Series Of Amides Research Articles

Phosphine-Catalyzed Ring-Opening Regioselective Addition of Cyclopropenones with Amides.

A series of amides, including α-bromo hydroxamates, N-alkoxyamides, and N-aryloxyamides, were subjected to phosphine-catalyzed ring-opening O-selective addition with cyclopropenones, producing various special α,β-unsaturated esters containing oxime ether motif, in moderate to excellent yields, with high regioselectivity, and exclusive O-selectivity. The methodology is highly atom-economical, with simple operation procedures, and compatible with a wide substrate scope (more than 44 examples).

Revisiting the dipeptidyl carboxypeptidase inhibitor captopril as a source of pan anti-trypanosomatid agents

The protozoan parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. are responsible for continued propagation of neglected tropical diseases such as African sleeping sickness, Chagas disease and leishmaniasis respectively. Following a report that captopril targets Leishmania donovani dipeptidyl carboxypeptidase, a series of simple proline amides and captopril analogues were synthesized and found to exhibit 1–2 μM in vitro inhibition and selectivity against Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. The results were corroborated with computational docking studies. Arguably, the synthetic proline amides represent the structurally simplest examples of in vitro pan antiprotozoal compounds.

A Study on the Effect of Quaternization of Polyene Antibiotics' Structures on Their Activity, Toxicity, and Impact on Membrane Models.

Polyene antibiotics have been used in antifungal therapy since the mid-twentieth century. They are highly valued for their broad spectrum of activity and the rarity of pathogen resistance to their action. However, their use in the treatment of systemic mycoses often results in serious side-effects. Recently, there has been a renewed interest in the development of new antifungal drugs based on polyenes, particularly due to the emergence of highly dangerous pathogenic strains of fungi, such as Candida auris, and the increased incidence of mucormycosis. Considerable understanding has been established regarding the structure-biological activity relationships of polyene antifungals. Yet, no previous studies have examined the effect of introducing quaternized fragments into their molecular structure. In this study, we present a series of amides of amphotericin B, nystatin, and natamycin bearing a quaternized group in the side chain, and discuss their biological properties: antifungal activity, cytotoxicity, and effects on lipid bilayers that mimic fungal and mammalian cell membranes. Our research findings suggest that the nature of the introduced quaternized residue plays a more significant role than merely the introduction of a constant positive charge. Among the tested polyenes, derivatives 4b, 5b, and 6b, which contain a fragment of N-methyl-4-(aminomethyl)pyridinium in their structure, are particularly noteworthy due to their biological activity.

Synthesis and in vitro cytotoxicity of benzoxazole-based PPARα/γ antagonists in colorectal cancer cell lines.

A series of benzoxazole-based amides and sulfonamides were synthesized and evaluated for their human peroxisome proliferator-activated receptor (PPAR)α and PPARγ activity. All tested compounds showed a dual antagonist profile on both PPAR subtypes; based on transactivation results, seven compounds were selected to test their in vitro antiproliferative activity in a panel of eight cancer cell lines with different expression rates of PPARα and PPARγ. 3f was identified as the most cytotoxic compound, with higher potency in the colorectal cancer cell lines HT-29 and HCT116. Compound 3f induced a concentration-dependent activation of caspases and cell-cycle arrest in both colorectal cancer models. Docking experiments were also performed to shed light on the putative binding mode of this novel class of dual PPARα/γ antagonists.

Synthesis of Amides via the Amination of Aldehydes with Hydroxylamines Promoted by TBAF·3H2O.

A metal-free, mild, and efficient method for the synthesis of amides has been developed from the amination of aldehydes with hydroxylamines promoted by TBAF·3H2O in the presence of KOH. Control experiments showed that the nitrone was the intermediate of this amination. By this method, a series of amides, biologically active compounds bebenil and a COX inhibitor were obtained in moderate to good yields.

Oxidative rearrangement of enaminones to α-keto amides in the presence of KI, TBHP and octanoic acid

A novel method for the direct conversion of enaminones to α-keto amides has been developed. This transformation involves an oxidative rearrangement of enaminones under free radical conditions. In the presence of KI, TBHP and octanoic acid, a series of α-keto amides were obtained in moderate to excellent yields. This reaction demonstrates excellent functional group compatibility, utilizes readily available materials, and is easy to perform. Additionally, when o-hydroxyphenyl enaminone was utilized as the substrate, the reaction yielded 3-iodochromone in a high yield.

Structure-Activity Relationship Studies on Highly Functionalized Pyrazole Hydrazones and Amides as Antiproliferative and Antioxidant Agents.

Aminopyrazoles represent interesting structures in medicinal chemistry, and several derivatives showed biological activity in different therapeutic areas. Previously reported 5-aminopyrazolyl acylhydrazones and amides showed relevant antioxidant and anti-inflammatory activities. To further extend the structure-activity relationships in this class of derivatives, a novel series of pyrazolyl acylhydrazones and amides was designed and prepared through a divergent approach. The novel compounds shared the phenylamino pyrazole nucleus that was differently decorated at positions 1, 3, and 4. The antiproliferative, antiaggregating, and antioxidant properties of the obtained derivatives 10-22 were evaluated in in vitro assays. Derivative 11a showed relevant antitumor properties against selected tumor cell lines (namely, HeLa, MCF7, SKOV3, and SKMEL28) with micromolar IC50 values. In the platelet assay, selected pyrazoles showed higher antioxidant and ROS formation inhibition activity than the reference drugs acetylsalicylic acid and N-acetylcysteine. Furthermore, in vitro radical scavenging screening confirmed the good antioxidant properties of acylhydrazone molecules. Overall, the collected data allowed us to extend the structure-activity relationships of the previously reported compounds and confirmed the pharmaceutical attractiveness of this class of aminopyrazole derivatives.

Synthetic Derivatives of Natural ent-Kaurane Atractyligenin Disclose Anticancer Properties in Colon Cancer Cells, Triggering Apoptotic Cell Demise.

The antitumor activity of different ent-kaurane diterpenes has been extensively studied. Several investigations have demonstrated the excellent antitumor activity of synthetic derivatives of the diterpene atractyligenin. In this research, a series of new synthetic amides and their 15,19-di-oxo analogues obtained from atractyligenin by modifying the C-2, C-15, and C-19 positions were designed in order to dispose of a set of derivatives with different substitutions at the amidic nitrogen. Using different concentrations of the obtained compounds (10-300 μM) a reduction in cell viability of HCT116 colon cancer cells was observed at 48 h of treatment. All the di-oxidized compounds were more effective than their alcoholic precursors. The di-oxidized compounds had already reduced the viability of two colon cancer cells (HCT116 and Caco-2) at 24 h when used at low doses (2.5-15 μM), while they turned out to be poorly effective in differentiated Caco-2 cells, a model of polarized enterocytes. The data reported here provide evidence that di-oxidized compounds induced apoptotic cell death, as demonstrated by the appearance of condensed and fragmented DNA in treated cells, as well as the activation of caspase-3 and fragmentation of its target PARP-1.

Synthesis, Characterization, in vitro Biological Evaluation of a Series of Benzothiazole Amides as Antibacterial Agents

A series of benzothiazole amides (VH01-06) were synthesized by using modified Schotten-Baumann reaction conditions, all the resultant compounds were obtained in good yields and purity. The molecular structure of the compounds was characterized using physical and spectral methods. The structures of the compounds were consistent with the analytical data obtained for FT-IR, 1H NMR, 13C NMR and HRMS ESI-Mass spectroscopic techniques. Further, compounds were subjected to the in vitro antibacterial activity screening against various strains that includes Gram-positive bacteria (methicillin-resistant Staphylococcus aureus (MRSA) ATCC 3359 and methicillin-sensitive Staphylococcus aureus (MSSA) ATCC 2592) and Gram-negative bacteria (Escherichia coli J53 R1, Escherichia coli ATCC 25922, Klebsiella pneumoniae ATCC 10031 and Klebsiella pneumonia BAA-1075). Based on the biological screening results, compounds VH01-06 were found to possesses limited antibacterial properties against selected strains, since the recorded activity was found at 100 µM concentration. While compound VH05 displayed specific activity against E. coli ATCC 25923 at 200 µg/mL.

Arylacryl amides: Design, synthesis and the protection against cisplatin-induced acute kidney injury via TLR4/STING/NF-κB pathway

Arylpropionic ester scaffold was found as anti-inflammatory agents for the treatment and prevention of acute kidney injury (AKI). To further study the structure–activity relationship (SAR) of this scaffold, a series of acryl amides were designed, synthesized, and evaluated their anti-inflammation. Of these, compound 9d displayed the protective effect on renal tubular epithelial cells to significantly enhance the survival rate through inhibiting NF-κB phosphorylation and promoting cell proliferation in cisplatin-induced HK2 cells. Furthermore, 9d can interact with TLR4 to inhibit TLR4/STING/NF-κB pathway in the RAW264.7 cell. In vivo AKI mice model, 9d significantly downregulated the level of serum creatinine (Scr), blood urea nitrogen (BUN) and the inflammatory factors (IL-1β, IL-6, TNF-α) to improve kidney function. Morphological and KIM-1 analyses showed that 9d alleviated cisplatin-induced tubular damage. In a word, 9d was a promising lead compound for preventive and therapeutic of AKI.

Novel secondary pyridinyl amides: Synthesis, in vitro antiproliferative screenings, and molecular docking studies

A novel series of secondary pyridinyl amides, reinforced with the methylsulfonyl pharmacophore unit, was designed and synthesized. Further, we determined the antiproliferative activities of these compounds through experimental assays and analyzed their interactions with Breakpoint Cluster Region/Abelson (bcr/abl), Epidermal Growth Factor Receptor (EGFR), and Human Epidermal Growth Factor Receptor 2 (HER2) tyrosine kinases using molecular autodocking techniques. We grouped these amides into three categories, classified by the type of spacer that binds the pyridine ring to the amide nitrogen atom. Additionally, within each group, we strategically positioned the amide moiety at the ortho, meta, or para position on the pyridyl ring. Among the studied amides, compound 3 exhibited the best overall antiproliferative activity against human immortalized myelogenous leukemia (K562) (IC50 = 26 µM), human leukemia monocytic cell line (THP-1) (IC50 = 81 µM), and human hepatocellular carcinoma (HepG2) (IC50 = 210 µM). Molecular docking studies revealed that compound 3 binds effectively to bcr/abl, EGFR, and HER2 tyrosine kinases, demonstrating strong interactions with crucial active site amino acids, indicative of its targeted antiproliferative mechanism. All investigated compounds showed either very minor or no cytotoxicity against human dermal fibroblast adult cells.

Synthesis and Antioxidant Activities of Novel Pyrimidine Acrylamides as Inhibitors of Lipoxygenase: Molecular Modeling and In Silico Physicochemical Studies.

The pyrimidine ring is present in various biomolecules such as DNA and RNA bases, aminoacids, vitamins, etc. Additionally, many clinically used drugs including methotrexate and risperidone contain the pyrimidine heterocyclic scaffold as well. Pyrimidine derivatives present diverse biological activities including antioxidant and anticancer activities and can be considered as privileged scaffolds in drug discovery for the treatment of various diseases. Piperidine pyrimidine amides have gained significant attention due to their enzymatic inhibitory activity. Based on our experience and ongoing investigation on cinnamic acid derivatives, their hybrids and substituted pteridines acting as lipoxygenase inhibitors, antioxidants, anti-cancer, and anti-inflammatory agents a series of novel piperidine pyrimidine cinnamic acids amides have been designed and synthesized. The novel hybrids were studied for their antioxidant and anti-inflammatory potential. They exhibit moderate antioxidant activity in the DPPH assay which may be related to their bulkiness. Moreover, moderate to good lipid peroxidation inhibition potential was measured. With regards to their lipoxygenase inhibitory activity, however, two highly potent inhibitors out of the nine tested derivatives were identified, demonstrating IC50 values of 10.7 μM and 1.1 μM, respectively. Molecular docking studies to the target enzyme lipoxygenase support the experimental results.

Synthesis and Structure of Unsymmetrical Anthracenyl-Isoxazole Antitumor Agents Via the Diastereoselective Bromination of 3-(9′-Anthryl)-Isoxazole Esters

In pursuit of unsymmetrical precursors for the novel series of anthracenyl-isoxazole amide (AIM) antitumor agents, a series of substituted anthracenes were subjected to bromination and re-aromatization in our study, during which we solved four single crystal X-ray diffractometry (Sc-xrd) structures which we report herein. The C-9 nitrile oxide, after its reaction with bromine, was isolated, but when subjected to re-aromatization, it returned to the starting 10-bromo nitrile oxide 1, which did provide an accurate crystal structure, with R = 0.018. The 10-halogenated 3-(9’-anthryl)-isoxazole esters were subjected to bromination and re-aromatization. Surprisingly, the yields obtained in the presence of the isoxazole were reasonably good (62–68% isolated yields), and the major diastereomers allowed for the characterization using Sc-xrd. The penta bromo product 2 showed a trans, trans, cis relationship for the four bromines on the A-ring of the anthracene, and we observed that for the unit cell, the atropisomers displayed a 1:1 ratio at the chiral axis between the isoxazole and anthrancene rings. Similarly, the 10-chloro 3 indicated a ratio of 1:1 at the chiral axis in the crystal structure. A base-induced re-aromatization afforded 3,10-dihalogenated analogues selectively in very good yields (X = Cl, 89%; X = Br 92%), of which the dibromo 4 was characterized using Sc-xrd. The improved yields of the unique diastereomeric bromination products suggested the consideration of a novel electrophilic aromatic substitution mechanism driven by the stereo-electronic environment, imposed by the isoxazole ester substituent. The promise of the application of this chemistry in the future development of AIM antitumor agents is suggested.

Discovery of a novel series of pyridone amides as NaV1.8 inhibitors

The NaV1.8 channel, mainly found in the peripheral nervous system, is recognized as one of the key factors in chronic pain. The molecule VX-150 was initially promising in targeting this channel, but the phase II trials of VX-150 did not show expected pain relief results. By analyzing the interaction mode of VX-150 and NaV1.8, we developed two series with a total of 19 molecules and examined their binding affinity to NaV1.8 in vitro and analgesic effect in vivo. One compound, named 2j, stood out with notable activity against the NaV1.8 channel and showed effective pain relief in models of chronic inflammatory pain and neuropathic pain. Our research points to 2j as a strong contender for developing safer pain-relief treatments.

Thiuram Disulfide Mediated Cu-Catalyzed Amidation of Terminal Alkynes: An Efficient Synthesis of Alkynyl Amides.

Terminal alkynes undergo a CO-free aminocarbonylation reaction mediated by thiuram disulfides. Thiuram disulfide acts as the source of the carbamoyl group in the amidation of terminal alkynes in the presence of copper-based reagent and catalyst. A series of alkynyl amides has been prepared with several structural variations following the current one-pot two-step protocol. The reaction proceeds through a mixed disulfide intermediate, which has been isolated and characterized by single-crystal XRD analysis.

Discovery of Unique Bis-Substituted Aromatic Amide Derivatives as Novel Highly Potent Antibiotics for Combating Methicillin-Resistant Staphylococcus aureus (MRSA).

Due to the increasing antibiotic resistance, developing novel antimicrobials to fight infections caused by resistant bacteria is imperative. Herein, a series of novel bis-substituted aromatic amides were designed and synthesized through modifying the hit compound 1, and their antimicrobial activities were evaluated. Among them, compound 4t, as the most potent lead, exhibited excellent antimicrobial activities against Gram-positive bacteria, including clinical methicillin-resistant Staphylococcus aureus (MRSA) isolates, while keeping weak hemolytic and mammalian cytotoxic activities. Furthermore, compound 4t displayed rapid bactericidal capabilities, low tendency to produce resistance, and favorable capacities to destroy bacterial biofilms. Further explorations indicated that compound 4t induces bacterial death by binding to cardiolipin (CL) on the bacterial membrane, disrupting the cell membrane, and facilitating the accumulation of reactive oxygen species (ROS). Additionally, compound 4t showed remarkable anti-MRSA activity in vivo, demonstrating compound 4t could be developed as a potential candidate to combat MRSA infections.

Asymmetric Hydrogenation of α-Alkyl-Substituted β-Keto Esters and Amides through Dynamic Kinetic Resolution.

Asymmetric hydrogenation of α-alkyl-substituted β-keto esters and amides with the DIPSkewphos/3-AMIQ-Ru(II) catalyst system through dynamic kinetic resolution was examined. A series of β-keto esters and amides with a simple or functionalized α-alkyl group were applicable to this reaction, affording the α-substituted β-hydroxy esters and amides in ≥99% ee (anti/syn ≥ 99:1) in many cases. The 5 g scale reaction was readily achieved. The mode of enantio- and diastereoselection in the transition state model was proposed.

Amides of moronic acid and morolic acid with the tripeptides MAG and GAM targeting antimicrobial, antiviral and cytotoxic effects.

A series of amides of selected plant triterpenoids, moronic acid and morolic acid, with the tripeptides MAG and GAM, was designed and synthesized. Two required tripeptides 5 and 10 were synthesized by a step-wise chain elongation of the ethyl esters of either glycine or l-methionine at their N-terminus using Boc-protected amino acids in each step. The tripeptides 5 and 10 were used for the synthesis of 13-23, the derivatives of moronic acid (11) and morolic acid (12), to get a series of amide derivatives of the less frequently studied triterpenoids 11 and 12. The target compounds, and their intermediates, were subjected to an investigation of their antimicrobial, antiviral and cytotoxic activity. Selectivity of the pharmacological effects was found. Generally, the target compounds inhibited only the G+ microorganisms. Compound 16 inhibited Staphylococcus aureus (I = 99.6%; c = 62.5 μM) and Enterococcus faecalis (I = 85%; c = 250 μM). Several compounds showed moderate antiviral effects, both anti-HIV-1, 19 (EC50 = 57.0 ± 4.1 μM, CC50 > 100 μM), 20 (EC50 = 17.8 ± 2.1 μM, CC50 = 41.0 ± 5.2 μM) and 23 (EC50 = 12.6 ± 0.82 μM, CC50 = 38.0 ± 4.2 μM), and anti-HSV-1, 22 (EC50 = 27.7 ± 3.5 μM, CC50 > 100 μM) and 23 (EC50 = 30.9 ± 3.3 μM, CC50 > 100 μM). The target compounds showed no cytotoxicity in cancer cells, however, several of their intermediates were cytotoxic. Compound 21 showed cytotoxicity in HeLa (IC50 = 7.9 ± 2.1 μM), G-361 (IC50 = 8.0 ± 0.6 μM) and MCF7 (IC50 = 8.6 ± 0.2 μM) cancer cell lines, while being non-toxic in normal fibroblasts (BJ; IC50 > 50 μM).

BF3·OEt2-mediated transamidation of unprotected primary amides under solvent-free conditions.

A BF3·OEt2-mediated transamidation between unactivated amides and amines is reported, enabling access to diverse secondary and tertiary amides under transition-metal-free and solvent-free conditions. The operationally simple procedure provides a novel manifold for converting amide-amide bonds with excellent chemoselectivity. In particular, a series of amides including challenging thioamides enable direct transamidation to products with modest to excellent yields. Meanwhile, additional experiments were conducted to elucidate the mechanism of this transformation, and a plausible mechanism was proposed based on the results and related literature.

Synthetic derivatives of natural cinnamic acids as potential anti-colorectal cancer agents.

Cinnamic acid and its derivatives represent attractive building blocks for the development of pharmacological tools. A series of piperoniloyl and cinnamoyl-based amides (6-9 a-f) have been synthesized and assayed against a wide panel of colorectal cancer (CRC) cells, with the aim of finding promising anticancer agents. Among all twenty-four synthesized molecules, 7a, 7e-f, 9c, and 9f displayed the best antiproliferative activity. The induced G1 cell cycle arrest and the increase in apoptotic cell death was seen in FACS analysis and western Blotting in the colon tumor cell lines HCT116, SW480, LoVo, and HT29, but not in the nontumor cell line HCEC. In particular, 9f overcame the resistance of HT29 cells, which have a mutant p53 and BRAF. Furthermore, 9f, amide of piperonilic acid with the 3,4-dichlorobenzyl substituent upregulated p21, which is involved in cell cycle arrest as well as in apoptosis induction. Cinnamic acid derivatives might be potential anticancer compounds, useful for the development of promising anti-CRC agents.