Benzamide Derivatives Research Articles

Design and Synthesis of Novel N‐(2‐aminophenyl)benzamide Derivatives as Histone Deacetylase Inhibitors and Their Antitumor Activity Study

Histone deacetylases (HDACs) are promising therapeutic targets for cancer therapy because inhibition of HDACs triggers growth arrest or apoptosis of tumor cells. In the present study, a new series of fluorinated N‐(2‐aminophenyl)benzamide derivatives were synthesized to investigate potential inhibition of HDACs and associated anticancer activity. Among the synthesized derivatives, compound 24a showed potent inhibitory activity of HDACs and higher antitumor efficacy in human cancer cell lines (HCT‐116, MCF‐7, and A549) compared with SAHA. Moreover, animal studies demonstrated that compound 24a showed potent in vivo antitumor efficacy in an HCT‐116 colon cancer xenograft mouse model.

Dual Role of the Rhodium(III) Catalyst in C-H Activation: [4 + 3] Annulation of Amide with Allylic Alcohols to 7-Membered Lactams.

[4 + 3] annulation of primary and secondary benzamide and cinnamamide derivatives using allyl alcohol as a coupling partner catalyzed by Rh(III) is reported, where Rh(III) is playing a dual role of an oxidant and a catalyst for C-H activation. The Rh-catalyst oxidizes allyl alcohol to its carbonyl derivative, and the in situ-generated carbonyl compound reacts with benzamide in the presence of the Rh-catalyst, forming the corresponding alkylated products. Mechanistic studies show that AgSbF6 is also playing a dual role. Apart from being a halide scavenger, AgSbF6 catalyzes the cyclization of the alkylated product, forming the desired lactam. The current method has good synthetic application and is useful for synthesizing a few biologically active compounds that can act as the dopamine D3 receptor ligand, including berberine-like analogues. The deuteration study and control experiments helped us to propose the mechanism.

Design, synthesis, and evaluation of some novel N-benzothiazol-2-yl benzamide derivatives as allosteric activators of human glucokinase

Design, synthesis, and evaluation of some novel N-benzothiazol-2-yl benzamide derivatives as allosteric activators of human glucokinase

The Novel Benzamide Derivative, VKNG-2, Restores the Efficacy of Chemotherapeutic Drugs in Colon Cancer Cell Lines by Inhibiting the ABCG2 Transporter.

The overexpression of ATP-binding cassette transporter, ABCG2, plays an important role in mediating multidrug resistance (MDR) in certain types of cancer cells. ABCG2-mediated MDR can significantly attenuate or abrogate the efficacy of anticancer drugs by increasing their efflux from cancer cells. In this study, we determined the efficacy of the novel benzamide derivative, VKNG-2, to overcome MDR due to the overexpression of the ABCG2 transporter in the colon cancer cell line, S1-M1-80. In vitro, 5 μM of VKNG-2 reversed the resistance of S1-M1-80 cell line to mitoxantrone (70-fold increase in efficacy) or SN-38 (112-fold increase in efficacy). In contrast, in vitro, 5 μM of VKNG-2 did not significantly alter either the expression of ABCG2, AKT, and PI3K p110β protein or the subcellular localization of the ABCG2 protein compared to colon cancer cells incubated with the vehicle. Molecular docking data indicated that VKNG-2 had a high docking score (−10.2 kcal/mol) for the ABCG2 transporter substrate-drug binding site whereas it had a low affinity on ABCB1 and ABCC1 transporters. Finally, VKNG-2 produced a significant concentration-dependent increase in ATPase activity (EC50 = 2.3 µM). In conclusion, our study suggests that in vitro, VKNG-2 reverses the resistance of S1-M1-80, a cancer cell line resistant to mitoxantrone and SN-38, by inhibiting the efflux function of the ABCG2 transporter.

Discovery, SAR, and putative mode of action of N-benzyl-2-methoxybenzamides as potential bleaching herbicides.

Herbicides acting on biosynthesis of plant pigments have contributed greatly to weed control in recent years. In our previous studies, 2-methoxybenzamides were discovered as a novel type of lead compound for the development of bleaching herbicides. A total of 67 benzamide analogues were synthesized and evaluated for herbicidal activity. The structure-activity relationship (SAR) revealed that a methoxyl substitution at the 2-position of the benzoyl moiety is essential for the herbicidal activity of benzamide derivatives, and introduction of small substituents at the meta- or para-position of the benzylamine moiety is also beneficial. Compounds 4, 43 and 44 showed 100% inhibition against Abutilon theophrasti and Amaranthus retroflexus at an application rate of 150 g a.i.ha-1 . The relationship between the structure and herbicidal activity of 2-methoxybenzamides was discussed intensively. Compounds 4, 43 and 44 may serve as novel candidates with a bleaching effect. © 2021 Society of Chemical Industry.

Arene ruthenium, rhodium and iridium complexes containing benzamide derivative ligands: Study of interesting bonding modes, antibacterial, antioxidant and DNA binding studies

The benzamide derivative ligands of benzothiazole (L1) and benzimidazole (L2) upon reaction with halide bridged metal precursors of platinum group yielded a series of complexes (1-6) formulated as [(arene)M(κ1(N)-L)Cl2], where, L = L1 and L2, M = Ru, Rh and Ir, arene = Cp*, p-cymene. Structural studies revealed the bonding of the ligands to the metal centers takes through the nitrogen donor atom of the benzothiazole and benzimidazole moiety in a monodentate fashion. Further reaction of rhodium and iridium complexes with NaN3 in methanol yielded di-azido κ1(N3) monodentate complexes by substituting two chlorides. In the case of ruthenium, azido complexes could not be isolated. Additional treatment of the di-azido complexes with diethyl acetylene dicarboxylate (DEAD) yielded two different bonded triazolo complexes of rhodium (11 and 13) and iridium (12 and 14). In rhodium triazolo complexes, the ligands displayed a chelating mode of bonding through the carbonyl oxygen and the nitrogen atom of the benzothiazole/benzimidazole ring while in iridium triazolo complexes, the ligands retained a monodentate bonding through the nitrogen atom of the benzothiazole/benzimidazole ring and formed two triazole rings. All these complexes were characterized by various spectroscopic techniques. NMR analysis revealed the triazolo ring coordinated to the metal center via the central nitrogen in both the rhodium and iridium triazolo complexes. These complexes as well as the ligands have been studied for antibacterial, antioxidant activity as well as DNA binding studies where a few of the compounds have shown good activity. Amongst these compounds, complex 7 possessed the highest antibacterial and radical scavenging activity while ligand L1 and complexes 1 and 2 showed good affinity as DNA binders.

Synthesis, in vitro and computational studies of novel glycosyl-1, 2, 3-1H-triazolyl methyl benzamide derivatives as potential α-glucosidase inhibitory activity

A series of novel glycosyl-1,2,3-1H-triazolyl methyl benzamide analogues were synthesized by the unambiguous strategy and evaluated for α-glucosidase inhibitory activity. Glycosyl benzamide exhibited a dose-dependent inhibition of α-glucosidase activity. The In-vitro α-glucosidase inhibition activity results indicated that all the synthesized triazolyl methyl benzamide compounds (IC50 values ranging from 25.3 ± 0.8 to 118.5 ± 5.3 μM) exhibited more inhibitory activity in comparison with the standard drug acarbose (IC50 = 750.0 ± 12.5 μM). Among all, the 3 deacetylated glycosyl methyl benzamide derivatives (4c, 4d and 4f) showed promising α-glucosidase enzyme inhibitory activities with IC50 value 25.3 ± 0.8, 26.1 ± 1.5 and 30.6 ± 2.1 respectively. Furthermore, these compounds were subjected to molecular docking and molecular dynamics simulation studies. The molecular docking studies were performed between (PDB ID: 3A4A) target protein and these synthesized molecules. The compounds displayed good docking energies in the range of −7.5 to −7.8 Kcal/mol. This work could be used as an initial approach in identifying potential novel molecules with the promising activity of type-2 diabetes mellitus.

Development of multifunctional polyester using disperse dyes based through a combination of mosquito repellents

Advancement of new protection methodologies to counter mosquito-borne diseases always remains a public intrigue. Among all reported and researched methods, mosquito repellent textiles may prove an effective product, as textiles being the basic need, cover most parts of the human body. This investigation focuses on the synthesis of novel mosquito repellent dyes from a combination of mosquito repellents like N, N‑diethyl-3-methyl benzamide (DEET) derivative, ethyl anthranilate, and 4‑hydroxy coumarin. Resultant dyes were analysed by FTIR, 1HNMR, UV spectroscopy, mass spectroscopy, and elemental analysis. The synthesized dyes were utilized for the dyeing of polyester. Dyed polyester demonstrated 100% mosquito repellency along with other functional properties such as antibacterial activity (>93%) and UV protection (UPF>124). The mosquito repellency was retained to a significant extent even after 20 washes. The synthesized dyes also displayed an efficient antioxidant activity and low algal toxicity. As most of the textiles are coloured, the synthesized novel disperse dyes can act as a tool for the multifunctional modification of polyester-based textile substrates.

Direct Synthesis, Characterization and Theoretical Studies of N‐(6‐Amino‐1,3‐dimethyl‐2,4‐dioxo‐1,2,3,4‐tetrahydropyrimidin‐5‐yl)benzamide Derivatives

AbstractWith the far‐flung importance of uracil and amides in innumerable fields of chemistry and biology, a coherent synthesis that nullifies the use of prodigal reagents, methods and catalysts are hugely accepted. From the present outcomes, we report a highly atom profitable nucleophilic addition reaction of aromatic aldehydes and heterocyclic amines for the generation of amides having an excellent yield and high reproducibility. The main force responsible for the forward reaction is the presence of the nitroso group at the C‐5 position on uracil scaffold, which drives the formation of formidable range products. The conclusive mechanism is based on the dehydrogenation reaction of the carbinolamine product formed during the nucleophilic addition reaction of the aromatic aldehyde with the free heterocyclic amino group to yield the corresponding amides. The synthesized compounds were predicated for biological properties and proved it to be an ideal G protein‐coupled receptor kinase2 (GRK2) inhibitor. Out of all, the compound 3 f showed the most preeminent properties when compared to Paroxetine, studied using molecular docking. At the same time, computed ADME analysis proved them as an ideal drug candidate. Our findings not only prophesize new methods for the synthesis of bioactive‐amides using a cross‐coupling strategy but also demonstrates their novel applications as a human GRK2 inhibitor.

Synthesis and anticancer assessment of some new 2-amino-3-cyanopyridine derivatives

The 2-Aminonicotinonitrile derivative was reacted with different bi-functional reagents such as formamide, thiourea, acetic anhydride, and phthalic anhydride under optimized conditions to give pyrimidine, thiourea, acetamide, and isoindoline derivatives, respectively, When it was treated with active methylene reagents as malononitrile, phenacyl bromide, and ethyl bromoacetate under varied experimental modulation, it afforded 1, 8-naphthyridine, ethyl, and methylamino nicotinonitrile derivatives, respectively. Also, it was reacted with p-toluene sulfonyl chloride, chloroacetyl chloride, and benzoyl chloride to give sulfonamide, 2-chloro-N-acetamide, and benzamide derivatives, respectively. Likewise, it was reacted with diethyl malonate, ethyl cyanoacetate, and cyano acetic acid to give ethylpropanoate, naphthyridine, and cyano acetamide derivatives, respectively. However, treatment of ethylpropanoate and cyano acetamide derivatives with hydrazine hydrate gave pyrazole and 5-amino-pyrazole nicotinonitrile derivatives, respectively. In addition, it was reacted with p-anisaldehyde, phenyl isocyanate, and triethyl orthoformate to give benzylamino nicotinonitrile, phenyl urea, and N-formamide derivatives, respectively. Furthermore, it was reacted with nitrous acid then coupled with aniline; it was also reacted with isatine and 1,3- dibromo propane to give oxoindoline derivative, and the dimer. Elemental analyses, together with spectroscopic data including IR, 1H-NMR in addition to 13C-NMR and mass spectra submit proofs for the chemical structures for all compounds.

Theoretical and experimental verification of molecular properties of novel benzamide derivatives using computational platforms and in vitro antibacterial activity

A series of N-(benzo[d]oxazol-2-ylcarbamothioyl)-2/4-substituted benzamides were synthesized by the reaction of 2-aminobenzoxazole with apposite benzoyl isothiocyanate. The structure of the newly synthesized compounds was confirmed by chemical tests, elemental (C, H, N, and S), and spectral (IR, 1H NMR, 13C NMR, and mass) analysis. All the synthesized compounds were evaluated experimentally for their antibacterial activity against Gram-positive and Gram-negative bacteria. The test results show moderate to potent antibacterial activity compared to the standard drug. The binding interactions of newly synthesized ligand and protein were correlated using a molecular docking study using a binding pocket of GlcN-6-P synthase.

Design and synthesis of new 4-(2-nitrophenoxy)benzamide derivatives as potential antiviral agents: molecular modeling and in vitro antiviral screening

Novel benzamide derivatives as anti adenovirus, HSV-1, coxsackievirus, and SARS-CoV-2: in vitro and in silico study.

Design, Synthesis, Molecular Docking Studies and Antitubercular Evaluation of Hexahydroquinolin-2-yl Benzamide Derivatives

A new series of hexahydroquinolin-2-yl benzamide derivatives (BZ1-10) were designed and synthesized. The synthesized compounds were characterized by 1H NMR, IR and ESI-MS spectra and also subjected for molecular docking studies with the target DNA gyrase enzyme (PBD ID: 4B6C). The molecular docking results of synthesized derivatives indicated the best docking score of -5.105 and -5.02 for BZ9 and BZ4, respectively. All the synthesized compounds were screened for antitubercular activity against H37RV strain, among all, two compounds exhibited significant activity at 12.5 μg/mL and 25 μg/mL concentrations. Thus, the MIC values are in between range of 12.5 and 6.25 μg/mL concentrations. The teratogenicity assay of synthesized compounds was performed in zebrafish larvae, out of the ten compounds, BZ4, BZ6 and BZ8 compounds were found to safer at 0.5 μM concentration without any abnormalities.

In-vitro hypoglycemic activity of lawsonia inermis Linn. Leaf extracts

in-vitro hypoglycemic activity of lawsonia inermis Linn. Leaf extracts

Room-temperature C-H bond alkynylation by merging cobalt and photocatalysts.

A new protocol is developed for the mono- and bis-ortho-C-H alkynylation of easily accessible benzamide derivatives using alkynyl bromides at room temperature by merging cobalt and photocatalysts. The diverse reactivity of various alkynyl bromides towards the C-H alkynylation and competing C-H/N-H bond annulation reactions has been demonstrated to give the corresponding products in good yields with excellent functional group tolerance.

Novel pyrrolizines bearing 3,4,5-trimethoxyphenyl moiety: design, synthesis, molecular docking, and biological evaluation as potential multi-target cytotoxic agents

In the present study, two new series of pyrrolizines bearing 3,4,5-trimethoxyphenyl moiety were designed, synthesised, and evaluated for their cytotoxic activity. The benzamide derivatives 16a–e showed higher cytotoxicity than their corresponding Schiff bases 15a–e. Compounds 16a,b,d also inhibited the growth of MCF-7/ADR cells with IC50 in the range of 0.52–6.26 μM. Interestingly, the new compounds were less cytotoxic against normal MRC-5 cells (IC50=0.155–17.08 μM). Mechanistic studies revealed the ability of compounds 16a,b,d to inhibit tubulin polymerisation and multiple oncogenic kinases. Moreover, compounds 16a,b,d induced preG1 and G2/M cell cycle arrest and early apoptosis in MCF-7 cells. The molecular docking analyses of compounds 16a,b,d into the active site in tubulin, CDK-2, and EGFR proteins revealed higher binding affinities compared to the co-crystallised ligands. These preliminary results suggested that compounds 16a,b,d could serve as promising lead compounds for the future development of new potent anticancer agents. Highlights Two new series of pyrrolizines bearing 3,4,5-trimethoxyphenyl moieties were synthesized. Compounds 16a,b,d displayed the highest cytotoxicity against the three cancer cell lines. Kinase profiling test revealed inhibition of multiple oncogenic kinases by compounds 16a,b,d. Compounds 16a,b,d exhibited weak to moderate inhibition of tubulin-polymerization. Compounds 16a,b,d induced preG1 and G2/M cell cycle arrest and early apoptosis in MCF-7 cells. Docking studies revealed high binding affinities for compounds 16a,b towards tubulin and CDK-2.

Correction: Iron-catalyzed para-selective C–H silylation of benzamide derivatives with chlorosilanes

Correction for ‘Iron-catalyzed para-selective C–H silylation of benzamide derivatives with chlorosilanes’ by Pei Liu et al., Org. Chem. Front., 2021, DOI: 10.1039/d1qo00243k.

Iron-catalyzed para-selective C–H silylation of benzamide derivatives with chlorosilanes

This paper developed the para-selective silylation of benzamide derivatives with chlorosilanes using FeCl2 catalysis.

Synthesis, Characterization and Biological Activities of N-(4-(3,4-Dichlorophenoxy)-phenyl)-4-alkoxybenzamide Derivatives

An alkoxy benzamide derivatives are have been synthesized in four steps. Alkylation, halo phenol coupling, nitro group reduction and acid amine coupling gave in decent yield. Likewise, these targets were synthesized by coupling of 4-(3,4-dichlorophenoxy) aniline with N-(4-(3,4-dichlorophenoxy)phenyl)- 4-alkoxybenzamide by using (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexa fluorophosphate, hexa fluorophosphate azabenzotriazole tetramethyl uronium) (HATU), N,N-diisopropylethylamine (DIPEA) in dimethylformamide (DMF) at 0 ºC to room temperature. Reduction of nitro group in the presence of 10% Pd/C, H2 (g) in MeOH at room temperature. Obtained in decent to excellent yield. Anti-tuberculosis activity of all synthesized derivatives (7a-l) was complete against the H37RV strain as per reported broth dilution method mentioned in experimental section. Bio-assay results showing that derivatives 7c, 7e and 7i exhibited exceptional activity against the H37RV strain with MIC value 62.5 μg/mL. Furthermore, other derivatives were showed poor potency against same strain when compared with standard drugs isoniazid and rifampicin.

Visible-light-induced denitrogenative phosphorylation of benzotriazinones: a metal- and additive-free method for accessing ortho-phosphorylated benzamide derivatives

The first metal-free, visible-light-induced denitrogenative phosphorylation of 1,2,3-benzotriazinones is presented.