Benzamide Group Research Articles

Design, synthesis, biological evaluation and molecular docking study of novel quinolone derivatives as potent HDAC1 (Histone Deacetylase) inhibitors and anticancer agents

Histone deacetylases (HDACs), especially HDAC1, are attractive targets for anticancer drug design because of their significant role in transcriptional repression and chromatin remodeling. Benzamide groups are widely reported as the most effective zinc binding groups (ZBGs) in design of HDAC inhibitors. Quinolone derivatives, exhibiting various therapeutic effects, are attractive scaffolds for developing novel HDAC inhibitors with potentially supposed therapeutic profiles. To explore the potential of 4-quinolones as a novel scaffold for a cap of HDACis, 14 novel structures were rationally designed and synthesized. Four cancer cell lines (HCT116, HT29, MCF7, and A549) and one normal cell (CHO) were applied to investigate the cytotoxicity of synthesized compounds. Furthermore, the inhibitory activity of the synthesized compounds was analyzed against pan-HDAC isozymes (HDAC1, HDAC2, HDAC3 and HDAC6). Five compounds (5a, 5b, 5c, 5e and 5h) showed strong cytotoxicity and HDAC inhibition even superior to entinostat as the reference drug. Collectively, these results suggest that compounds with an electron-donating group at the positions 6 or 8 of the quinolone ring (cap) appear to enhance the anti-proliferative potency. After performing induce-fit docking (on HDAC1, 2, 3, 6) for all the synthesized compounds, a significant correlation was identified between the MTT results, the inhibitory activity of pan-HDAC, and the docking scores of HDAC1. Therefore, compounds 5e and 5a (the most potent compounds) were identified as the most favorable leads for further investigation of HDAC1-specific enzyme inhibition. Compounds 5a and 5e showed impressive HDAC1 inhibitory potency with IC50 values of 0.48 μM and 0.36 μM, respectively, equal or more than that of Entinostat. Compound 5e (3 µM) also exhibited significant induction of apoptosis in the HCT116 cell line (the percentage of apoptotic cells was 81.87%), even stronger than the reference drug Entinostat (the percentage of apoptotic cells was 37.5%) at the same concentration which is consistent with their antiproliferative activities as well. 100 ns molecular dynamic (MD) simulation revealed that compound 5e can form stable interactions with HDAC1 through coordination with zinc ion, strong hydrophobic interactions and formation of hydrogen bonds. These results suggested that compound 5e can be promising lead for further development of potent anticancer and HDAC inhibitor drugs.

Preparation, Identification And Biological Activity Of Some Metals Complexes With A New Ligand (4-Nitro-N-((6-Oxo-6,9-Dihydro-1H-Purin-2-Yl)Carbamothioyl)Benzamid)

This study aimed to synthesize and characterize a novel guanine derivative, namely ( 4-nitro-N-((6-oxo-6,9-dihydro-1H-purin-2-yl)carbamothioyl)benzamid) (abbreviated as NPBL4). This compound possesses an intriguing chemical structure, consisting of a guanine moiety (a bicyclic heterocyclic base) linked to a benzamide group through a carbamothioyl linker. The synthesis of this nitrogenous base derivative involved two steps. Firstly 4-nitro-N-thioformylbenzamide was synthesized by reacting 4-nitrobenzoyl chloride with ammonium thiocyanate in acetone. Subsequently, the obtained 4-nitro-N-thioformylbenzamide was reacted with guanine to yield the desired ligand. In addition to the ligand synthesis, the study focused on preparing complexes of various metal ions (Mn+2, Co+2, Ni+2, Cu+2, Zn+2, Cd+2, and Pd+2) with the prepared guanine derivative. The ligand and complexes were subjected to comprehensive characterization using techniques such as infrared spectra, ultraviolet-visible spectra, 1H-NMR, 13C-NMR spectra, elemental analysis (C.H.N.S.), molar conductivity measurement, magnetic susceptibility, atomic absorption, melting point determination, and study the biological activity for the complexes. The results of these characterization studies led to the determination of the general formulas for the prepared complexes, which were found to be [MCl2(NPB)2], where M represents the respective metal ion (Mn+2, Co+2, Ni+2, Cu+2, Zn+2, Cd+2, and Pd+2). Notably, the geometric shape of all the prepared complexes was determined to be an octahedron. In summary, this study successfully synthesized and characterized a novel guanine derivative (NPB) and investigated its complexes with various metal ions. The findings provided valuable insights into the chemical properties and structural features of these compounds.

Effect of chirality in the supramolecular polymerization of N-annulated perylenediimides: Cancelling pathway complexity.

Herein, the synthesis of two chiral NPBIs, (S)-1 and (R)-1, is reported and their self-assembling features investigated. The reported NPBIs form chiral supramolecular polymers with a rich dichroic pattern by the π-stacking of the aromatic backbones and the formation of an array of H-bonds between the amide functional groups. Furthermore, the peripheral 3,4,5-trialkoxy benzamide groups can form seven-membered pseudocycles by the intramolecular H-bonding interaction between the NH of the peripheral amides and one of the carbonyls of the imide units thus yielding a kinetically controlled self-assembly process. Unlike achiral NPBI 1, that has been reported to form up to four supramolecular polymorphs, the reported chiral NPBIs form only a J-type aggregated species. The results presented herein reveal how subtle changes exert an enormous influence on the supramolecular polymerization outcome.

Design, Synthesis, Docking Studies, and Biological Evaluation of Novel 2-Hydroxyacetophenone Derivatives as Anti-HIV-1 Agents.

The persistence of HIV mutations and the existence of multidrug resistance have produced an opportunity for an array of innovative anti-HIV medicines with a variety of structures that target HIV key enzymes. The goal of this work was to find a new class of anti-HIV drugs founded on HIV integrase inhibitor pharmacophores. A novel class of 2-hydroxy acetophenone analogs featuring substituted benzamide or N-phenylthiourea groups was designed and synthesized based on the general pharmacophore of HIV-1 integrase inhibitors (INs). Most of the synthesized analogs were found to be moderately active against the virus, with EC50 values ranging from 40 to 140 μM. Additionally, it was found that most of the compounds presented no considerable cytotoxicity (CC50 > 500 μΜ). The most potent compounds substituting with 4-fluorobenzamide (compound 7) and 4-methylbenzamide (compound 9) rings inhibited the HIV-1 replication by EC50 values of 40 and 45 μΜ, respectively. Docking studies using the crystallographic data available for PFV IN indicated that the Mg2+ coordination might be the possible mechanism of the anti-viral activity. Our findings proved that the synthesized analogs may suggest a very good basis for the development of new anti-HIV-1 agents.

Modular and diverse synthesis of amino acids via asymmetric decarboxylative protonation of aminomalonic acids.

Stereoselective protonation is a challenge in asymmetric catalysis. The small size and high rate of transfer of protons mean that face-selective delivery to planar intermediates is hard to control, but it can unlock previously obscure asymmetric transformations. Particularly, when coupled with a preceding decarboxylation, enantioselective protonation can convert the abundant acid feedstocks into structurally diverse chiral molecules. Here an anchoring group strategy is demonstrated as a potential alternative and supplement to the conventional structural modification of catalysts by creating additional catalyst-substrate interactions. We show that a tailored benzamide group in aminomalonic acids can help build a coordinated network of non-covalent interactions, including hydrogen bonds, π-π interactions and dispersion forces, with a chiral acid catalyst. This allows enantioselective decarboxylative protonation to give α-amino acids. The malonate-based synthesis introduces side chains via a facile substitution of aminomalonic esters and thus can access structurally and functionally diverse amino acids.

Design, synthesis and biological evaluation of novel imidazole-based benzamide and hydroxamic acid derivatives as potent histone deacetylase inhibitors and anticancer agents

New imidazoles bearing benzamide or hydroxamic acid group (as Zn binding groups) were designed and synthesized as HDAC inhibitors. Cytotoxicity of the compounds was evaluated against three types of cancer cells including HCT-116, A549, PC3 and a normal cell line (CHO). The inhibitory activities of the compounds were investigated against pan-HDAC isozymes including HDACs 1, 2, 3 and 6 and the activity of the most potent pan-HDAC inhibitors was evaluated against HDAC1. Most of the compounds showed significant cytotoxicity on cancer cells and did not show significant cytotoxicity on normal CHO cell line. Compound 7d showed promising antiproliferative activity against all the tested cancer cells, stronger than the other compounds. This compound showed significant cytotoxicity against HCT-116 cell line. Compounds 7c, 6a, 7b showed strong pan-HDAC inhibitory activity in HCT-116 cell line near equal to Entinostat. Compounds 7d and 7c inhibited HDAC1 strongly with IC50 values of 0.56 μM and 0.77 μM, respectively, which is comparable to Entinostat (IC50 = 0.49 μM) and is in good agreement with their cytotoxic effects. Annexin V-FITC/Propidium iodide staining assay in HCT116 cancer cells treated with compound 7d promoted cell apoptosis more potently compared to Entinostat as the reference compound. Molecular docking studies of compound 7d showed accepted binding mods of interaction between this compound and the HDAC1 enzyme.

Prediction of bioactivities of microsomal prostaglandin E2 synthase-1 inhibitors by machine learning algorithms.

There is a strong interest in the development of microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors of their potential to safely and effectively treat inflammation. Herein, 70 QSAR models were built on the dataset (735 mPGES-1 inhibitors) characterized with RDKit descriptors by multiple linear regression (MLR), support vector machine (SVM), random forest (RF), deep neural networks (DNN), and eXtreme Gradient Boosting (XGBoost). The other three regression models on the dataset are represented by SMILES using self-attention recurrent neural networks (RNN) and Graph Convolutional Networks (GCN). For the best model (Model C2), which was developed by SVM with RDKit descriptors, the coefficient of determination (R2 ) of 0.861 and root mean squared error (RMSE) of 0.235 were achieved for the test set. Additionally, R2 of 0.692 and RMSE of 0.383 were obtained on the external test set. We investigated the applicability domain (AD) of Model C2 with the rivality index (RI), the prediction of Model C2 on 78.92% of molecules in the test set, and 78.33% of molecules in the external test set were reliable. After dissecting the RDKit descriptors of Model C2, we found important physicochemical properties of highly active mPGES-1 inhibitors. Besides, by analyzing the attention weight of each atom of each inhibitor from the attention layer, we found that the benzamide group and the trifluoromethyl cyclohexane group are favorable substructures for mPGES-1 inhibitors.

Palladium-Catalyzed C(sp2)-H Arylation of Peptides Directed by Aspartic Acid.

Herein, we report a palladium-catalyzed C(sp2)-H di- or monoarylation of short peptides containing N-terminal benzamide groups using aspartic acid (Asp) as an endogenous directing group. This strategy has the following merits: a broad substrate scope, selective diarylation of peptides, and gram-scale synthesis. Furthermore, this strategy can be successfully utilized to synthesize peptide-peptide conjugates.

Treatment of Clozapine-Associated Sialorrhea: The Role of Benzamide Derivatives.

Hypersalivation is one of the most prevalent and distressing adverse effects associated with clozapine treatment. Currently, there is no standard therapeutic approach toward how to overcome it. Clinicians use various medications for managing this adverse effect. However, some of the agents are not effective enough, whereas others can induce other adverse effects. Recently, several reviews have been published on the treatment of clozapine-associated hypersalivation, in which the focus was on drugs from various pharmacological groups, and little attention was paid to drugs from the group of substituted benzamides. The intention of this brief narrative review is to draw the attention of clinicians to the use of the benzamide group for the treatment of this unpleasant adverse effect. A MEDLINE search was conducted to identify published treatment studies and case reports in the literature from 2000 to September 2021, concerning a treatment of clozapine-associated hypersalivation, mainly substituted benzamides. Accumulating evidence during the last 2 decades indicates that agents derived from the benzamide group may be effective and safe agents for treatment of clozapine-associated hypersalivation. Whether with a psychotropic effect or without, medications from this group may produce a beneficial response. Substitute benzamide derivatives have emerged as effective and well-tolerated agents for treatment clozapine-associated hypersalivation.

Strategy of Integrating Ultraviolet Absorption and Antimicrobial Activity in a Single Molecule: DFT Calculation and Experiment.

In the present study, (3,5-benzamide-2,4-dihydroxyphenyl)(phenyl) methanone (UV-CB) was synthesized and investigated as an ultraviolet (UV) absorber and a bacteriostatic agent. The optimized geometry, energy levels, charges, and UV electronic absorption bands of UV-CB in the singlet were calculated by density functional theory (DFT) calculations. The quantum chemical method was used to investigate the geometry and natural bond orbital (NBO) parameters. And the computational studies indicated that the intramolecular hydrogen bond (IMHB) was formed between the 2,4-dihydroxybenzophenone (UV-C) group and the N-(hydroxymethyl)benzamide (NBA) group, which was beneficial to the stability after the combination. The results of the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) tests illustrated that UV-CB is a promising antibacterial agent. The successful synthesis of UV-CB with anti-UV performance and antibacterial ability evidences that DFT calculation is an available approach to design and analyze novel compounds.

Identification of new FK866 analogues with potent anticancer activity against pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases for which chemotherapy has not been very successful yet. FK866 ((E)-N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide) is a well-known NAMPT (nicotinamide phosphoribosyltransferase) inhibitor with anti-cancer activities, but it failed in phase II clinical trials. We found that FK866 shows anti-proliferative activity in three PDAC cell lines, as well as in Jurkat T-cell leukemia cells. More than 50 FK866 analogues were synthesized that introduce substituents on the phenyl ring of the piperidine benzamide group of FK866 and exchange its buta-1,4-diyl tether for 1-oxyprop-3-yl, (E)-but-2-en-1,4-diyl and 2- and 3-carbon tethers. The pyridin-3-yl moiety of FK866 was exchanged for chlorinated and fluorinated analogues and for pyrazin-2-yl and pyridazin-4-yl groups. Several compounds showed low nanomolar or sub-nanomolar cell growth inhibitory activity. Our best cell anti-proliferative compounds were the 2,4,6-trimethoxybenzamide analogue of FK866 ((E)-N-(4-(1-(2,4,6-trimethoxybenzoyl)piperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide) (9), the 2,6-dimethoxybenzamide (8) and 2-methoxybenzamide (4), which exhibited an IC50 of 0.16 nM, 0.004 nM and 0.08 nM toward PDAC cells, respectively.

Synthesis and liquid crystalline behavior of hydrazide-functionalized triphenylenedicarboxyimides

ABSTRACT Seven hydrazide-functionalised triphenylenedicarboxyimides (TDIs) which contain a benzamide group bearing different polar substitutes connected to the imide N atom have been studied with the aim to establish the effect of hydrogen bonding and polar substituents on their mesomorphism properties. Six of seven hydrazides each form two types of hexagonal columnar liquid crystalline (LC) phase, including a low-temperature Colho phase and a high-temperature Colhd phase, which were confirmed by characteristic pseudo focal conic fan-shaped textures and XRD measurements. Temperature-dependent FT-IR studies indicated that hydrogen bonding is not strong enough to exist in the LC phases of these hydrazides and disfavours the stabilisation of the columnar mesophase. Nevertheless, dipole–dipole effects were found to favour the mesophase stabilities of these compounds, and the position of the lateral substituent attached to the end benzene ring has a significant impact on the self-assembly by affecting the overall dipole moment.

Discriminations of active from inactive HDAC8 inhibitors Part II: Bayesian classification study to find molecular fingerprints

ABSTRACTIn continuation of our earlier work (Doi: 10.1080/07391102.2019.1661876), a statistically validated and robust Bayesian model was developed on a large diverse set of HDAC8 inhibitors. The training set comprised of 676 small molecules and 293 compounds were considered as test set molecules. The findings of this analysis will help to explore some major directions regarding the HDAC8 inhibitor designing approach. Acrylamide (G1-G3, G9), N-substituted 2-phenylimidazole (G4-G8, G9, G12-G13, G16-G19), benzimidazole (G10-G11), piperidine substituted pyrrole (G13-G14) groups, alkyl/aryl amide (G15) and aryloxy carboxamide (G20) fingerprints were found to play a crucial role in HDAC8 inhibitory activity whereas -CH-N=CH- (B1, B4-B6, B14) motif, benzamide (B2-B3, B9-B13, B16-B17) groups and heptazepine (B7-B8, B15, B18-B20) group were found to influence negatively the HDAC8 inhibitory activity. The importance of such fingerprints was further validated by the HDAC8 enzyme and related inhibitor interactions at the receptor level. These results are in close agreement with those of our previous work that validate each other. Moreover, this comparative learning may enrich future endeavours regarding the designing strategy of HDAC8 inhibitors.

A new chemotype with promise against Trypanosoma cruzi

Pyridyl benzamide 2 is a potent inhibitor of Trypanosoma cruzi, but not other protozoan parasites, and had a selectivity-index of ≥10. The initial structure–activity relationship (SAR) indicates that benzamide and sulfonamide functional groups, and N-methylpiperazine and sterically unhindered 3-pyridyl substructures are required for high activity against T. cruzi. Compound 2 and its active analogs had low to moderate metabolic stabilities in human and mouse liver microsomes.

Synthesis of New Quinazolin‐4‐(3H)‐one Derivatives and Evaluation of Their Biological Activities

AbstractA new series of quinazolin‐4‐ones are conveniently synthesized in a one‐pot procedure from anthranilamide derivatives and aldehydes using p‐toluenesulfonic acid as a catalyst. The aim of inserting azo pyridyl and 4‐amino benzamide groups in the structure of quinazolin‐4‐one derivatives is to achieve skeletal appearance with more antibacterial and antifungal properties. Therefore, the biological activities of the synthetic compounds were studied. The results revealed that almost all compounds exhibit antimicrobial activities.

Structure-Function Evaluation of Imidazopyridine Derivatives Selective for δ-Subunit-Containing γ-Aminobutyric Acid Type A (GABAA) Receptors.

δ-Selective compounds 1 and 2 (DS1, compound 22; DS2, compound 16) were introduced as functionally selective modulators of δ-containing GABA type A receptors (GABAAR). In our hands, [3H]EBOB-binding experiments with recombinant GABAAR and compound 22 showed no proof of δ-selectivity, although there was a minimally higher preference for the α4β3δ and α6β2/3δ receptors with respect to potency. In order to delineate the structural determinants of δ preferences, we synthesized 25 derivatives of DS1 and DS2, and investigated their structure-activity relationships (SAR). Four of our derivatives showed selectivity for α6β3δ receptors (29, 38, 39, and 41). For all of them, the major factors that distinguished them from compound 22 were variations at the para-positions of their benzamide groups. However, two compounds (29 and 39), when tested in the presence of GABA, revealed effects at several additional GABAAR. The newly synthesized compounds will still serve as useful tools to investigate α6β3δ receptors.

Determination of Fragmentation Schemes and Metabolites of Fluorinated Histone Deacetylase Inhibitors for Use as Positron Emission Tomography Imaging Agents Using HPLC-MS/MS

High performance liquid chromatography coupled with tandem mass spectrometry was developed and validated as a method for the analysis of fluorinated histone deacetylase inhibitors (F-HDACi), and then employed to study their metabolism in biosystems. Four HDACi analogs labeled with the positron emission nuclide 18F constitute a group of potential positron emission tomography imaging agents, which were developed by the Institute of Nuclear Energy Research (INER) and coded as INER-1577 #1, #2, #3, and #4 during animal studies for the diagnosis of dementia. The performance of the method was found to be suitable for the determination of analog #3, and it was employed to determine the structures and fragmentation mechanisms of all four analogs and to study the biotransformations of analogs #3 and #4. The results indicated that the method used for the determination of analog #3 was suitable for determining the abundance of the analogs in chemical and biochemical tests with high precision, accuracy, reproducibility, and recovery. Weaknesses in the chemical bonding of the analogs were found to involve the fluoro, dimethylamino, and benzamide groups in a fragmentation mechanism deduced via tandem mass spectrometry. The metabolites of analogs #3 and #4 in rat liver microsomes and rat plasma were also identified to clarify their characteristic behaviors in biosystems. The major product of analogs #3 in liver microsomes was produced by hydroxylation of the benzylic carbon atom, but in rat plasma the metabolites of analog #3 were produced by hydrolysis of the benzamide group to give a diaminobiphenyl compound with the simultaneous replacement of a fluorine atom by a hydroxyl group. The metabolites of analog #4 in liver microsomes were produced by hydroxylation of the benzylic carbon atom and hydrolysis of the benzamide bond. The results of the studies characterized the chemical and biochemical behaviors of the series F-HADCi analogs.

The compound (3-{5-[(2,5-dimethoxyphenyl)amino]-1,3,4-thiadiazolidin-2-yl}-5,8-methoxy-2H-chromen-2-one) inhibits the prion protein conversion from PrPC to PrPSc with lower IC50 in ScN2a cells

Prion diseases are fatal neurodegenerative disorders of the central nervous system characterized by the accumulation of a protease resistant form (PrPSc) of the cellular prion protein (PrPC) in the brain. Two types of cellular prion (PrPC) compounds have been identified that appear to affect prion conversion are known as Effective Binders (EBs) and Accelerators (ACCs). Effective binders shift the balance in favour of PrPC, whereas Accelerators favour the formation of PrPSc. Molecular docking indicates EBs and ACCs both bind to pocket-D of the SHaPrPC molecule. However, EBs and ACCs may have opposing effects on the stability of the salt bridge between Arg156 and Glu196/Glu200. Computational docking data indicate that the hydrophobic benzamide group of the EB, GFP23 and the 1-(3,3-dimethylcyclohexylidene)piperidinium group of the ACC, GFP22 play an important role in inhibition and conversion from SHaPrPC to SHaPrPSc, respectively. Experimentally, NMR confirmed the amide chemical shift perturbations observed upon the binding of GFP23 to pocket-D of SHaPrPC. Consistent with its role as an ACC, titration of GFP22 resulted in widespread chemical shift changes and signal intensity loss due to protein unfolding. Virtual screening of a ligand database using the molecular scaffold developed from the set of EBs identified six of our compounds (previously studied using fluorescence quenching) as being among the top 100 best binders. Among them, compounds 5 and 6 were found to be particularly potent in decreasing the accumulation SHaPrPSc in ScN2a cells with an IC50 of ∼35µM and 20µM.

Synthesis and biological evaluation of novel synthetic chalcone derivatives as anti-tumor agents targeting Cat L and Cat K

A series of chalcone derivatives bearing benzamide or benzenesulfonamide moieties were synthesized and evaluated for their anti-tumor effect on HCT116, MCF7 and 143B cell lines in vitro. SAR analysis showed that compounds bearing a benzenesulfonamide group had greater potency than those bearing a benzamide group. It was also shown that compounds with a mono-methyl or mono-halogen group at the 3-position on the terminal phenyl ring were more effective than those with trifluoromethyl or methoxy groups. Compound 8e exhibited the most potent anti-tumor activities against HCT116, MCF7 and 143B cell lines, with IC50 values of 0.597, 0.886 and 0.791μM, respectively. Molecular docking studies and enzymatic assays demonstrated that the anti-tumor activity of compound 8e might be regulated by Cat L and Cat K.

Modified biphenyl Hsp90 C-terminal inhibitors for the treatment of cancer

Heat Shock Protein 90 (Hsp90) is a molecular chaperone under clinical investigation for the treatment of neurodegenerative diseases and cancer. Neuroprotective Hsp90 C-terminal inhibitors (novologues) contain a biaryl ring system, and include KU-596, which was modified and investigated for potential anti-cancer activity. Incorporation of a benzamide group onto the biaryl novologues in lieu of the acetamide yielded compounds that manifest anti-cancer activity. Further exploration of the central phenyl ring led to compounds with enhanced anti-proliferative activity. The design, synthesis, and evaluation of these new analogs against breast and prostate cancer cell lines is reported herein, where it was found that 8b and 10 manifest potent anti-proliferative activity and a robust degradation of Hsp90 client-dependent proteins.