Amide Analogues Research Articles

Synthesis and Biological Evaluation of N-(1H-Indol-6-ylmethyl)benzenesulfonamide Analogs as Metabolic Inhibitors of Mitochondrial ATP Production in Pancreatic Cancer Cells.

A library of 26 indolyl sulfonamides and 12 amide and ester analogs based upon the 6-indolyl framework has been synthesized in an effort to target pancreatic cancer. The cytotoxicity of the indolyl sulfonamide compounds has been determined using a traditional (48-h compound exposure) assay against 7 pancreatic cancer cell lines and 1 non-cancerous cell line. The potential role of the compounds as metabolic inhibitors of ATP production was evaluated using a rapid screening (2-h compound exposure) assay developed within our laboratories. The IC50 values of the active compounds were determined using the rapid assay and six compounds displayed an IC50 value <5 μM against one or more pancreatic cancer cell lines. The ester analogs also display activity as potential metabolic inhibitors of ATP production with four of the six compounds displaying an IC50 value <5 μM against one or more pancreatic cancer cell lines.

Synthesis and anti-leishmanial activities of uniflorol analogues

AbstractChromanones are a subset of the benzopyran family, and display diverse biological activities, both as natural products and synthetic derivatives. Among these, we selected the natural product uniflorol, a 4-chromanone with an α,β-unsaturated ketone side chain, as a lead compound due to its reported anti-leishmanial properties. We designed and synthesised four series of novel compounds, varying the substitution patterns around the benzopyran core, and evaluated the compounds for anti-leishmanial activity against amastigotes of L. infantum. We prepared and characterised 24 novel compounds; upon screening, 12 compounds demonstrated activity values of &lt;50 μM, with the most potent compound, 16d, having an IC50 of 7.29 μM. Activity was favoured in compounds bearing a phenylalkenyl motif, such as cinnamyl, styryl or a more lipophilic extension, and amide analogues retained activity. Uniflorol analogues display promise as novel architectures towards the development of potential anti-leishmanial agents.

Computational Investigation of Novel Compounds as Dual Inhibitors of AChE and GSK-3β for the Treatment of Alzheimer's Disease

Background: Alzheimer's disease (AD) stands out as one of the most devastating and prevalent neurodegenerative disorders known today. Researchers have identified several enzymatic targets associated with AD among which Glycogen synthase kinase-3β (GSK-3β) and Acetylcholinesterase (AChE) are prominent ones. Unfortunately, the market offers very few drugs for treating or managing AD, and none have shown significant efficacy against it. Objectives: To address this critical issue, the design and discovery of dual inhibitors will represent a potential breakthrough in the fight against AD. In the pursuit of designing novel dual inhibitors, we explored molecular docking and dynamics analyses of tacrine and amantadine uredio-linked amide analogs such as GSK-3β and AChE dual inhibitors for curtailing AD. Tacrine and adamantine are the FDA-approved drugs that were structurally modified to design and develop novel drug candidates that may demonstrate concurrently dual selectivity towards GSK-3β and AChE. Methods: In the following study, molecular docking was executed by employing AutoDock Vina, and molecular dynamics and ADMET predictions were made using Desmond, Qikprop modules of Schrödinger. Results: Our findings revealed that compounds DST2 and DST11 exhibited remarkable molecular interactions with active sites of GSK-3β and AChE, respectively. These compounds effectively interacted with key amino acids, namely Lys85, Val135, Asp200, and Phe295, resulting in highly favourable docking energies of -9.7 and -12.7 kcal/mol. Furthermore, through molecular dynamics simulations spanning a trajectory of 100 ns, we confirmed the stability of ligands DST2 and DST11 within the active cavities of GSK-3β and AChE. The compounds exhibiting the most promising docking results also demonstrated excellent ADMET profiles. Notably, DST21 displayed an outstanding human oral absorption rate of 76.358%, surpassing the absorption rates of other molecules. Conclusion: Overall, our in-silico studies revealed that the designed molecules showed potential as novel anti-Alzheimer agents capable of inhibiting both GSK-3β and AChE simultaneously. So, in the future, the designing and development of dual inhibitors will harbinger a new era of drug design in AD treatment.

Capturing acyl-enzyme intermediates with genetically encoded 2,3-diaminopropionic acid for hydrolase substrate identification.

Catalytic mechanism-based, light-activated traps have recently been developed to identify the substrates of cysteine or serine hydrolases. These traps are hydrolase mutants whose catalytic cysteine or serine are replaced with genetically encoded 2,3-diaminopropionic acid (DAP). DAP-containing hydrolases specifically capture the transient thioester- or ester-linked acyl-enzyme intermediates resulting from the first step of the proteolytic reaction as their stable amide analogs. The trapped substrate fragments allow the downstream identification of hydrolase substrates by mass spectrometry and immunoblotting. In this protocol, we provide a detailed step-by-step guide for substrate capture and identification of the peptidase domain of the large tegument protein deneddylase (UL36USP) from human herpesvirus 1, both in mammalian cell lysate and live mammalian cells. Four procedures are included: Procedure 1, DAP-mediated substrate trapping in mammalian cell lysate (~8 d); Procedure 2, DAP-mediated substrate trapping in adherent mammalian cells (~6 d); Procedure 3, DAP-mediated substrate trapping in suspension mammalian cells (~5 d); and Procedure 4, substrate identification and validation (~12-13 d). Basic skills to perform protein expression in bacteria or mammalian cells, affinity enrichment and proteomic analysis are required to implement the protocol. This protocol will be a practical guide for identifying substrates of serine or cysteine hydrolases either in a complex mixture, where genetic manipulation is challenging, or in live cells such as bacteria, yeasts and mammalian cells.

Experimental and computational studies of novel amide analogues of ferulic acid as potential MDM2 inhibitors to retrieve p53 function

Phytochemicals are naturally occurring substances that possess heightened levels of antioxidants. Among these, ferulic acid (FA) is widely found in fruits and vegetables, including sweet corn, tomatoes, rice bran, and is recognized for its antioxidant qualities. Various diseases include cancer, cardiomyopathy, skin, brain disorders, viral infections and diabetes are the oxidative stress-based diseases could benefit from FA's treatment. However, ferulic acid's antioxidant properties were lowered by its hydophobicity, which prevents it from autoxidation of fats and oils. However, its physicochemical and pharmacological properties can be improved by the addition of amide groups which is highly desirable. In the present investigation, two new amide analogues of ferulic acid, FA2 and FA3, were designed, synthesized and screened to assess the potential of these compounds in computational and invitro experiments. Ferulic acid analogues were biologically evaluated on K562 cells, and the results revealed that FA3, a synthesized analogue of ferulic acid, demonstrated a greater degree of inhibition that FA2 as well as the original molecule of ferulic acid, suggesting its strong antioxidant activity. Utilizing MDM2 as a receptor, we carried out docking and dynamic studies to gain an understanding of the potential molecular mechanism by which the action was carried out. The docking and dynamic results showed that FA3 has showed higher rates binding energy -6.04 Kcal/Mol than FA2 -4.55 04 Kcal/Mol, and ferulic acid -4.19 Kcal/Mol. All the molecules are interacted with the residues involved in p53 binding of MDM2 protein. This study clearly revealed that FA3 ferulic acid analogue interacts with MDM2 amino acids that might have inhibited by the binding of MDM2 to p53.

Synthesis, characterization, and antibacterial effectiveness of gemifloxacin C-3 modified amide analogs: A theoretical and experimental approach

In search of a newer, efficient, and adaptable antimicrobial solution to combat the resistance that has developed due to the widespread extensive and in appropriate use of antibiotics. Seven new amide analogs of Gemifloxacin (G-D01-G-D07), an important member of the fluoroquinolone (FQ's) was synthesized by modifying the C-3 position in a quick and facile way, using Schotten Baumann reaction approach exhibiting highly efficient yields and short reaction times. Their in-silico pharmacokinetic and toxicity studies were determined by SwissADME and Protox-II webserver, and found that all the compounds obeys the lipinski's rule and didn't exhibit any vital organ toxicity. The introduction of selected amines to form amide analogs (G-D01-G-D07) was assured by their spectroscopic characterization, structural stability studies by DFT parameters and Microbiological assay evaluates these synthesized analogs as potent antibacterial and antifungal agents against studied species. At the B3LYP/6–311 G level of theory, the molecular structures, reactivity, and electronic characteristics of candidate compounds exhibiting the most promising antibacterial actions were examined, and their quantum mechanical parameters were calculated. The energy gaps of all the synthesized compounds were found in ranges between 0.1088 and 0.1091 eV, indicating good softness, thermal and kinetic stability. This can be correlated by the activity of these analogs against Klebsiella pneumonia, and Citrobacter freundii, where synthesized derivatives G-D06 and G-D03, G-D04, and G-D07 exhibit activities more than the parent drug. The binding affinity of complexes revealed by docking was found in the range between -14.31 and -16.20 kcal/ mol, which indicates their high antibacterial potential against one of the major targets Klebsiella pneumoniae cytidine deaminase CDA protein by using AutoDock Vina and MD simulations by GROMACS, confirming them as potential antibacterial agents.

NMI-SO2Cl2-Mediated Amide Bond Formation: Facile Synthesis of Some Dihydrotriazolopyrimidine Amide Derivatives as Potential Anti-Inflammatory and Anti-Tubercular Agents.

Facile access to some novel biologically relevant dihydrotriazolopyrimidine carboxylic acid-derived amide analogues using NMI/SO2Cl2, and aromatic and aliphatic primary and secondary amines, is reported herein. The role of N-methylimidazole (NMI) as the base and sulfuryl chloride (SO2Cl2) as the coupling reagent has been effectively realized in accessing these molecules in good to excellent yields. The feasibility of the developed protocol has also been extended to the gram-scale synthesis of N-benzylbenzamide in a 75% yield from benzoic acid and benzyl amine. The newly synthesized compounds were tested via in vitro anti-inflammatory and anti-tubercular activity studies. The compounds 6aa and 6be were found to be the most active anti-inflammatory agents, whereas 6cb and 6ch were found to exhibit promising anti-tubercular potency when compared to other synthesized molecules. The structure-activity relationship (SAR) studies revealed the importance of the presence of electron-donating functionalities in enhancing the anti-inflammatory potential of the newly synthesized molecules. However, the presence of electron-withdrawing substituents was found to be significant for improving their anti-tubercular potency.

New Analogues of Amides and Quinolinones Produced by Streptomyces sp. YIM S01983.

Streptomide (1), a new amide analogue, streptomynone (2), a new quinolinone, and ten known compounds including three aliphatic acids (3-5), two amides (6-7), four cyclic dipeptides (8-11), and an adenosine (12) were isolated from the fermentation broth of Streptomyces sp. YIM S01983 isolated from a sediment sample collected in Bendong Village, Huadong Town, Chuxiong, China. Their structures were determined by analysis of the 1D/2D-NMR and HR-ESI-MS spectra. Compound 12 presented weak antimicrobial activities against Candida albicans and Aligenes faecalis (MIC=64 μg/mL). Compounds 7 and 12 showed weak cytotoxic activity against MHCC97H.

Incorporation of Carboxylate Pendant Arms into 18-Membered Macrocycles: Effects on [nat/203Pb]Pb(II) Complexation.

We present a detailed investigation on the coordination chemistry of [nat/203Pb]Pb(II) with chelators H4PYTA and H4CHX-PYTA. These chelators belong to the family of ligands derived from the 18-membered macrocyclic backbone PYAN and present varying degrees of rigidity due to the presence of either ethyl or cyclohexyl spacers. A complete study of the stable Pb(II) complexes is carried out via NMR, X-Ray crystallography, stability constant determination and computational studies. While these studies indicated that Pb(II) complexation is achieved, and the thermodynamic stability of the resulting complexes is very high, a certain degree of fluxionality does exist in both cases. Nevertheless, radiolabeling studies were carried out using SPECT (single photon emission computed tomography) compatible isotope lead-203 (203Pb, t1/2=51.9 h), and while both chelators complex the radioisotope, the incorporation of carboxylate pendant arms appears to be detrimental towards the stability of the complexes when compared to the previously described amide analogues. Additionally, incorporation of a cyclohexyl spacer does not improve the kinetic inertness of the system.

Synthesis of N-Trifluoromethyl Thiocarbamates and Ureas from 3-Aminopyridine-Derived Carbamates

AbstractThe synthesis of N-trifluoromethyl thiocarbamates and ureas from 3-pyridyl isothiocyanates via the nucleophilic substitution reaction of perfluorophenyl pyridin-3-yl(trifluoromethyl)carbamate is described. Recently, Schoenebeck’s group reported a straightforward method to access N-trifluoromethyl analogues of amides and related carbonyl compounds. However, N-trifluoromethyl thiocarbamates and ureas derived from pyridine-containing amines remain a synthetic challenge. In this paper, the strategy relies on the operationally simple preparation of perfluorophenyl pyridin-3-yl(trifluoromethyl)carbamates, which can smoothly undergo nucleophilic substitution reactions with thiophenol, sodium mercaptide, and amine. Various functional groups such as amide, halogen, ether, and ester were tolerated under these reaction conditions. Notably, alkylamine structures containing pyridine heterocyclic rings are also compatible to access N-trifluoromethyl thiocarbamates.

Complexation of Hexavalent Neptunium(VI) with Oxydiacetic Acid and Its Amide Derivatives in Aqueous Solution: Spectrophotometry and DFT Calculations.

Unfolding the solution coordination chemistry of high-valent transuranium elements with the "CHON"-type ligands is important to understand the fundamental chemistry of actinides and to design more efficient extractants for partitioning of transuranium elements in advanced nuclear fuel cycles. Here, the complexation of a hexavalent neptunyl ion (NpO22+ or Np(VI)) with oxydiacetic acid (ODA) has been systematically investigated in comparison with its amide analogues N,N-dimethyl-3-oxa-glutaramic acid (DMOGA) and N,N,N',N'-tetramethyl-3-oxa-glutaramide (TMOGA) both experimentally and computationally. The formation of both 1:1 and 1:2 complexes between Np(VI) and the three ligands was identified by spectrophotometry, and their stability constants were obtained and compared with those of hexavalent U(VI) and Pu(VI). The corresponding bonding nature is elucidated by using energy decomposition analysis (EDA), electrostatic potential (ESP), ELF contours, and natural orbitals for chemical valence (NOCV) methods, which shows that the Np-O bonds are essentially ionic in character and the unoccupied 6d orbitals of Np play a key role in enhancing the covalent interactions between Np(VI) and the three ligands.

High-performance liquid chromatographic enantioseparation of azole analogs of monoterpene lactones and amides focusing on the separation characteristics of polysaccharide-based chiral stationary phases

High-performance liquid chromatography-based enantioseparation of newly prepared azole analogs of monoterpene lactones and amides was studied. Effects of additives and mobile phase composition were evaluated both in normal and polar organic modes. Applying amylose tris-(3,5-dimethylphenylcarbamate) selector in normal and polar organic modes acid and base additives were found to affect the peak profiles, without significantly influencing the enantiorecognition ability of the studied selector. In most cases, differences observed in retention times and enantioselectivities were lower than 10 and 20 % under normal phase and polar organic conditions, respectively. Under normal phase conditions decreased retention was observed for all the studied analytes with increased eluent polarity. Interestingly, enantioselectivity was only slightly (<10 %) influenced by the variation in the n-hexane/2-propanol ratio between 80/20 and 20/80 v/v. In polar organic mode, five different neat solvents (acetonitrile, methanol, ethanol, 1-propanol, and 2-propanol) were tested, and the best results were obtained with acetonitrile and ethanol in the case of Lux Amylose-1 column with enantioresolutions most often above 2. Based on results obtained with amylose and cellulose-based columns the amylose tris-(3,5-dimethylphenylcarbamate) selector is found to offer a superior performance both in normal and polar organic modes. When evaluating the possible effects of the selector immobilization, no striking differences were found in the normal phase. Usually, enantioselectivities and resolutions were higher (10–20 %), while retention factors of the first peaks were lower (20–30 %), on the coated-type column. In contrast, in polar organic mode, the retention characteristics and enantiorecognition ability of the coated and immobilized selectors were heavily affected by the nature of the polar solvent.Special attention has been paid to the history-dependent behavior of polysaccharide-based selectors. A confidence interval-based evaluation is suggested to help comparison of the histereticity observed in different systems. Several examples are shown to confirm that the recently discovered hysteresis is a common characteristic of polysaccharide-based selectors.

Chiral cyanobiphenyl dimers – significance of the linking group for mesomorphic properties and helical induction

Chiral cyanobiphenyl dimers display rarely observed room-temperature twist-bend nematic (NTB) phase when the linking group is an ester, while the amide analogues are strong inducers of helical organization in the chiral nematic phase.

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.

Moxifloxacin Amide Analogs as Antibacterial and Antifungal Agents: Synthesis, Characterization, and Enzyme Inhibition Studies

Moxifloxacin Amide Analogs as Antibacterial and Antifungal Agents: Synthesis, Characterization, and Enzyme Inhibition Studies

Strategies for developing retinoic acid receptor alpha-selective antagonists as novel agents for male contraception

Reported here are the synthesis and in vitro evaluation of a series of 26 retinoic acid analogs based on dihydronaphthalene and chromene scaffolds using a transactivation assay. Chromene amide analog 21 was the most potent and selective retinoic acid receptor α antagonist identified from this series. In vitro evaluation indicated that 21 has favorable physicochemical properties and a favorable pharmacokinetic PK profile in vivo with significant oral bioavailability, metabolic stability, and testes exposure. Compound 21 was evaluated for its effects on spermatogenesis and disruption of fertility in a mouse model. Oral administration of compound 21 at low doses showed reproducibly characteristic albeit modest effects on spermatogenesis, but no effects on fertility were observed in mating studies. The inhibition of spermatogenesis could not be enhanced by raising the dose and lengthening the duration of dosing. Thus, 21 may not be a good candidate to pursue further for effects on male fertility.

The design, synthesis, and inhibition of Clostridioides difficile spore germination by acyclic and bicyclic tertiary amide analogs of cholate

Clostridioides difficile infection (CDI) is a major identifiable cause of antibiotic-associated diarrhea. In our previous study (J. Med. Chem., 2018, 61, 6759–6778), we have identified N-phenyl-cholan-24-amide as a potent inhibitor of spore germination. The most potent compounds in our previous work are N-arylamides. We were interested in the role that the conformation of the amide plays in activity. Previous research has shown that secondary N-arylamides exist exclusively in the coplanar trans conformation while tertiary N-methyl-N-arylamides exist in a non-planar, cis conformation. The N-methyl-N-phenyl-cholan-24-amide was 17-fold less active compared to the parent compounds suggesting the importance of the orientation of the phenyl ring. To lock the phenyl ring into a trans conformation, cyclic tertiary amides were prepared. Indoline and quinoline cholan-24-amides were both inhibitors of spore germination; however, the indoline analogs were most potent. Isoindoline and isoquinoline amides were inactive. We found that the simple indoline derivative gave an IC50 value of 1 μM, while the 5′-fluoro-substituted compound (5d) possessed an IC50 of 400 nM. To our knowledge, 5d is the most potent known spore germination inhibitor described to date. Taken together, our results indicate that the trans, coplanar conformation of the phenyl ring is required for potent inhibition.

Synthesis, In Silico Logp Study, and In Vitro Analgesic Activity of Analogs of Tetrapeptide FELL.

The inflammatory process represents a specific response of the organism's immune system. More often, it is related to the rising pain in the affected area. Independently of its origin, pain represents a complex and multidimensional acute or chronic subjective unpleasant perception. Currently, medical doctors prescribe various analgesics for pain treatment, but unfortunately, many of them have adverse effects or are not strong enough to suppress the pain. Thus, the search for new pain-relieving medical drugs continues. New tetrapeptide analogs of FELL with a generaanalgesic-Glu-X3-X4-Z, where X = Nle, Ile, or Val and Z = NH2 or COOH, containing different hydrophobic amino acids at positions 3 and 4, were synthesized by means of standard solid-phase peptide synthesis using the Fmoc/OtBu strategy in order to study the influence of structure and hydrophobicity on the analgesic activity. The purity of all compounds was monitored by HPLC, and their structures were proven by ESI-MS. Logp values (partition coefficient in octanol/water) for FELL analogs were calculated. Analgesic activity was examined by the Paw-pressure test (Randall-Selitto test). The obtained results reveal that Leu is the best choice as a hydrophobic amino acid in the FELL structure. The best analgesic activity is found in the parent compound FELL and its C-terminal amide analog.

Further Study of the Polar Group's Influence on the Antibacterial Activity of the 3-Substituted Quinuclidine Salts with Long Alkyl Chains.

Quaternary ammonium compounds (QACs) are among the most potent antimicrobial agents increasingly used by humans as disinfectants, antiseptics, surfactants, and biological dyes. As reports of bacterial co- and cross-resistance to QACs and their toxicity have emerged in recent years, new attempts are being made to develop soft QACs by introducing hydrolyzable groups that allow their controlled degradation. However, the development of such compounds has been hindered by the structural features that affect the bioactivity of QACs, one of them being polarity of the substituent near the quaternary center. To further investigate the influence of the polar group on the bioactivity of QACs, we synthesized 3-aminoquinuclidine salts for comparison with their structural analogues, 3-acetamidoquinuclidines. We found that the less polar amino-substituted compounds exhibited improved antibacterial activity over their more polar amide analogues. In addition to their better minimum inhibitory concentrations, the candidates were excellent at suppressing Staphylococcus aureus biofilm formation and killing bacteria almost immediately, as shown by the flow cytometry measurements. In addition, two candidates, namely QNH2-C14 and QNH2-C16, effectively suppressed bacterial growth even at concentrations below the MIC. QNH2-C14 was particularly effective at subinhibitory concentrations, inhibiting bacterial growth for up to 6 h. In addition, we found that the compounds targeted the bacterial membrane, leading to its perforation and subsequent cell death. Their low toxicity to human cells and low potential to develop bacterial resistance suggest that these compounds could serve as a basis for the development of new QACs.

Synthesis and Receptor Binding Studies of α5 GABAAR Selective Novel Imidazodiazepines Targeted for Psychiatric and Cognitive Disorders.

GABA mediates inhibitory actions through various GABAA receptor subtypes, including 19 subunits in human GABAAR. Dysregulation of GABAergic neurotransmission is associated with several psychiatric disorders, including depression, anxiety, and schizophrenia. Selective targeting of α2/3 GABAARs can treat mood and anxiety, while α5 GABAA-Rs can treat anxiety, depression, and cognitive performance. GL-II-73 and MP-III-022, α5-positive allosteric modulators have shown promising results in animal models of chronic stress, aging, and cognitive disorders, including MDD, schizophrenia, autism, and Alzheimer's disease. Described in this article is how small changes in the structure of imidazodiazepine substituents can greatly impact the subtype selectivity of benzodiazepine GABAAR. To investigate alternate and potentially more effective therapeutic compounds, modifications were made to the structure of imidazodiazepine 1 to synthesize different amide analogs. The novel ligands were screened at the NIMH PDSP against a panel of 47 receptors, ion channels, including hERG, and transporters to identify on- and off-target interactions. Any ligands with significant inhibition in primary binding were subjected to secondary binding assays to determine their Ki values. The newly synthesized imidazodiazepines were found to have variable affinities for the benzodiazepine site and negligible or no binding to any off-target profile receptors that could cause other physiological problems.