of 1H-1,2,3-triazole analogs (7a-7d and 9a-9s) were synthesized via "click" chemistry and evaluated for in vitro carbonic anhydrase-II (bovine and human) inhibitory activity. The synthesis of intermediates, 7a and 7c, was achieved by using (S)-(-)ethyl lactate as a starting material. These compounds (7a and 7c) underwent Suzuki-Miyaura cross-coupling reaction with different arylboronic acids in 1,4-dioxane, reflux at 90-120°C for 8h using Pd(PPh3)4 as a catalyst (5mol%), and K2CO3 (3.0 equiv)/K2PO4 (3.0 equiv) as a base to produce target 1H-1,2,3-triazole molecules (9a-9s) for a good yield of 67-86%. All the synthesized compounds were characterized through NMR spectroscopic techniques. Furthermore, all those compounds have shown significant inhibitory potential for both sources of carbonic anhydrase-II (CA-II). In the case of bCA-II, compounds 9i, 7d, 9h, 9o, 9g, and 9e showed potent activity with IC50 values in the range of 11.1-17.8µM. Whereas for hCA-II, compounds 9i, 9c, 9o, and 9j showed great potential with IC50 values in the range of 10.9-18.5µM. The preliminary structure-activity relationship indicates that the presence of the 1H-1,2,3-triazole moiety in those synthesized 1H-1,2,3-triazole analogs (7a-7d and 9a-9s) significantly contributes to the overall activity. However, several substitutions on this scaffold affect the activity to several folds. The selectivity index showed that compounds 9c, 9k, and 9p are selective inhibitors of hCA-II. Kinetics studies showed that these compounds inhibited both enzymes (bCA-II and hCA-II) in a competitive manner. Molecular docking indicates that all the active compounds fit well in the active site of CA-II. This study has explored the role of 1H-1,2,3-triazole-containing compounds in the inhibition of CA-II to combat CA-II-related disorders.

Discovery of DNA-Targeting HDAC Inhibitors with Potent Antitumor Efficacy In Vivo That Trigger Antitumor Immunity.

We observed a synergistic antiproliferation effect with combined use of a DNA minor groove binder and a histone deacetylase (HDAC) inhibitor. Inspired by this result, a new series of benzimidazole-hydroxamate hybrids were designed and synthesized to target both DNA minor groove and HDAC. The most active compounds 9k and 9l not only exhibited improved HDAC inhibitory activities compared to SAHA but also possessed potent antiproliferation activities against tumor cells. Importantly, compounds 9k and 9l showed good in vivo antitumor efficacies in both HEL xenograft model and murine melanoma model. We also found that 9k and 9l promote the antigen presentation and activate T cells, thereby triggering antitumor immunity. Moreover, these inhibitors reshaped the tumor immune microenvironment by inhibiting the recruitment of Treg cells and promoting the polarization of tumor-infiltrating macrophages to M2 type with antitumor activity. Our study validated the effectiveness of incorporating a DNA-binding fragment in HDAC inhibitors as novel multitargeting antitumor agents.

Design, synthesis, in vitro determination and molecular docking studies of 4-(1-(tert-butyl)-3-phenyl-1H-pyrazol-4-yl) pyridine derivatives with terminal sulfonamide derivatives in LPS-induced RAW264.7 macrophage cells

In the present work, a new series of 4-(1-(tert-butyl)-3-phenyl-1H-pyrazol-4-yl) pyridine possessing terminal ethyl or propyl sulfonamides was designed and synthesized. The cytotoxic effect of the final compounds was measured by applying MTT assay in LPS-Induced RAW264.7 macrophage cells. The final target compounds were screened for their anti-inflammatory effect through their ability to inhibit NO and PGE2 production and cytokines production (TNF-α, IL-6, IL-1β) in LPS-induced RAW264.7 macrophage at 10 μM concentration. Compounds 8d, 9d, and 9k showed the highest inhibitory effect on NO production. Compounds 8d and 9k exhibited high PGE2 inhibition with IC50 values of 3.47, 2.54 μM, respectively. Compounds 8d and 9k exhibited high cytokines inhibition ≥60%. The most potent compounds 8d and 9k were tested to determine their effect on iNOS and COX-2 mRNA expression level. Compound 9k activity on iNOS and COX-2 proteins level, pro-inflammatory mediators and cytokines was determined and showed remarkable inhibition for both proteins level. Compounds 8d, 9k showed high binding affinity to COX-2 active site and exhibited similar binding interactions of the native ligand celecoxib.

Design, synthesis biological activity, and docking of novel fluopyram derivatives containing guanidine group

Succinate dehydrogenase (SDH), a crucial bridge enzyme between the respiratory electron transfer chain and tricarboxylic acid (or Krebs) cycle, has been identified as an ideal target for the development of effective fungicide. In this study, a series of 24 novel SDH inhibitors (SDHIs) were designed, synthesized, and characterized by 1H NMR, 13C NMR, and HRMS. In vitro fungicidal activity experiments, most of the compounds exhibited broad-spectrum antifungal activities against five plant pathogenic fungi. Compounds 9j and 9k showed excellent activities against Pythium aphanidermatum with EC50 values of 9.93 mg/L and 10.50 mg/L, respectively, which were superior to the lead compound Fluopyram with an EC50 value of 19.10 mg/L. Furthermore, the toxicity of these compounds was also tested against Meloidogyne incognita J2 nematodes. The results indicated that compound 9x exhibited moderate nematicidal activity (LC50/48 h = 71.02 mg/L). Molecular docking showed that novel guanidine amide of 9j formed hydrogen bonds with crucial residues, which was crucial to the binding of an inhibitor and SDH. This present work indicates that these derivatives may serve as novel potential fungicides targeting SDH.

Luotonin A and Its Derivatives as Novel Antiviral and Antiphytopathogenic Fungus Agents.

Plant diseases caused by viruses and fungi have posed a serious threat to global agricultural production. The discovery of new leads based on natural products is an important way to innovate pesticides. In this work, natural product luotonin A was found to have good antiviral activity against tobacco mosaic virus (TMV) for the first time. A series of luotonin A derivatives were designed, synthesized, and evaluated for their antiviral activities and fungicidal activities systematically. Most compounds displayed better antiviral activities against TMV than commercial ribavirin. Compounds 9k, 12b, and 12d displayed about similar inhibitory effects as ningnanmycin (inhibitory rates of 55, 57, and 59% at 500 μg/mL for inactivation, curative, and protection activities in vivo, respectively), the best antiviral agent at present, and emerged as novel antiviral leads for further research. We selected 9k for further antiviral mechanism research via transmission electron microscopy and molecular docking, which revealed that compound 9k can interact with TMV coat protein through the hydrogen bond, leading to its polymerization, thus preventing virus assembly. Further fungicidal activity tests showed that these compounds also showed broad-spectrum fungicidal activities against 14 kinds of phytopathogenic fungi. Especially, compound 14 with a 100% antifungal effect against Botrytis cinereal emerged as a lead for further research. This work provides a reference for the development of agricultural active ingredients based on Chinese medicine plants.

Design, synthesis, and biological evaluation of tetrahydroisoquinoline-based diaryl urea derivatives for suppressing VEGFR-2 signaling

A novel structural series of tetrahydroisoquinoline-based compounds that incorporate the diaryl urea moiety was designed, synthesized, and biologically evaluated as suppressors of VEFGR-2 signaling. As a consequence, compounds 9k and 9s exhibited comparable or superior cytotoxic activity to that of gefitinib against the tested three cell lines, including A549, MCF-7, and PC-3. Importantly, both of them downregulated the expression of VEGFR-2, and inhibited VEGFR-2 phosphorylation at the concentration of 0.5 or 1.0 μmol/l. Besides, they suppressed human umbilical vein endothelial cell tube formation at the concentration of 4.0 μmol/l. Considering their capability of down-regulating VEGFR-2 expression and inhibiting VEGFR-2 phosphorylation, 9k and 9s may serve as suppressors of angiogenesis for further investigation.

Design, synthesis and biological evaluation of novel 2-sulfonylindoles as potential anti-inflammatory therapeutic agents for treatment of acute lung injury

Acute lung injury (ALI) is primarily driven by inflammation that severely impacts lung function. Novel 2-sulfonylindoles were recently shown to exhibit anti-inflammatory activity through the inhibition of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production. Here, we synthesized 31 compounds which contained 2-sulfonylindole structure. The compounds 8a, 9g, 9h and 9k exhibited dose-dependent anti-inflammatory activity in vitro. Structural-activity relationship analysis revealed that the introduction of sulfonyl group in indole nucleus may be successful to obtain new anti-inflammatory structures and leads. The compounds 9h and 9k also decreased liposaccharide (LPS)-induced IL-6, IL-1β and vascular cell adhesion molecule-1 (VCAM-1) mRNA expression, both in vitro and in an in vivo model of ALI. Furthermore, the compounds 9h and 9k at a high dose (20 mg/kg) significantly protected against LPS-induced ALI in mice. These results show that compounds 9h and 9k could be a promising lead structure for the treatment of ALI.

A new class of pyrazolo[5,1-c][1,2,4]triazines as γ-aminobutyric type A (GABAA) receptor subtype ligand: synthesis and pharmacological evaluation

A comparison between compounds with pyrazolo[1,5-a]pyrimidine structure (series 4–6) and pyrazolo[5,1-c][1,2,4]triazine core (series 9) as ligands at GABAA-receptor subtype, was evaluated. Moreover, for pyrazolotriazine derivatives having binding recognition, the interaction on recombinant rat α(1–3,5) GABAA receptor subtypes, was performed. Among these latter, emerge compounds 9c, 9k, 9l, 9m and 9n as α1-selective and 9h as α2-selective ligands.

Design, Synthesis and Bioactivities of Novel Isoxazole-Containing Pyrazole Oxime Derivatives.

In this study, in order to find novel biologically active pyrazole oxime derivatives, twenty-eight new pyrazole oxime compounds containing a substituted isoxazole ring were synthesized and evaluated for their acaricidaland insecticidal activities. Bioassays exhibited that some target compounds indicated good acaricidal and insecticidal activities against Tetranychus cinnabarinus, Aphis medicaginis, Mythimna separata, and Nilaparvata lugens. Especially, compounds 9c, 9h, 9u, and 9v showed 100.00%, 90.56%, 90.78%, and 90.62% insecticidal activities against A. medicaginis at the concentration of 20 μg/mL, respectively, compounds 9k and 9u had 70.86% and 100.00% insecticidal activities against M. separata at 20 μg/mL, respectively.

Synthesis and evaluation of new pyridyl/pyrazinyl thiourea derivatives: Neuroprotection against amyloid-β-induced toxicity

Herein, we report synthesis and evaluation of new twenty six small molecules against β amyloid (Aβ)-induced opening of mitochondrial permeability transition pore (mPTP) using JC-1 assay which measures the change of mitochondrial membrane potential (ΔΨm). The neuroprotective effect of seventeen compounds against Aβ-induced mPTP opening was superior to that of the standard Cyclosporin A (CsA). Fifteen derivatives eliciting increased green to red fluorescence percentage less than 40.0% were evaluated for their impact on ATP production, cell viability and neuroprotection against Aβ-induced neuronal cell death. Among evaluated compounds, derivatives 9w, 9r and 9k had safe profile regarding ATP production and cell viability. In addition, they exhibited significant neuroprotection (69.3, 51.8 and 48.2% respectively). Molecular modeling study using CDocker algorithm predicted plausible binding modes explaining the elicited mPTP blocking activity. Hence, this study suggests compounds 9w, 9r and 9k as leads for further development of novel therapy to Alzheimer's disease.

Synthesis of some ester derivatives of 4′-demethoxyepipodophyllotoxin/2′-chloro-4′-demethoxyepipodophyllotoxin as insecticidal agents against oriental armyworm, Mythimna separata Walker

Podophyllotoxin is a naturally occurring non-alkaloid toxin isolated from the roots and rhizomes of Podophyllum peltatum and P. hexandrum. In continuation of our program aimed at the discovery and development of natural product-based insecticides, two series of ester derivatives of 4′-demethoxyepipodophyllotoxin/2′-chloro-4′-demethoxyepipodophyllotoxin were prepared. The structures of the target compounds were well characterized by 1H NMR, IR, optical rotation and mp. The precise three-dimensional structural information of 8j was further determined by single-crystal X-ray diffraction. Their insecticidal activity was tested against Mythimna separata Walker. These compounds showed delayed insecticidal activity. Among all derivatives, some compounds showed more potent insecticidal activity than toosendanin against M. separata; especially compounds 8k and 9k exhibited the most potent activity with the final mortality rates of 71.4%. Their structure–activity relationships were discussed.

Discovery of 3-benzyl-1,3-benzoxazine-2,4-dione analogues as allosteric mitogen-activated kinase kinase (MEK) inhibitors and anti-enterovirus 71 (EV71) agents

Enterovirus 71 (EV71) is a kind of RNA virus and one of the two causes of Hand, foot and mouth disease (HFMD). Inhibitors that target key components of Ras/Raf/MEK/ERK pathway in host cells could impair replication of EV71. A series of 3-benzyl-1,3-benzoxazine-2,4-diones were designed from a specific MEK inhibitor G8935, by replacing the double bond between C3 and C4 within the coumarin scaffold with amide bond. One compound (9f) showed submicromolar inhibitory activity among the 12 derivatives. Further optimization on 9f led to two active compounds (9k and 9m) with nanomolar bioactivities (55nM and 60nM). The results of enzymatic assays also demonstrated that this series of compounds were allosteric inhibitors of unphosphorylated MEK1. The binding mode of compound 9k was predicted by molecular dynamic simulation and the key interactions were same as published MEK1/2 allosteric inhibitors. In the cell-based assays, compounds 9k and 9m could effectively suppress the ERK1/2 pathway, expression of EV71 VP1, and EV71 induced cytopathic effect (CPE) in rhabdomyosarcoma (RD) cells.

Regioselective synthesis, antimicrobial evaluation and theoretical studies of 2-styryl quinolines.

2-Styryl quinolines (9a-l) have been synthesized regioselectively from 2-methyl-quinoline by using NaOAc in water acetic acid binary solvents and evaluated for their antibacterial activity against both Gram-positive and Gram-negative strains. Among these, the compounds 12 and 8 were found to be active against both bacterial strains. Compounds 9b, 9f, 9g, 9i, 9j and 9k were the most active among the series exhibiting MIC values ranging between 1.9 and 31.2 μg ml(-1) against different bacterial strains. Compounds 9j and 9k were found to be as potent as the standard drug ciprofloxacin against Micrococcus luteus, Klebsiella planticola and Staphylococcus aureus. In addition, the compounds showed bactericidal activity; compound 9j was found to be better than ciprofloxacin, with an MBC value of 0.9 μg ml(-1) against both M. luteus and K. planticola. The compounds also inhibited biofilm formation, and compound 9j was found to be equipotent to erythromycin against M. luteus and S. aureus MLS16. Further, theoretical studies such as those on druggable properties and PMI plot have been carried out.

Synthesis and biological evaluation of novel fluconazole analogues bearing 1,3,4-oxadiazole moiety as potent antifungal agents.

A novel series of fluconazole based mimics incorporating 1,3,4-oxadiazole moiety were designed and synthesized. All the title compounds were characterized by (1)H-NMR, (13)C-NMR, and Q-TOF-MS. Preliminary results revealed that most of analogues exhibited significant antifungal activity against seven pathogenic fungi. Compounds 9g and 9k (MIC80≤0.125μg/mL, respectively) were found more potent than the positive controls itraconazole and fluconazole as broad-spectrum antifungal agents. The observed docking results showed that the 1,3,4-oxadiazole moiety enhanced the affinity binding to the cytochrome P450 14α-demethylase (CYP51).

4-Aryl-5-(4-Piperidyl)-3-Isoxazolol GABAA Antagonists: Synthesis, Pharmacology, and Structure−Activity Relationships

A series of 4-aryl-5-(4-piperidyl)-3-isoxazolol GABAA antagonists have been synthesized and pharmacologically characterized. The meta-phenyl-substituted compounds 9k and 9m and the para-phenoxy-substituted compound 9l all display high affinities (Ki=10-70 nM) and antagonist potencies in the low nanomolar range (Ki=9-10 nM). These potencies are significantly higher than those of previously reported 4-PIOL antagonists and considerably higher than that of the standard GABAA antagonist SR 95531.

Synthesis of N‐Substituted (3S,4S)‐ and (3R,4R)‐Pyrrolidine‐3,4‐diols: Search for New Glycosidase Inhibitors.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of N‐Substituted (3S,4S)‐ and (3R,4R)‐Pyrrolidine‐3,4‐diols: Search for New Glycosidase Inhibitors

AbstractN‐Substituted (3S,4S)‐ and (3R,4R)‐pyrrolidine‐3,4‐diols 9 and 10, respectively, were derived from (+)‐L‐ and (−)‐D‐tartaric acid, respectively. Compounds 9k, 9l, and 9m with the N‐substituents, BnNH(CH2)2, 4‐PhC6H4CH2NH(CH2)2 and 4‐ClC6H4CH2NH(CH2)2, respectively, showed modest inhibitory activities toward α‐D‐amyloglucosidases from Aspergillus niger and from Rhizopus mold (Table 1). Unexpectedly, several (3R,4R)‐pyrrolidine‐3,4‐diols 10 showed inhibitory activities toward α‐D‐mannosidases from almonds and from jack bean (Table 3). N‐Substitution by the NH2(CH2)2 group, i.e., 10g, led to the highest potency.

Halothiophene Benzimidazoles as P1 Surrogates of Inhibitors of Blood Coagulation Factor Xa.

AbstractFor Abstract see ChemInform Abstract in Full Text.