Benzamide Analogues Research Articles

Design, synthesis, and anticancer evaluation of novel N-[5-(1,3,4,5-tetrahydroxycyclohexyl)-1,3,4-thiadiazole-2-yl] benzamide analogues through integrated computational and experimental approaches

BackgroundThe main aim of the current study is to develop, synthesize, in silico, in vitro and in vivo potentials of N-[5-(1,3,4,5-tetrahydroxycyclohexyl)-1,3,4-thiadiazole-2-yl] benzamide derivatives for a possible anticancer drug to improve their efficiency and selectivity against cancer cells, computational approaches aided in the rational design of these chemicals. Spectroscopic methods verified the chemical structures of the target compounds. The structures of the synthesized analogs were determined by elemental analysis, IR, 1H NMR, 13C NMR and MS. Structure shows the presence of 1,3,4, thiadiazole also responsible for anticancer activity. The 10 analogs were synthesized and showed encouraging anticancer efficacy in preliminary biological evaluation, suggesting they might be suitable lead candidates for more optimization and preclinical exploration.ResultN-[5-(1,3,4,5-tetrahydroxycyclohexyl)-1,3,4-thiadiazole-2-yl] benzamide derivatives were synthesized (5a-5j) showed an optimum IC50 value in in vitro activity by SRB assay using MCF-7 as a strain, and the few selected analogs 5b,5 g & 5 h were subjected for in vivo anticancer activity by DMBA induction of tumors in mice.ConclusionThrough a computational and experimental approach, this study results a way for newer derivatives for the class of anticancer drugs.

Developing new drugs for adult T-cell leukemia/lymphoma by targeting hypoxia: insights from toxicity of MS-275 and its analogs

The low survival rate of adult T-cell leukemia/lymphoma (ATL) underscores the critical need for innovative therapeutic agents. While the pharmacokinetics of HDACis have been documented in several hematological neoplasms, there is a notable gap in research regarding their activity against ATL. Given that hypoxia can induce unpredictable effects on lymphoma cells, this study aimed to evaluate the toxic effects of MS-275 and novel analogs on ATL cells in hypoxic condition for the first time. Protein-protein interaction and gene set enrichment analyses were performed, the expression of HIF1A and downstream targets were assessed, and molecular docking was conducted on MS-275 and novel analogs with HIF-1α. For in vitro studies, at first benzamide analogs of MS-275 were synthesized and then, viability of MT-2 cells was evaluated in hypoxic condition. Enrichment analyses confirmed the involvement of hub genes in HIF-1 signaling pathway and volcano plot revealed over expression of HIF1A, GAL3ST1 and CD274. Molecular docking indicated favorable interaction between MS-275 and analogs with HIF-1α PAS-B domain. Results of alamarBlue assay demonstrated that MS-275 and analogs significantly (p < 0.001) reduced viability of MT-2 cells in hypoxic condition. Findings of the present study hold promise for developing new drugs targeting hypoxia-induced changes in ATL.

Investigation of the site 2 pocket of Grp94 with KUNG65 benzamide derivatives

Glucose-regulated protein 94 (Grp94) is an isoform of the heat shock protein 90 kDa (Hsp90) family of molecular chaperones. Inhibiting Grp94 has been implicated for many diseases. Co-crystal structures of two generations of Grp94 inhibitors revealed the importance of investigating the ester group, which is projected into the site 2 pocket unique to Grp94. Therefore, a series of KUNG65 benzamide analogs was designed and synthesized to evaluate their impact on the affinity and selectivity for Grp94. The data demonstrated that substituents with small and saturated ring systems that contain hydrogen bond acceptors exhibited increased affinity for Grp94, whereas larger saturated ring system manifested increased selectivity for Grp94 over Hsp90α.

Synthesis and evaluation of the antitumor activity of 2-amino-4-tetrahydroindazole-substituted benzamide derivatives as HSP90 inhibitors

A new series of 2-cycloalkylamino-4–3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl benzamide analogs was synthesized and evaluated for their in vitro antineoplastic activity. These compounds are analogs of 2-(4-hydroxy-cyclohexylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl) benzamide (AT533), which has been previously identified as a potent inhibitor of heat shock protein 90 (HSP90). These newly synthesized analogs showed moderate-to-excellent anti-cancer activity against Eca109, A549, and MDA-MB-231 human carcinoma cells. In particular, JD-10, JD-13, and JD-14 demonstrated more potent antineoplastic effects than AT533 in tumor cells. Molecular docking studies indicated that these novel derivatives bind to the ATP-binding pocket of HSP90.

Synthesis of bitopic ligands based on fallypride and evaluation of their affinity and selectivity towards dopamine D2 and D3 receptors

The difference in the secondary binding site (SBS) between the dopamine 2 receptor (D2R) and dopamine 3 receptor (D3R) has been used in the design of compounds displaying selectivity for the D3R versus D2R. In the current study, a series of bitopic ligands based on Fallypride were prepared with various secondary binding fragments (SBFs) as a means of improving the selectivity of this benzamide analog for D3R versus D2R. We observed that compounds having a small alkyl group with a heteroatom led to an improvement in D3R versus D2R selectivity. Increasing the steric bulk in the SBF increase the distance between the pyrrolidine N and Asp110, thereby reducing D3R affinity. The best-in-series compound was (2S,4R)-trans-27 which had a modest selectivity for D3R versus D2R and a high potency in the β-arrestin competition assay which provides a measure of the ability of the compound to compete with endogenous dopamine for binding to the D3R. The results of this study identified factors one should consider when designing bitopic ligands based on Fallypride displaying an improved affinity for D3R versus D2R.

Design, docking, MD simulation and in-silco ADMET prediction studies of novel indole-based benzamides targeting estrogen receptor alfa positive for effective breast cancer therapy

Breast cancer is one of the most common malignancies in women, afflicting millions of lives each year. Our current study suggests that the development of the most promising 7-substituted -1-(4-(piperidine-1-yl methoxy)benzyl)-1H-indole-3-carboxamide derivatives results in potent anticancer agents through in-silico investigations. The molecular docking was performed against estrogen receptor alpha (ER-α) positive (PDB ID: 3UUD) of breast cancer cells to anticipate the binding modes of the designed compounds and the likely mode of action. The interactions between the ligands and amino acid residues were thoroughly elucidated. The stability of the docked protein-ligand complexes was further confirmed by 100 ns molecular simulations methods. From in-silico studies, indole-based benzamides exhibited satisfactory physicochemical, drug-likeness and toxicity properties. To conclude, the most promising substituted benzamide analogs on the indole ring could serve as a possible modulator against ER-α positive breast cancer.

To Target or Not to Target Schistosoma mansoni Cyclic Nucleotide Phosphodiesterase 4A?

Schistosomiasis is a neglected tropical disease with high morbidity. Recently, the Schistosoma mansoni phosphodiesterase SmPDE4A was suggested as a putative new drug target. To support SmPDE4A targeted drug discovery, we cloned, isolated, and biochemically characterized the full-length and catalytic domains of SmPDE4A. The enzymatically active catalytic domain was crystallized in the apo-form (PDB code: 6FG5) and in the cAMP- and AMP-bound states (PDB code: 6EZU). The SmPDE4A catalytic domain resembles human PDE4 more than parasite PDEs because it lacks the parasite PDE-specific P-pocket. Purified SmPDE4A proteins (full-length and catalytic domain) were used to profile an in-house library of PDE inhibitors (PDE4NPD toolbox). This screening identified tetrahydrophthalazinones and benzamides as potential hits. The PDE inhibitor NPD-0001 was the most active tetrahydrophthalazinone, whereas the approved human PDE4 inhibitors roflumilast and piclamilast were the most potent benzamides. As a follow-up, 83 benzamide analogs were prepared, but the inhibitory potency of the initial hits was not improved. Finally, NPD-0001 and roflumilast were evaluated in an in vitro anti-S. mansoni assay. Unfortunately, both SmPDE4A inhibitors were not effective in worm killing and only weakly affected the egg-laying at high micromolar concentrations. Consequently, the results with these SmPDE4A inhibitors strongly suggest that SmPDE4A is not a suitable target for anti-schistosomiasis therapy.

Synthesis, QSAR study and Pharmacological Evaluation of Novel Triazolidine-2-thione Analogues as Antimicrobial, Anti-inflammatory and Antioxidant agents.

The triazole analogues are molecules of immense attraction because of their wide pharmacological applications. Present research deals with the synthesis of triazole-2-thione analogues and their QSAR study. The synthesized analogs are also evaluated for their antimicrobial, anti-inflammatory, and antioxidant effect. It was revealed that the benzamide analogues (3a, 3d) and triazolidine analogue (4b) were found to be most active against P. aeruginosa and E. coli with pMIC values of 1.69, 1.69 and 1.72, respectively. The antioxidant study of the derivatives showed that 4b was the most active antioxidant with 79% protein denaturation inhibition. The highest anti-inflammatory activity was shown by 3f, 4a and 4f. This study provides certain potent leads for further development of more potential anti-inflammatory, antioxidant and antimicrobial agents.

Novel Hybrid Indole-Based Caffeic Acid Amide Derivatives as Potent Free Radical Scavenging Agents: Rational Design, Synthesis, Spectroscopic Characterization, In Silico and In Vitro Investigations

Antioxidant small molecules can prevent or delay the oxidative damage caused by free radicals. Herein, a structure-based hybridization of two natural antioxidants (caffeic acid and melatonin) afforded a novel hybrid series of indole-based amide analogues which was synthesized with potential antioxidant properties. A multiple-step scheme of in vitro radical scavenging assays was carried out to evaluate the antioxidant activity of the synthesized compounds. The results of the DPPH assay demonstrated that the indole-based caffeic acid amides are more active free radical scavenging agents than their benzamide analogues. Compared to Trolox, a water-soluble analogue of vitamin E, compounds 3a, 3f, 3h, 3j, and 3m were found to have excellent DPPH radical scavenging activities with IC50 values of 95.81 ± 1.01, 136.8 ± 1.04, 86.77 ± 1.03, 50.98 ± 1.05, and 67.64 ± 1.02 µM. Three compounds out of five (3f, 3j, and 3m) showed a higher capacity to neutralize the radical cation ABTS•+ more than Trolox with IC50 values of 14.48 ± 0.68, 19.49 ± 0.54, and 14.92 ± 0.30 µM, respectively. Compound 3j presented the highest antioxidant activity with a FRAP value of 4774.37 ± 137.20 μM Trolox eq/mM sample. In a similar way to the FRAP assay, the best antioxidant activity against the peroxyl radicals was demonstrated by compound 3j (10,714.21 ± 817.76 μM Trolox eq/mM sample). Taken together, compound 3j was validated as a lead hybrid molecule that could be optimized to maximize its antioxidant potency for the treatment of oxidative stress-related diseases.

Satellite ligand effects on magnetic exchange in dimers. A structural, magnetic and theoretical investigation of Cu2L2X4 (L = methylisothiazolinone and X = Cl-, Br-).

Halide-bridged polymers have gained significant interest due to their diverse properties and potential applications. Stacked Cu2L2X4 dimers, where L is an organic ligand and X can be Cl- or Br-, are of interest because a chloride analogue where L = 2-pyridone, had previously been reported to exhibit bulk ferromagnetism, which augured great potentiality for this class of compounds. The synthesis, structural characterization, magnetic susceptibility measurements, and computational studies of two isostructural CuClMI (MI = methylisothiazolinone) and CuBrMI polymers of Cu(II), along with a related CuClPYR (PYR = 2-pyridone) is reported. CuClMI and CuBrMI were found to exhibit AFM bulk properties, due to FM/AFM alternating chains along the halide-bridged polymer axis, while FM bulk properties were confirmed for CuClPYR exhibiting a FM spin ladder. In combination with a benzamide analogue, CuClBA, three O-donor amides, CuClMI, CuClBA and CuClPYR were analyzed and revealed that the kinetic exchange is affected by the identity, but more importantly, the orientation of the satellite ligands. The torsional angle of the ligand with the dimer plane is shown to significantly affect the magnetic exchange in the dimer, and between dimers, explaining the reported FM bulk properties of CuClPYR. This finding is exceedingly important, as it suggests that a spin device can be constructed to flip between singlet/triplet states by manipulating the orientation of the satellite/terminal ligand.

Efficient Synthesis of 4‐Bromo‐N‐(1‐phenylethyl)benzamide, Arylation by Pd(0) Catalyst, Characterization and DFT Study

AbstractThe (S)‐4‐bromo‐N‐(1‐phenylethyl)benzamide (3) was synthesized in excellent yield (93 %) by the reaction of 4‐bromobenzoic acid (1) and (S)‐1‐phenylethanamine (2) with the coupling reagent titanium tetrachloride (TiCl4). Further, the Pd(0) catalyst was employed to form (S)‐4‐bromo‐N‐(1‐phenylethyl)benzamide analogues (5 a‐i) by reacting various aryl boronic acids with 4‐bromo‐N‐(1‐phenylethyl)benzamide (3) in moderate to good yields (62‐89 %). Furthermore, DFT studies were carried out to compute optimized geometries, frontier molecular orbitals, polarizability (α), hyperpolarizability (β), MESP, reactivity descriptors, and NMR spectra. The measured NMR values matched the experimental NMR values well. In this series (5 a‐i), we predicted that the highest energy difference between the HOMO‐LUMO of compound (5 a) has 4.98 eV, resulting in a more stable compound, and compound (5 g) has the lowest energy difference between the HOMO‐LUMO 4.63 eV, resulting in the least stable compound. Compound (5h) has the highest hyperpolarizability (β) value, exhibits a better non‐linear optical (NLO) behaviour compared as compare to other synthesized compounds in the series.

Structure-Based Bioisosterism Design, Synthesis, Biological Evaluation and In Silico Studies of Benzamide Analogs as Potential Anthelmintics

A recent screen of 67,012 compounds identified a new family of compounds with excellent nematicidal activity: the ortho-substituted benzamide families Wact-11 and Wact-12. These compounds are active against Caenorhabditis elegans and parasitic nematodes by selectively inhibiting nematode complex II, and they display low toxicity in mammalian cells and vertebrate organisms. Although a big number of benzamides were tested against C. elegans in high-throughput screens, bioisosteres of the amide moiety were not represented in the chemical space examined. We thus identified an opportunity for the design, synthesis and evaluation of novel compounds, using bioisosteric replacements of the amide group present in benzamides. The compound Wact-11 was used as the reference scaffold to prepare a set of bioisosteres to be evaluated against C. elegans. Eight types of amide replacement were selected, including ester, thioamide, selenoamide, sulfonamide, alkyl thio- and oxo-amides, urea and triazole. The results allowed us to perform a structure–activity relationship, highlighting the relevance of the amide group for nematicide activity. Experimental evidence was complemented with in silico structural studies over a C. elegans complex II model as a molecular target of benzamides. Importantly, compound Wact-11 was active against the flatworm Echinococcus granulosus, suggesting a previously unreported pan-anthelmintic potential for benzamides.

Discovery and functional characterization of N-(thiazol-2-yl)-benzamide analogs as the first class of selective antagonists of the Zinc-Activated Channel (ZAC)

The Zinc-Activated Channel (ZAC) is an atypical member of the Cys-loop receptor (CLR) superfamily of pentameric ligand-gated ion channels, with its very different endogenous agonists and signalling properties. In this study, a compound library screening at ZAC resulted in the identification of 2-(5-bromo-2-chlorobenzamido)-4-methylthiazole-5-methyl ester (1) as a novel ZAC antagonist. The structural determinants for ZAC activity in 1 were investigated by functional characterization of 61 analogs at ZAC expressed in Xenopus oocytes by two-electrode voltage clamp electrophysiology, and couple of analogs exerting more potent ZAC inhibition than 1 were identified (IC50 values: 1–3 μM). 1 and N-(4-(tert-butyl)thiazol-2-yl)-3-fluorobenzamide (5a, TTFB) were next applied in studies of the functional properties and the mode of action of this novel class of ZAC antagonists. TTFB was a roughly equipotent antagonist of Zn+- and H+-evoked ZAC signaling and of spontaneous ZAC activity, and the slow on-set of its channel block suggested that its ZAC inhibition is state-dependent. TTFB was found to be a selective ZAC antagonist, exhibiting no significant agonist, antagonist or modulatory activity at 5-HT3A, α3β4 nicotinic acetylcholine, α1β2γ2S GABAA or α1 glycine receptors at 30 μM. 1 displayed largely non-competitive antagonism of Zn2+-induced ZAC signalling, and TTFB was demonstrated to target the transmembrane and/or intracellular domains of the receptor, which collectively suggests that the N-(thiazol-2-yl)-benzamide analog acts a negative allosteric modulator of ZAC. We propose that this first class of selective ZAC antagonists could constitute useful pharmacological tools in future explorations of the presently poorly elucidated physiological functions governed by this CLR.

Design, synthesis and anti-fibrosis evaluation of imidazo[1,2–a]pyridine derivatives as potent ATX inhibitors

A series of imidazo[1,2–a]pyridine compounds bearing urea moiety (8–27) were designed, synthesized and evaluated for their ATX inhibitory activities in vitro by FS-3 based enzymatic assay. Delightfully, benzylamine derivatives (14–27) exhibited higher ATX inhibitory potency with IC50 value ranging from 1.72 to 497 nM superior to benzamide analogues (8–13). Remarkably, benzylamine derivative 20 bearing 4-hydroxypiperidine exerted an amazing inhibitory activity (IC50 = 1.72 nM) which exceeded the positive control GLPG1690 (IC50 = 2.90 nM). Simultaneously, the binding model of 20 with ATX was established which rationalized the well performance of 20 in enzymatic assay. Accordingly, further in vivo studies were carried out to evaluate direct anti-fibrotic effects of 20 through Masson staining. Notably, 20 effectively alleviated lung structural damage with fewer fibrotic lesions at an oral dose of 60 mg/kg, qualifying 20 as a promising ATX inhibitor for IPF treatment.

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.

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.

Design and synthesis of newer N-benzimidazol-2yl benzamide analogues as allosteric activators of human glucokinase

Allosteric activators of human glucokinase (GK) had revealed significant hypoglycemic effects for therapy of type-2 diabetes (T2D) in animal as well as human models. Some newer N-benzimidazol-2yl substituted benzamide analogues were prepared and assessed for activation of GK accompanied by molecular docking investigations for predicting the bonding interactions of these derivatives with the residues in allosteric site of GK protein. Amongst the derivatives synthesized, compounds 2 and 7 strongly increased catalytic action of GK (GK activation fold >2.0 in comparison to control) in vitro. The results of in-vitro testing were supported by the molecular docking investigations of these analogues with GK protein’s allosteric site residues (showed appreciable H-bond interactions with Arg63 residue of GK). Derivatives investigated in present study afforded few lead compounds for the discovery of harmless and strong allosteric GK activating compounds for treating T2D.

PET Imaging of Melanoma Using Melanin-Targeted Probe.

Melanin exists in the most of melanoma lesions. Melanin plays an important role in melanoma progression, metastasis, therapy response, and the overall survival of patients. Therefore, melanin is a critical target for melanoma diagnosis and therapy. Many melanin targeting probes, such as radioisotope-labeled benzamide analogs, have been developed for melanoma diagnosis using positron emission tomography (PET). The N-(2-(diethylamino)-ethyl)-18F-5-fluoropicolinamide (18F-P3BZA) probe is one of the benzamide analogs and has been preliminarily tested for clinical diagnosis of melanoma in our recent studies. It has shown high specificity and favorable in vivo performance for PET of melanoma. Herein, we describe the detailed synthesis protocol of 18F-P3BZA and PET/CT imaging procedure for animal models and patients.

Synthesis of 2-methoxybenzamide derivatives and evaluation of their hedgehog signaling pathway inhibition.

Aberrant hedgehog (Hh) signaling is implicated in the development of a variety of cancers. Smoothened (Smo) protein is a bottleneck in the Hh signal transduction. The regulation of the Hh signaling pathway to target the Smo receptor is a practical approach for development of anticancer agents. We report herein the design and synthesis of a series of 2-methoxybenzamide derivatives as Hh signaling pathway inhibitors. The pharmacological data demonstrated that compound 21 possessed potent Hh pathway inhibition with a nanomolar IC50 value, and it prevented Shh-induced Smo from entering the primary cilium. Furthermore, mutant Smo was effectively suppressed via compound 21. The in vitro antiproliferative activity of compound 21 against a drug-resistant cell line gave encouraging results.

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

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