Design, Synthesis, and Antimicrobial Activity of Amide Derivatives Containing Cyclopropane.

As an important small organic molecule, cyclopropane is widely used in drug design. In this paper, fifty-three amide derivatives containing cyclopropane were designed and synthesized by introducing amide groups and aryl groups into cyclopropane through the active splicing method, and their antibacterial and antifungal activities were evaluated in vitro. Among them, thirty-five compounds were new compounds, and eighteen compounds were known compounds (F14, F15, F18, F20-F26, F36, and F38-F44). Bioassay results disclosed that four, three, and nine of the compounds showed moderate activity against Staphylococcus aureus, Escherichia coli, and Candida albicans, respectively. Three compounds were sensitive to Candida albicans, with excellent antifungal activity (MIC80 = 16 µg/mL). The molecular docking results show that compounds F8, F24, and F42 have good affinity with the potential antifungal drug target CYP51 protein.

Improved N-phenylpyrrolamide inhibitors of DNA gyrase as antibacterial agents for high-priority bacterial strains.

In this work, we describe an improved series of N-phenylpyrrolamide inhibitors that exhibit potent activity against DNA gyrase and are highly effective against high-priority gram-positive bacteria. The most potent compounds show low nanomolar IC50 values against Escherichia coli DNA gyrase, and in addition, compound 7c also inhibits E. coli topoisomerase IV in the nanomolar concentration range, making it a promising candidate for the development of potent dual inhibitors for these enzymes. All tested compounds show high selectivity towards the human isoform DNA topoisomerase IIα. Compounds 6a, 6d, 6e and 6f show MIC values between 0.031 and 0.0625 µg/mL against vancomycin-intermediate S. aureus (VISA) and Enterococcus faecalis strains. Compound 6g shows an inhibitory effect against the methicillin-resistant S. aureus strain (MRSA) with a MIC of 0.0625 µg/mL and against the E. faecalis strain with a MIC of 0.125 µg/mL. In a time-kill assay, compound 6d showed a dose-dependent bactericidal effect on the MRSA strain and achieved bactericidal activity at 8 × MIC after 8 h. The duration of the post-antibiotic effect (PAE) on the MRSA strain for compound 6d was 2 h, which corresponds to the PAE duration for ciprofloxacin. The compounds were not cytotoxic at effective concentrations, as determined in an MTS assay on the MCF-7 breast cancer cell line.

Discovery of novel amide derivatives against VEGFR-2/tubulin with potent antitumor and antiangiogenic activity.

Dual-target agents have more advantages than drug combinations for cancer treatment. Here, we designed and synthesized a series of novel VEGFR-2/tubulin dual-target inhibitors through a molecular hybridization strategy, and the activities of all the synthesized compounds were tested against tubulin and VEGFR-2. Among which, compound 19 exhibited strong potency against tubulin and VEGFR-2, with IC50 values of 0.76 ± 0.11 µM and 15.33 ± 2.12 nM, respectively. Additionally, compound 19 not only had significant antiproliferative effects on a series of human cancer cell lines, especially MGC-803 cells (IC50 = 0.005 ± 0.001 µM) but also overcame drug resistance in Taxol-resistant MGC-803 cells, with an RI of 1.8. Further studies showed that compound 19 could induce tumor cell apoptosis by reducing the mitochondrial membrane potential, increasing the level of ROS, facilitating the induction of G2/M phase arrest, and inhibiting the migration and invasion of tumor cells in a dose-dependent manner. In addition, compound 19 also exhibits potent antiangiogenic effects by blocking the VEGFR-2/PI3K/AKT pathway and inhibiting the tubule formation, invasion, and migration of HUVECs. More importantly, compound 19 demonstrated favorable pharmacokinetic profiles, robust in vivo antitumor efficacy, and satisfactory safety profiles. Overall, compound 19 can be used as a lead compound for the development of tubulin/VEGFR-2 dual-target inhibitors.

Design, synthesis and inhibition evaluation of novel chalcone amide α-glucosidase inhibitors.

Aim: The purpose of this study is to design and synthesize a series of novel chalcone amide α-glucosidase (AG) inhibitors (L1-L10) based on virtual screening and molecular dynamics (MD) simulation. Materials & methods: Target compounds (L1-L10) were synthesized from 2-hydroxyacetophenone and methyl 4-formylbenzoate. Results: In vitro activity test shows that most compounds have good AG inhibition. Specially, compound L4 (IC50 = 8.28 ± 0.04 µM) had the best inhibitory activity, superior to positive control acarbose (IC50 = 8.36 ± 0.02 µM). Molecular docking results show that the good potency of L4 maybe attributed to strong interactions between chalcone skeleton and active site, and the torsion of carbon nitrogen bond in amide group. Conclusion: Compound L4 maybe regard as a good anti-Type II diabetes candidate to preform further study.

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Concise Synthesis of Pseudane IX, Its N-Oxide, and Novel Carboxamide Analogs with Antibacterial Activity.

A four-step synthesis of the natural product pseudane IX, starting from 3-oxododecanoic acid phenylamide and including only one chromatographic purification, was accomplished with an overall yield of 52%. The same synthetic sequence, but with a controlled partial reduction of a nitro group in the penultimate intermediate, led to the N-oxide of pseudane IX (NQNO). A shortened three-step variation of the synthesis allowed for the preparation of novel carboxamide analogs of the natural product. An agar diffusion assay against six different bacterial strains revealed significant antibacterial activity of the novel analogs against S. aureus at a concentration of 100 µg/mL. One of the novel compounds showed a remarkably broad spectrum of antibacterial activity, comparable to that of the positive control NQNO.

Design, synthesis and biological evaluation of naphthyl amide derivatives as reversible monoacylglycerol lipase (MAGL) inhibitors.

Monoacylglycerol lipase (MAGL) is a key enzyme responsible for the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG), and has attracted great interest due to its involvement in various physiological and pathological processes, such as cancer progression. In the past, a number of covalent irreversible inhibitors have been reported for MAGL, however, experimental evidence highlighted some drawbacks associated with the use of these irreversible agents. Therefore, efforts were mainly focused on the development of reversible MAGL inhibitor in recent years. Here, we designed and synthesized a series of naphthyl amide derivatives (12-39) as another type of reversible MAGL inhibitors, exemplified by ± 34, which displayed good MAGL inhibition with a pIC50 of 7.1, and the potency and selectivity against endogenous MAGL were further demonstrated by competitive ABPP. Moreover, the compound showed appreciable antiproliferative activities against several cancer cells, including H460, HT29, CT-26, Huh7 and HCCLM-3. The investigations culminated in the discovery of the naphthyl amide derivative ± 34, and it may represent as a new scaffold for MAGL inhibitor development, particularly for the reversible ones.

Non-benzenoid N-aryl oxalamide: synthesis of troponyl-oxalamide peptides by Pd(II)-catalyzed C(sp3)-H functionalization of glycinamides.

Aryl oxalamides are constituents of various promising drug-like molecules. Their aryl groups are derived from the benzenoid aromatic moiety. However, non-benzenoid aromatic molecules, troponoids, are found in various bioactive natural products. It would be thought-provoking to explore non-benzenoid aryl oxalamide derivatives. This report describes the synthesis of N-troponyl-oxalamide peptides by Pd(II)-catalyzed C(sp3)-H functionalization of N-troponyl glycinate peptides. This is the first instance of ß-hydride elimination at the palladium complex of N-troponyl glycinates that generates imine in situ, rendering the synthesis of oxalamides. Importantly, the crystal structures of representative oxalamide derivatives form distinctive foldameric structures, such as ß-sheet type structures, owing to the presence of additional troponyl carbonyl groups. Hence, these non-benzenoid oxalamides are potential scaffolds for tuning the structure and function of N-troponyl peptides, which could provide innovative avenues of research in the development of emerging structural and functional peptides.

Synthesis and biological evaluation of novel 3,6- amide and thioamide substituted- 2,3,4,9-tetrahydro-1H-carbazoles for anti-cancer activity.

Herein, we report the synthesis of new compounds with demonstrated anticancer properties based on the 2,3,4,9-tetrahydro-1H-carbazole scaffold. The Fischer indolization method was used to close the heterocyclic motif. The synthesis method's scope and limitations were thoroughly assessed through a series of experiments. Biological assays revealed that two thioamide compounds exhibited significant anticancer activity against MCF-7, HTC116, and A596 cell lines. Comprehensive in vitro profiling included evaluation of cell cytotoxicity, morphological alterations, colony formation and cell adhesion in 3D cultures, cell cycle analysis, DNA damage induction, impact on mitochondria, and apoptosis. Ex ovo studies further demonstrated these compounds' potential to inhibit angiogenic processes. Our results indicate that the newly developed compounds activate processes leading to DNA damage and disruption of mitochondrial function.

Investigating the effect of ligand structure on the anticancer properties of several new Co(II) complexes of vitaminB3-based phosphoramides.

Nicotinamide, known as Vitamin-B3, has shown promising potential in improving various medical conditions. Carbacylamidophosphates (CAPh) are versatile phosphoramide ligands with a wide range of applications in both biochemistry and chemistry. Herein, to obtain compounds with enhanced anticancer activity and study the effect of the structure on this activity, four new Co(II) complexes of vitaminB3-based CAPh ligands with the formula of CoCl2[3-NC5H4CONHPO(NC5H10)2]2(C1), CoCl2[3-NC5H4CONHPO(NC5H9CH3)2]2(C2), CoCl2[3-NC5H4CONHPO(NC6H12)2]2(C3), and CoCl2[3-NC5H4CONHPO(NC4H10)2]2(C4) were designed and synthesized. FT-IR, UV-Vis, Atomic Absorption (AAS),1H, 13C, and 31PNMR, and Mass spectroscopies beside CHN and Molar conductivity methods were utilized to characterize the synthesized compounds. Using MTT-assay and Flow Cytometry, the anticancer effects of these complexes were studied on three distinct cell lines, including one normal cell line (MCF10A) and two cancer cell lines (MDA-MB-231, MCF-7). Results showed that our ligands could form complexes by coordinating with cobalt, which, not only have a very strong killing effect on cancer cells but also have a higher level of safety for normal cells and are more cost-efficient than Cisplatin. C3 was the most effective complex at inhibiting the growth of MCF-7 and MDA-MB-231 cells which exhibited a remarkable 97.5 % reduction in cancer cell growth and a Selectivity Index up to > 37. This is an impressive 93 and 54 times more selective and safer than commonly used drugs like Cisplatin and Doxorubicin, respectively.Flow Cytometry analysis shows complex-induced breast cancer cell apoptosis.The ligands' amine structure and ring size can directly impact the complexes' anticancer effect and safety for normal cells.

Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria.

Malaria remains a global health concern as drug resistance threatens treatment programs. We identified a piperidine carboxamide (SW042) with anti-malarial activity by phenotypic screening. Selection of SW042-resistant Plasmodium falciparum (Pf) parasites revealed point mutations in the Pf_proteasome ß5 active-site (Pfß5). A potent analog (SW584) showed efficacy in a mouse model of human malaria after oral dosing. SW584 had a low propensity to generate resistance (minimum inoculum for resistance [MIR] >109) and was synergistic with dihydroartemisinin. Pf_proteasome purification was facilitated by His8-tag introduction onto ß7. Inhibition of Pfß5 correlated with parasite killing, without inhibiting human proteasome isoforms or showing cytotoxicity. The Pf_proteasome_SW584 cryoelectron microscopy (cryo-EM) structure showed that SW584 bound non-covalently distal from the catalytic threonine, in an unexplored pocket at the ß5/ß6/ß3 subunit interface that has species differences between Pf and human proteasomes. Identification of a reversible, species selective, orally active series with low resistance propensity provides a path for drugging this essential target.

Design, Synthesis and Antitumor Activity of a Novel Class of SHP2 Allosteric Inhibitors with a Furanyl Amide-Based Scaffold.

SHP2 plays a critical role in modulating tumor growth and PD-1-related signaling pathway, thereby serving as an attractive antitumor target. To date, no antitumor drugs targeting SHP2 have been approved, and hence, the search of SHP2 inhibitors with new chemical scaffolds is urgently needed. Herein, we developed a novel SHP2 allosteric inhibitor SDUY038 with a furanyl amide scaffold, demonstrating potent binding affinity (KD = 0.29 µM), enzymatic activity (IC50 = 1.2 µM) and similar binding interactions to SHP099. At the cellular level, SDUY038 exhibited pan-antitumor activity (IC50 = 7-24 µM) by suppressing pERK expression. Furthermore, SDUY038 significantly inhibited tumor growth in both xenograft and organoid models. Additionally, SDUY038 displayed acceptable bioavailability (F = 14%) and half-life time (t1/2 = 3.95 h). Conclusively, this study introduces the furanyl amide scaffold as a novel class of SHP2 allosteric inhibitors, offering promising lead compounds for further development of new antitumor therapies targeting SHP2.

Discovery of Novel α,ß-Unsaturated Amide Derivatives as Candidate Antifungals to Overcome Fungal Resistance.

In our previous study, coumarin-containing CYP51 inhibitor A32 demonstrated potent antiresistance activity. However, compound A32 demonstrated unsatisfied metabolic stability, necessitating modifications to overcome these limitations. In this study, α,ß-unsaturated amides were used to replace the unstable coumarin ring, which increased metabolic stability by four times while maintaining antifungal activity, including activity against resistant strains. Subsequently, the sterol composition analysis and morphological observation experiments indicated that the target of these novel compounds is lanosterol 14α-demethylase (CYP51). Meanwhile, biofilm growth was inhibited and resistance genes (ERG11, CDR1, CDR2, and MDR1) expression was downregulated to find out how the antiresistance works. Importantly, compound C07 demonstrated the capacity to stimulate reactive oxygen species, thus displaying potent fungicidal activity. Moreover, C07 exhibited encouraging effectiveness in vivo following intraperitoneal administration. Additionally, the most potent compound C07 showed satisfactory pharmacokinetic properties and low toxicity. These α,ß-unsaturated amide derivatives, particularly C07, are potential candidates for treating azole-resistant candidiasis.

Dicopper Complexes of p-Cresol-2,6-bis(amide-tether-dpa4-X) (X = MeO and Cl): Selective ROS Generation and Cytotoxicity Enhancement Controlled by Electronic and Hydrophobic Effects of the MeO and Cl Groups.

Two new p-cresol-2,6-bis(amide-tether-dpa4-X) ligands (HL4-X, X = MeO and Cl) and their dicopper complexes [Cu2(µ-1,1-OAc)(µ-1,3-OAc)(L4-MeO)]Y (Y = PF6 1a, OAc 1b) and [Cu2(µ-1,3-OAc)2(L4-Cl)]Y (Y = ClO4 2a, OAc 2b) were synthesized. The electronic and hydrophobic effects of the MeO and Cl groups were examined compared with nonsubstituted complex [Cu2(µ-1,1-OAc)(µ-1,3-OAc)(L)]+ (3). The electronic effects were found in crystal structures, spectroscopic characterization, and redox potentials of these complexes. 1b and 2b were reduced to Cu(I)Cu(I) with sodium ascorbate and reductively activated O2 to produce H2O2 and HO•. The H2O2 release and HO• generation are promoted by the electronic effects. The hydrophobic effects increased the lipophilicity of 1b and 2b. Cellular ROS generation of 1b, 2b, and 3 was visualized by DCFH-DA. To examine the intracellular behavior, boron dipyrromethene (Bodipy)-modified complexes 4B and 5B corresponding to 1b and 2b were synthesized. These support that 1b and 2b are localized at the ER and Golgi apparatus. The cytotoxicity of 1b and 2b against various cell lines was examined by MTT assay. 1b and 2b were 7- and 41-fold more cytotoxic than 3. 1b generated ROS selectively in cancer cell but 2b nonselectively in cancer and normal cells, causing cancer- and normal-cell-selective cytotoxicity, respectively.

Discovery of a Series of 4-Amide-thiophene-2-carboxyl Derivatives as Highly Potent P2Y14 Receptor Antagonists for Inflammatory Bowel Disease Treatment.

The P2Y14 receptor has been proven to be a potential target for IBD. Herein, we designed and synthesized a series of 4-amide-thiophene-2-carboxyl derivatives as novel potent P2Y14 receptor antagonists based on the scaffold hopping strategy. The optimized compound 39 (5-((5-fluoropyridin-2-yl)oxy)-4-(4-methylbenzamido)thiophene-2-carboxylic acid) exhibited subnanomolar antagonistic activity (IC50: 0.40 nM). Moreover, compound 39 demonstrated notably improved solubility, liver microsomal stability, and oral bioavailability. Fluorescent ligand binding assay confirmed that 39 has the binding ability to the P2Y14 receptor, and molecular dynamics (MD) simulations revealed the formation of a unique intramolecular hydrogen bond (IMHB) in the binding conformation. In the experimental colitis mouse model, compound 39 showed a remarkable anti-IBD effect even at low doses. Compound 39, with a potent anti-IBD effect and favorable druggability, can be a promising candidate for further research. In addition, this work lays a strong foundation for the development of P2Y14 receptor antagonists and the therapeutic strategy for IBD.

Efficient one-step amide formation using amino porphyrins.

Amide bonds are one of the most prevalent phenomena in nature and are utilized frequently in drug and material design. However, forming amide bonds is not always efficient or high yielding, particularly when the amine used to conjugate to a carboxylic acid is a weak nucleophile. This limitation precludes many useful amino compounds from participating in conjugation reactions to form amides. A particularly valuable amino compound, which is also a very weak nucleophile, is the amino porphyrin, valued for its role as a photosensitizer, fluorescent agent, catalyst, or, upon metalation, even a very efficient contrast agent for magnetic resonance imaging (MRI). In this work, we propose fast and high-yield coupling of an unreactive amine - the amino porphyrin - to carboxylic acid via isothiocyanate conjugation. Reactions can be achieved in one step at room temperature in one hour, achieving quantitative conversion and near perfect selectivity. Both metalated and unmetalated porphyrin, as well as fluorescein isothiocyanate (FITC), demonstrated efficient conjugation. To illustrate the value of the proposed method, we created a new blood-pool MRI contrast agent that reversibly binds to serum albumin. This new blood-pool agent, known as MITC-Deox (MRI isothiocyanate that links with deoxycholic acid), substantially reduced T1 relaxation times in blood vessels in mice, remained stable for 1 hour, cleared from blood by 24 hours, and was eliminated from the body after 4 days. The proposed method for efficient amide formation is a superior alternative to existing coupling methods, opening a door to novel synthesis of MRI contrast agents and beyond.

High-yield and high-purity amide bond formation using DMTMM PF6 for DNA-encoded libraries.

In this study, we report on the ability of DMTMM PF6 to improve the amidation reaction. The on-DNA amidation reaction using DMTMM PF6 demonstrates higher conversion rates than those using HATU or DMTMM Cl, particularly with challenging sterically hindered amines and carboxylic acids. The developed method enables the expansion of available building blocks and the efficient synthesis of high-purity DNA-encoded libraries.

α-Glucosidase inhibition assay of galbanic acid and it amide derivatives: New excellent semi-synthetic α-glucosidase inhibitors.

α-Glucosidase inhibitory activity of galbanic acid and its new amide derivatives 3a-n were investigated. Galbanic acid and compounds 3a-n showed excellent anti-α-glucosidase activity with IC50 values ranging from 0.3 ± 0.3 µM to 416.0 ± 0.2 µM in comparison to positive control acarbose with IC50 value of = 750.0 ± 5.6. In the kinetic study, the most potent compound 3h demonstrated a competitive mode of inhibition with Ki = 0.57 µM. The interaction of the most potent compound 3h with the α-glucosidase was further elaborated by in vitro Circular dichroism assessment and in silico molecular docking and Molecular dynamics studies. Compound 3h was also non-cytotoxic on human normal cells. In silico study on pharmacokinetics and toxicity profile of the most potent galbanic acid derivatives demonstrated that these compounds are valuable lead compounds for further study in order to achieve new anti-diabetic agents.

Design and Synthesis of Aryl Amide Derivatives Containing Thiazole as Type III Secretion System Inhibitors against Pseudomonas aeruginosa.

To identify potent inhibitors of the type III secretion system (T3SS) in the foodborne pathogen Pseudomonas aeruginosa, we synthesized 35 thiazole-containing aryl amides by merging salicylic acid with various heterocycles through active splicing. Screening for exoS promoter activity led to the discovery of a highly effective T3SS inhibitor from these 35 compounds. Through subsequent experiments, it was confirmed that compound II-22 specifically targeted the T3SS of P. aeruginosa. Additionally, compound II-22 inhibited the secretion of the effector protein ExoS by modulating the CyaB-cAMP/Vfr-ExsA and ExsCED-ExsA regulatory pathways. Furthermore, compound II-22 suppressed the transcription of genes involved in the needle complex assembly, leading to reduced bacterial virulence. Further validation through inoculation tests using Galleria mellonella larvae demonstrated the strong in vivo efficacy of compound II-22. The study also revealed that compound II-22 enhanced the bactericidal activity of antibiotics, such as CIP (ciprofloxacin) and TOB (tobramycin). These results could help develop novel antimicrobial drugs to reduce bacterial resistance.

Design, Synthesis, and Biological Activity of Silicon-Containing Carboxamide Fungicides.

Bioisosteric silicon replacement has proven to be a valuable strategy in the design of bioactive molecules for crop protection and drug development. Twenty-one novel carboxamides possessing a silicon-containing biphenyl moiety were synthesized and tested for their antifungal activity and succinate dehydrogenase (SDH) enzymatic inhibitory activity. Among these novel succinate dehydrogenase inhibitors (SDHIs), compounds 3a, 3e, 4l, and 4o possessing appropriate clog P and topological polar surface area values showed excellent inhibitory effects against Rhizoctonia solani, Sclerotinia sclerotiorum, Botrytis cinerea, and Fusarium graminearum at 10 mg/L in vitro, and the EC50 values of 4l and 4o were 0.52 and 0.16 mg/L against R. solani and 0.066 and 0.054 mg/L against S. sclerotiorum, respectively, which were superior to those of Boscalid. Moreover, compound 3a demonstrated superior SDH enzymatic inhibitory activity (IC50 = 8.70 mg/L), exhibiting 2.54-fold the potency of Boscalid (IC50 = 22.09 mg/L). Docking results and scanning electron microscope experiments revealed similar mode of action between compound 3a and Boscalid. The new silicon-containing carboxamide 3a is a promising SDHI candidate that deserves further investigation.

More than an Amide Bioisostere: Discovery of 1,2,4-Triazole-containing Pyrazolo[1,5-a]pyrimidine Host CSNK2 Inhibitors for Combatting ß-Coronavirus Replication.

The pyrazolo[1,5-a]pyrimidine scaffold is a promising scaffold to develop potent and selective CSNK2 inhibitors with antiviral activity against ß-coronaviruses. Herein, we describe the discovery of a 1,2,4-triazole group to substitute a key amide group for CSNK2 binding present in many potent pyrazolo[1,5-a]pyrimidine inhibitors. Crystallographic evidence demonstrates that the 1,2,4-triazole replaces the amide in forming key hydrogen bonds with Lys68 and a water molecule buried in the ATP-binding pocket. This isosteric replacement improves potency and metabolic stability at a cost of solubility. Optimization for potency, solubility, and metabolic stability led to the discovery of the potent and selective CSNK2 inhibitor 53. Despite excellent in vitro metabolic stability, rapid decline in plasma concentration of 53 in vivo was observed and may be attributed to lung accumulation, although in vivo pharmacological effect was not observed. Further optimization of this novel chemotype may validate CSNK2 as an antiviral target in vivo.