Amide Derivatives Research Articles

Design and cytotoxic activity of thiazolidinones via one-pot, three component reaction under microwave and traditional method

Treatment of sulfamethoxazole (SMZ ) (1) with different aromatic aldehydes 2a-f within few minutes (5-8 min) afforded the corresponding Schiff bases 3a-f which were subjected to react with thioglycolic acid (4) under refluxing toluene/dimethlformamide (DMF) in (1:1) ratio for 12-17 h, yielded N-(5-methylisoxazol-3-yl)-4-(4-oxo-2-phenyl-1,3-thiazolidin-3-yl)benzenesulfon- amide derivatives 5a-f. On the other hand, the same products 5a-f were obtained when SMZ (1) was treated with a mixture of the same aromatic aldehydes 2a-f and thioglycolic acid 4 via one-pot, three-component reaction under microwave irradiation. The key advantages of this process were high yields 79-88%, shorter reaction times 6-11 min., easy work-up, and problems associated with toxic solvent use (cost, safety, pollution) were avoided. The structures of newly compounds were elucidated by elemental and spectral analyses. Three compounds 5a, 5b and 5f were tested for cytotoxicity against four human cancer cell lines MCF-7, HePG2, HCT 116 and 116 PC-3. Compound 5b exhibited the most potent cytotoxic properties on HePG2 and PC-3. Furthermore, it showed inhabitory effect against MCF-7 and HCT 116 cells.
 KEY WORDS: Sulfamethoxazole, 4-Thiazolidinones, Schiff bases, Multicomponent reaction, Microwave, Traditional methods and cytotoxicity
 Bull. Chem. Soc. Ethiop. 2024, 38(2), 481-491. 
 DOI: https://dx.doi.org/10.4314/bcse.v38i2.15

Thiophenpiperazine amide derivatives as new dual MOR and σ1R ligands for the treatment of pain

A new series of thiophenpiperazine amide derivatives as potent dual ligands for the μ-opioid (MOR) and sigma-1 (σ1R) receptors are reported. Compound 23 exhibited good affinity to σ1R (Ki = 44.7 ± 7.05 nM) and high selectivity to σ2R. Furthermore, Compound 23 exerted MOR agonism and σ1R antagonism and potent analgesic activity in animal moldes (the abdominal constriction test (ED50 = 3.83 mg/kg) and carrageenan-induced inflammatory hyperalgesia model (ED50 = 5.23 mg/kg)). We obtained new dual ligands that might serve as starting points for preparing targeted tools. Furthermore, 23 may be a useful chemical probe for understanding more fully analgesic effects associated with MOR agonism and σ1R antagonism.

Molecular phylogeny, Sequence-based drug design, Docking built virtual screening, dynamics simulations, and ADMET properties of thiazolino 2-pyridone amide derivatives as an inhibitor of Chlamydia trachomatis and SARS-CoV-2 protein

The propagation of emerging diseases and the expensive cost and time lost by using the classic methods, especially in the current scenario with the world being plagued by SARS-CoV-2 and Chlamydia trachomatis diseases, make finding another way to invent new medication very important. That's why we used computational approaches to predict protein-ligand interactions of thiazolino 2-pyridone amide derivatives. The high-throughput virtual screening requires extensive combing through existing datasets in the hope of finding possible matches to screen for new molecules able to inhibit SARS-CoV-2 and Chlamydia trachomatis diseases. In this study, 46 thiazolino-2-pyridone amide derivatives were chosen for planning the powerful inhibitors by utilizing various strategies: QSAR analysis, phylogenetic analysis, homology modeling, docking simulation, molecular dynamics (MD) simulation, as well as ADMET Screening. The 2D QSAR investigation uncovers that these compounds show a satisfactory connection with bioactivity. From that point onward, phylogenetic analysis and homology modeling were used to model the selected receptors, which were then evaluated using both the SAVES and PROSA servers, indicating the best correctness of the modeled protein with the experimental results. Additionally, a docking simulation investigation was carried out to comprehend the 46 thiazolino-2-pyridone amide derivatives' interactions with homologous proteins. Additionally, MD simulations coupled with MM/GBSA verified the chosen complex systems' stability over 1000 ps. Two compounds were chosen as possible inhibitors based on these findings. The expected thiazolino-2-pyridone amide's oral bioavailability and toxicity have been discovered under the ADMET. Thus, these discoveries can be leveraged to develop novel molecules with the necessary action.

An Efficient Synthesis and Characterization of Amine and Amide Derivatives of Ethyl 6‐(trifluoromethyl)nicotinate

AbstractA new bioactive amine and amide derivatives of trifluoromethyl pyridine was produced with good yields from commercially accessible and inexpensive starting materials and characterized using 1HNMR, 13CNMR, and mass spectrum analysis. We prepared all the intermediates in gram scale, it will be viable for industrial production, because the compounds contain a bioactive core component, trifluoromethylpyridine, they will be useful in developing new insecticides with improved therapeutic action.

Green synthesis of nanocellulose supported cu-bionanocomposites and their profound applicability in the synthesis of amide derivatives and controlling of food-borne pathogens

Copper bionanocomposites (CBNCS) were synthesized using Ipomoea carnea- sourced nanocellulose as support via an eco-friendly and cost-effective method. X-ray Diffractometer (XRD) pattern of CBNCS confirmed the octahedral structure of Cu2O, the face-centered cubic (FCC) crystal structure of Cu(0). XRD also revealed the crystal lattice of cellulose II. Surface Electron Microscope (SEM) and Transmission Electron Microscope (TEM) revealed the uniform distribution of copper nanoparticles (Cu NPs) with an average size of 10 nm due to the presence of nanocellulose. X-ray photoelectron spectroscopy (XPS) provided information about the electronic, chemical state and elemental composition of CBNCS. Thermogravimetric Analysis (TGA) showed the thermal stability of CBNCS. CBNCS catalyzed the rearrangement of oximes to primary amides in a very mild condition with a high yield of up to 92 %. CBNCS effectively inhibited the growth of Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) with lower minimum inhibitory concentration MIC values. Antioxidant activity and electrical conductivity of CBNCS were also determined.

Discovery of Trifluorobutene Amide Derivatives as Potential Nematicides: Design, Synthesis, Nematicidal Activity Evaluation, SAR, and Mode of Action Study.

Plant-parasitic nematodes are one of the major threats to crop protection. However, only limited nematicides are currently available and are confronted with a growing resistance problem, which necessitates the development of novel nematicides. In this study, a series of trifluorobutene amide derivatives was synthesized through the strategy of amide bond reversal, and their nematicidal activity against Meloidogyne incognita was evaluated. The bioassay showed that compounds C2, C10, and C18 and some analogues thereof exhibited good nematicidal activity. Among them, the derivatives of compound C2 containing a benzene ring [C26 (R = 2-CH3) and C33 (R = 2-Cl)] exhibited excellent bioactivity against M. incognita in vitro. The LC50/72h values reached 14.13 and 14.71 mg·L-1, respectively. Moreover, analogues of compounds C10 and C18 containing a thiophene ring [C43 (R = 5-CH3), C44 (R = 4-CH3), and C50 (R = 5-Cl)] exhibited significant bioactivity against M. incognita in vivo with inhibition rates of 68.8, 65.5, and 69.8% at 2.5 mg·L-1 in a matrix, respectively. Meanwhile, C44 and C50 also showed excellent control effects against M. incognita in both cups and microplots. The structure-activity relationship (SAR) of synthesized compounds was discussed in detail. Comparative molecular field analysis (CoMFA) was also conducted to develop the SAR profile. The preliminary mode of action investigation showed that compound C33 exhibited strong inhibition on egg hatching, motility, feeding behavior, and growth of Caenorhabditis elegans. At the same time, the impact of active compounds on biochemical indicators related to oxidative stress showed that compound C33 influenced the production of ROS (reactive oxygen species), and the accumulation of lipofuscin and lipids on C. elegans.

Rhodamine B Amide Derivatives with Anticancer Activity and Fluorescence Properties for Potential Theranostic Applications

AbstractRhodamine B (RHB) based derivatives are especially known for their dye characteristics. Nevertheless, very limited of such revealed promising in‐vivo and in‐vitro therapeutic potency; besides demonstrating great interest due to their excellent photophysical and structural proficiency. Therefore, novel RHB derivatives with significant biological activity are requisite. Hence, current work presents the contemporary design aspect, synthesis, characterization, and anticancer activity of five new RHB amides attained by reacting RHB specifically with simple small amines being side chains of existing anticancer drugs. Therefore, this strategy resulted in a dual effect i. e. fluorescence property and considerable anticancer activity among achieved RHB amides. Obtained fluorophores exhibited emission wavelength at ∼560 nm, a fluorescence quantum yield Φf=10 to 40 % in aqueous solutions, and showed operational stability in pH 4–10, conditions. Further, a study for in‐vitro cell‐based experiments was carried out, wherein AGS (Human gastric cancer) and B16F10 (Murine melanoma) cells were used to screen the compounds. Hydroxy phenyl piperazine substituted RHB amide showed greater growth inhibition than other compounds with an IC50 value of 1.18 μM and 9.07 μM in AGS and B16F10 cells. Fluorescence imaging was performed for the compounds in AGS cells with DAPI as the counterstain using confocal laser microscopy.

Efficient amidation of weak amines: synthesis, chiral separation by SFC, and antimicrobial activity of N-(9,10-dioxo-9,10-dihydroanthracen-1-yl) carboxamide.

An effective and straightforward method for the synthesis of 1-aminoanthracene-9,10-dione carboxamides by coupling a weakly reactive amine, 1-aminoanthracene-9,10-dione, and sterically hindered carboxylic acids was achieved using COMU as the coupling agent. Furthermore, making use of the advantages associated with the super-critical fluid chromatography (SFC) technique, a simplified and straightforward method for the chiral separation of optically active amide derivatives from the impurities associated with the reaction mixture, in a single step, was demonstrated. The antimicrobial activity of selected 1-aminoanthracene-9,10-dione carboxamides was studied. Advanced NMR and other spectral techniques were used for the thorough characterization of all the compounds. This study provides a general and simplified method for coupling a weak amine with a sterically hindered acid using COMU as a coupling agent, and demonstrates the separation of optically pure compounds from reaction related impurities in a single step using SFC, and identification of amide derivatives of 1-aminoanthracene-9,10-dione as potential antimicrobial agents.

Synthesis, in-vitro antioxidant and anti-inflammatory properties of novel amide derivatives of substituted 2-aminothiophenes and 3,4-dimethoxy cinnamic acid

Novel amide derivatives using substituted 2-aminothiophenes (1A–12A) were synthesized by following a suitable procedure. The synthesized compounds were characterized by physical and spectral data. The compounds were screened for in-vitro antioxidant and anti-inflammatory activities with reference to the standard drugs, Ascorbic acid and Ibuprofen respectively. The majority of the compounds showed good antioxidant activity in DPPH and hydroxyl radical scavenging assays. The synthesized compounds were also tested for in-vitro anti-inflammatory activity by protein denaturation and HRBC membrane stabilization methods. Among all, the compounds 2A and 3A showed significant in-vitro anti-inflammatory activity when compared with the standard drug Ibuprofen.

Ugi bisamides based on pyrrolyl-β-chlorovinylaldehyde and their unusual transformations.

By one-pot four- and three-component Ugi reactions involving convertible isocyanides and unexplored pyrrole-containing β-chlorovinylaldehyde, a small library of 20 bisamides with unusual behavior in post-Ugi transformations was prepared and characterized. Surprisingly, a well-documented approach to obtain peptide-containing carboxylic acids through acid hydrolysis of the convertible isocyanide moiety in the Ugi bisamides proceeded in an unexpected manner in our case, leading to the formation of derivatives of amides of heterylidenepyruvic acid. An optimized synthetic protocol for this transformation was elaborated and a plausible sequence involving the elimination of the 2-chloroacetamide moiety and the conversion of the β-chlorovinyl fragment into a vinyl one is provided.

Exchangeable disulfide bond containing highly flexible epoxy vitrimers with shape‐memory, self‐healing, and UV shielding attributes

AbstractWith the rise in momentous resource wastage and severe environmental pollution, a viable path for sustainability is through the use of reprocessable and recyclable materials like vitrimers. Herein, we demonstrated the synthesis of dynamic disulfide‐containing epoxy resin by condensing an amide derivative of 2,2′‐dithiodibenzoic acid with epichlorohydrin. The aforementioned epoxy resin was cured utilizing the two bio‐based curing agents poly(amido amine) and cystamine to produce three distinct epoxy vitrimers. The use of reactive diluent reduced the generation of volatile organic compounds during the curing process. The existence of disulfide bond and aliphatic moiety in the epoxy vitrimers established high elongation at break with good tensile strength. Owing to the dynamic bond, the vitrimers exhibited self‐healing properties with a healing efficiency of 71.48% along with good shape memory abilities. Additionally, the disulfide bond dynamic exchange reaction allowed the polymer chain architecture to topologically reorganize, making them reprocessable and degradable. Moreover, these epoxy vitrimers have the ability to shield ultraviolet radiation as well as inhibits oxidation, and have good chemical resistance properties. The investigated epoxy thermoset thus provides a lot of potential for application as a durable thin film material.

Direct pseudomorphic transformation of silica from rice husk into organo-functionalized MCM-41

Highly ordered bio-sourced MCM-41 functionalized with amide derivatives of amino acids (AA) was successfully synthesized and applied for protein separation.

Iodide-umpolung catalytic system for non-traditional amide coupling from nitroalkanes and amines.

An N-iodosuccinimide (NIS) catalyst was developed for use in the non-traditional synthesis of amide derivatives from nitroalkanes and amines. In contrast to traditional oxidative catalysis, this catalytic system involves reversing the polarities of two catalytic components (umpolung) by means of a hypervalent iodine reagent. A variety of functional groups were tolerated in the reaction, suggesting that they have the potential for use in other types of oxidative catalytic reactions.

Metal-free photoinduced generation and alkynylation of carbamoyl radicals: a facile synthesis of alkynyl amides.

A metal-free photoinduced alkynylation of carbamoyl radicals with hypervalent iodine(III) reagents for a facile synthesis of alkynyl amides is described. This protocol features good functional group tolerance and a broad substrate scope for direct synthesis of alkynyl amide derivatives in good to excellent yields under mild and redox-neutral reaction conditions. The synthetic application is demonstrated by the late-stage installation of alkynyl amides into natural products and active pharmaceutical relevant molecules. The mechanistic studies indicated the simultaneous existence of photoredox catalytic and direct photoexcited processes, and the quantum yields confirmed the occurrence of the radical chain propagation process.

Novel anthraquinone amide derivatives as potential glyoxalase-I inhibitors.

This study aimed to identify novel Glyoxalase-I (Glo-I) inhibitors with potential anticancer properties, focusing on anthraquinone amide-based derivatives. We synthesized a series of these derivatives and conducted in silico docking studies to predict their binding interactions with Glo-I. In vitro assessments were performed to evaluate the anti-Glo-I activity of the synthesized compounds. A comprehensive structure-activity relationship (SAR) analysis identified key features responsible for specific binding affinities of anthraquinone amide-based derivatives to Glo-I. Additionally, a 100 ns molecular dynamics simulation assessed the stability of the most potent compound compared to a co-crystallized ligand. Compound MQ3 demonstrated a remarkable inhibitory effect against Glo-I, with an IC50 concentration of 1.45 µM. The inhibitory potency of MQ3 may be attributed to the catechol ring, amide functional group, and anthraquinone moiety, collectively contributing to a strong binding affinity with Glo-I. Anthraquinone amide-based derivatives exhibit substantial potential as Glo-I inhibitors with prospective anticancer activity. The exceptional inhibitory efficacy of compound MQ3 indicates its potential as an effective anticancer agent. These findings underscore the significance of anthraquinone amide-based derivatives as a novel class of compounds for cancer therapy, supporting further research and advancements in targeting the Glo-I enzyme to combat cancer.

Synthesis of novel N-substituted benzyl N-(1,3-benzothiazol-2-yl) acetamides and their in vitro antibacterial activities

The novel Schiff bases 3a-3d were synthesized by reacting with 6- methyl-2-aminobenzothiazole and different substituted benzaldehydes. Afterwards, the obtained Schiff bases were reduced with NaBH4 to form amine compounds 4a-4d. In the final step, reaction of the amine with chloroacetyl chloride gave the novel amide derivatives 5a-5d. The structures of the all novel synthesized compounds were characterized by FT-IR, 1H NMR, 13C NMR, ESI MS, HETCOR, 2D (1H-1H) COSY and elemental analyses. To investigate the antimicrobial activities of the novel synthesized compounds, they were tested against some Gram-positive and Gram-negative bacterial and fungal species and the results were discussed.

Design, synthesis and anticancer evaluation of various aryl amide derivatives of thiazole-benzothiazole-pyrimidines

We have developed a new series of various aryl amide derivatives of thiazole-benzothaizole-pyrimidines (13a-j). Their chemical structures were characterized by 1HNMR, 13CNMR and mass spectral data. Further, in vitro anticancer properties of newly developed compounds 13a-j were investigated against four human cancer cell lines including MCF-7 (breast cancer), A549 (lung cancer), Colo-205 (colon cancer) & A2780 (ovarian cancer) by employing the MTT assay, and were compared with etoposide used as a standard reference. Most of the tested compounds displayed moderate to good anticancer activities compared to etoposide. The in vitro assay results indicated that compounds 13a, 13b, 13c and 13d possessed more potent activity as compared with the standard. One of the compounds, like 13a displayed superior anticancer activity.

Discovery of benzoheterocyclic-substituted amide derivatives as apoptosis signal-regulating kinase 1 (ASK1) inhibitors.

Three series of benzoheterocyclic-substituted amide derivatives were designed and synthesized as potent ASK1 inhibitors in this work. After undergoing continuous structural optimization, compound 17a was discovered to be a novel inhibitor of ASK1 with good potency (kinase, IC50 = 26 nM), noteworthy liver microsomal stability (human, T1/2 = 340.4 min), good pharmacokinetic parameters (rat, T1/2 p.o. = 2.11 h, AUClast p.o. = 10 900 h ng mL-1) and high oral bioavailability (rat, F = 97.9%), while also being inactive towards hERG (IC50 > 10 μM).

In silico prediction of some pharmacokinetic, safety, biological activity and molecular docking studies of 1-piperazine indole hybrid with nicotinic amide and nicotinic acid and their analogues.

In silico predictions are now being utilized in drug discovery and design to assess the physicochemical, pharmacokinetics, and safety properties of compounds at the beginning of the drug discovery process. This early evaluation of the physicochemical, pharmacokinetics, and safety properties of compounds helps the researchers to invest their time and resources only in the best prospective lead compounds by eliminating compounds with a low chance of success. The purpose of this study was to explore a promising lead compound designed from 1-piperazine indole hybrid with nicotinic amide and nicotinic acid analogs targeted on Trypanosoma brucei phosphofructokinase for Trypanosomiasis activity by using in silico predictions strategy. The physicochemical, safety, pharmacokinetic, and biological activity properties of those molecules were predicted by using ADMETlab 2.0, ACD labs Chem Sketch software version 14.0, Molinspiration software, and MolPredictX online tool. Our results indicate that several promising candidates exhibit favorable characteristics. Based on Molinspiration software both nicotinic acid and nicotinic amide derivatives showed higher kinase inhibitor activity and all nicotinic acid derivatives revealed enzyme inhibitors and GPCR ligand activity. According to the MolPredictX online tool, the most biologically active derivatives were NA-4, NA-11, and NAD-11. Overall, our findings offer valuable insights into the potential efficacy and safety of these compounds. It appears that almost all of the compounds have successfully passed the pharmacokinetic evaluations and integration of nicotinic acid into indole appears to be more beneficial than nicotinic amide regarding certain biological activities.

Copper-assisted anticancer activity of hydroxycinnamic acid terpyridine conjugates on triple-negative breast cancer.

The development of active therapeutic agents to treat highly metastatic cancer while minimizing damage to healthy cells is of utmost importance. Due to potential antioxidant properties, hydroxycinnamic acid derivatives (caffeic acid and p-coumaric acids) were found to inhibit highly metastatic breast cancer cell growth both in vitro and in vivo without much effect on normal cells. Especially due to the structure-activity relationships, ester and amide derivatives of hydroxycinnamic acids are reported to gain much higher radical scavenging ability than their naked hydroxycinnamic acid analogs like caffeic acid and p-coumaric acid. These results prompted us to design a set of ligands by incorporating an amide moiety on caffeic acid and p-coumaric acid to achieve the least toxicity towards healthy cell lines. Further, the Cu(II) complexes of amide-coupled caffeic acid and p-coumaric acid ligands have been explored for their therapeutic activity on triple-negative breast cancer and other cancer cells like colon, and prostate cancer. The Cu(II) complexes (4 & 5) were characterized by UV-Vis spectroscopy, FTIR, and X-band EPR spectroscopy. The trigonal bipyramidal geometry of complexes was confirmed by the X-band EPR spectra recorded in solution state at liquid N2 temperature. The purity of the complexes was determined by elemental analysis and HPLC traces. Initially, Calf thymus DNA (ct-DNA) binding studies with the complexes were explored. The results suggested the complexes (4 & 5) bind majorly through an intercalative mode of binding with ct-DNA, whereas no significant binding was observed for the bare organic ligands (2 & 3). The intercalation binding modes of 4 and 5 were further supported by UV-visible spectroscopy, ct-DNA melting point analysis, and CD spectroscopy. Moreover, these complexes showed better activity towards cisplatin-resistant TNBC cell lines (4T1, a TNBC cell line derived from the mammary gland tissue of a mouse). The combination of antioxidants and Cu(II) as the metal center made the complexes more cytotoxic toward cancer cell lines (4T1) (IC50 ∼ 3.5 ± 2.5 μM) and the least toxic toward healthy cells (L929) (IC50 ∼ 15 ± 5 μM). Finally, the mechanism of cell death was studied using JC-1 staining and a cell colony formation assay. These studies might help in designing safer anticancer drugs for treating more aggressive types of cancer.