Synthesis Of Analogues Research Articles

Photo-Induced Three-Component Reaction for the Construction Of α-Tertiary Amino Acid Derivatives.

The synthesis of α-tertiary amino acids (ATAAs), which are pivotal components in natural metabolism and pharmaceutical innovation, continues to attract significant research interest. Despite substantial advancements, the pursuit of a facile, versatile, and resource-efficient methodology remains an area of active development. In this work, we introduce a visible light-triggered three-component reaction involving readily available nitrosoarenes, N-acyl pyrazoles, and allyl or (bromomethyl)benzenes under mild conditions. This approach enables the straightforward assembly of a wide array of ATAA derivatives (42 examples) in commendably high yields (up to 89 %). Mechanistic investigations elucidate that the reaction proceeds through a dehydration condensation between nitrosoarenes and N-acyl pyrazoles to generate ketimine intermediates. This is followed by a light-driven halogen atom transfer (XAT) process and a radical addition, culminating in the formation of the desired products. The approach showcases excellent functional group compatibility and late-stage derivatization potential, offering new insights and avenues for the synthesis of ATAA analogs.

Synthesis of Antitumor Bicyclic Hexapeptide RA-VII Analogues Possessing an Aromatic Amino Acid at Residue 2.

RA-III acetate was treated with Lawesson's reagent to afford [Tyr-3-Ψ(CS-NH)-Ala-4]RA-III acetate. Treatment of this product with Hg(OAc)2/Li2CO3 and then methanol gave an oxazole intermediate. Acid-catalyzed arylation of the methylene carbon atom on the oxazole ring and subsequent partial hydrolysis of the oxazole ring in the resultant compounds afforded RA-VII analogues having an aromatic amino acid at residue 2. [5-Fluoro-d-Trp-2]RA-VII showed IC50 values of 0.038 and 0.077 μM against the HL-60 and HCT-116 cell lines, respectively.

Synthesis, Characterization, in Silico and in vitro Screening of Anticancer Activity of Novel Curcumin Analogues

Global problem of cancer associated side effects with current chemotherapeutics and promising anticancer activity of curcumins, intended present study to carry out the synthesis of some new curcumin analogues using chromone aldehydes and cyclic ketones. The study involved in silico screening and in vitro anticancer evaluation of new synthesized compounds against the breast cancer cell line MDA-MB-231 using the MTT assay. All synthesized compounds exhibited significant cytotoxicity, with IC50 values ranging from 34.04 ± 0.05 µg to 43.96 ± 0.05 µg, comparable to the standard drug cisplatin (IC50 = 29.25 ± 0.14 µg). Among all new synthesized curcumin analogues, compound 2 exhibited the highest anticancer activity. Molecular docking studies supported these findings, demonstrating strong binding affinities of the chromone compounds to key protein targets EGFR (PDB ID: 3UG2) and ERBB2 (PDB ID: 3H3B), critical in breast cancer pathogenesis. The strong cytotoxic effects and binding affinities suggest that curcumin analogues could serve as promising candidates for developing targeted anticancer therapies.

Design, synthesis and antifungal activity of arylhydrazine analogs containing diphenyl ether fragments.

Succinate dehydrogenase (SDH) represents a critical target in the development of novel fungicides. To address the growing issue of resistance and safeguard the economic viability of agricultural production, the pursuit of new succinate dehydrogenase inhibitors (SDHIs) has emerged as a significant focus of contemporary research. In this project, 32 arylhydrazine derivatives containing diphenyl ether structural units were synthesized and evaluated for their fungicidal activities against Rhizoctonia solani, Sclerotinia sclerotiorum, Alternaria alternata, Gibberella zeae, Alternaria solani and Colletotrichum gloeosporioides. In an in vitro fungicidal activity assay, compound D6 showed significant inhibitory activity against R. solani with a half-maximum effective concentration (EC50) of 0.09 mg L-1. The in vivo fungicidal activity demonstrated that compound D6 inhibited R. solani by 95.39% in rice leaves, which was significantly better than that of boscalid (85.76%). The results of SDH enzyme assay, molecular docking simulation, mitochondrial membrane potential assay, cytoplasmic release studies and morphological observations demonstrated that the target compound D6 not only had significant SDH inhibitory activity, but also affected the membrane integrity of mycelium. Bioactivity screening and validation of the mechanism of action indicated that compound D6 was a potentially unique SDHI, acting on SDH while also affecting cell membrane permeability, which deserved further study. © 2024 Society of Chemical Industry.

Unlocking the Secrets of Pheromones: Reproductive and Social Communication in Domestic Mammals

Pheromones play a pivotal role in the reproductive and behavioural management of livestock, influencing various physiological and behavioural responses within and across species. This review explores the application of pheromones in cattle, buffalo, sheep, goats, pigs, and equines, highlighting their significant impact on reproductive efficiency, stress reduction, and animal welfare. In cattle, pheromones are essential for estrus detection and the enhancement of maternal bonding. Similarly, in buffaloes, urinary pheromones have been identified as markers for estrus detection, aiding in overcoming the challenge of silent ovulation, while also contributing to penis erection and sperm quantity enhancement. In small ruminants such as sheep and goats, the "male effect" accelerates puberty and synchronizes estrus, which is crucial for optimizing breeding cycles. In pigs, the presence of boars accelerates puberty in gilts and reduces postpartum anestrus in sows, enhancing reproductive outcomes. Equines benefit from appeasing pheromones, which alleviate stress in foals and adult horses, particularly during transportation and other stressful events. The synthesis and application of synthetic analogs of these pheromones have demonstrated practical benefits in animal husbandry, offering promising avenues for improving reproductive performance and animal welfare. However, despite these advancements, the identification and characterization of specific pheromones across different species remain incomplete. Future research should focus on the molecular identification of these pheromones, their mechanisms of action, and the development of innovative applications to further enhance their utility in animal management.

A Case Study of an Antibiotic Discovery Laboratory Autonomous Learning Assignment—An Evaluation of Undergraduate Students’ Disciplinary Bias

Current higher education trends are moving towards interdisciplinary curricula to provide new tools for solving complex issues. However, course design and learning tracks still create divisions between scientific disciplines. This study aimed to evaluate the disciplinary bias of second-year undergraduate students of biotechnology engineering in the organic chemistry laboratory class through a laboratory setting involving blended disciplines. An experiment on antibiotic discovery that integrates parallel and combinatorial organic chemistry syntheses with microbiology techniques was chosen. As a part of an activity, students had free choice in designing the arrangement of the organic compounds and the two bacterial species by setting up the layout for a 96-well plate. The study visually analyzed students’ plate layouts (N = 74) according to discipline classification and the spatial arrangements of organic compounds (e.g., products and libraries). The results identified four themes that are suggested to reflect students’ vertical, lateral, and interdisciplinary thinking, as most were found to be in the procedural knowledge range and between Bloom’s application and analysis dimensions. Using this study’s thematic analysis methodology in chemistry and related educational fields can provide a pedagogical reflective tool and advance personalized teaching and interdisciplinarity.

(p)ppGpp Buffers Cell Division When Membrane Fluidity Decreases in Escherichia coli.

Fluidity is an inherent property of biological membranes and its maintenance (homeoviscous adaptation) is important for optimal functioning of membrane-associated processes. The fluidity of bacterial cytoplasmic membrane increases with temperature or an increase in the proportion of unsaturated fatty acids and vice versa. We found that strains deficient in the synthesis of guanine nucleotide analogs (p)ppGpp and lacking FadR, a transcription factor involved in fatty acid metabolism exhibited a growth defect that was rescued by an increase in growth temperature or unsaturated fatty acid content. The strain lacking (p)ppGpp was sensitive to genetic or chemical perturbations that decrease the proportion of unsaturated fatty acids over saturated fatty acids. Microscopy showed that the growth defect was associated with cell filamentation and lysis and rescued by combined expression of cell division genes ftsQ, ftsA, and ftsZ from plasmid or the gain-of-function ftsA* allele but not over-expression of ftsN. The results implicate (p)ppGpp in positive regulation of cell division during membrane fluidity loss through enhancement of FtsZ proto-ring stability. To our knowledge, this is the first report of a (p)ppGpp-mediated regulation needed for adaptation to membrane fluidity loss in bacteria.

Development of scalable processes to prepare a key chiral, nonracemic intermediate en route to LpxC inhibitors for gram-negative infections

Deaths resulting from drug-resistant gram-negative bacterial infections are a growing public health concern. Pyridone methylsulfone hydroxamic acid LpxC inhibitors, such as 1, are being developed for the treatment of serious gram-negative infections. Carboxylic acid 2 is a key intermediate in the synthesis of analogs of type 1. The current synthesis of 2 is unsuitable as a manufacturing process due to safety concerns and high cost. Two scalable and potentially lower cost processes have been developed, one based on chromatographic resolution of a novel intermediate and a second based on a classical resolution of the key intermediate 3. The advantages of these new chemical approaches are illustrated in the process details described in this letter.

Hemi Synthesis, Anti-inflammatory and In-silico Alpha-amylase Inhibition of Novel Carlina Oxide Analogs

Hemi Synthesis, Anti-inflammatory and In-silico Alpha-amylase Inhibition of Novel Carlina Oxide Analogs

Synthesis and Characterization of Monomeric Triarylbismuthine Oxide.

The synthesis and isolation of a bismuth-based analogue of the venerable triphenylphosphine oxide (Ph3PO) has remained a chimera to synthetic chemists for many years, due to its predicted high reactivity and instability. Through the hydrolysis of a cationic fluorotriarylbismuthonium(V) salt, we report here the isolation of unique hydroxytriarylbismuth(V) complexes, which served as precursor for the formation of the elusive monomeric triarylbismuthine oxide Dipp3Bi═O. Combined spectroscopic, crystallographic and computational studies provided insight into the bonding situation of the first monomeric triorganobismuth oxide complex. The Dipp3Bi═O and Mes3BiO·LiBArF complex exhibits O-atom transfer reactivity, an uncommon reactivity feature for Ar3Pn=O.

Synthesis of novel isostere analogues of naphthyridines using CuI catalyst: DFT computations (FMO, MEP), molecular docking and ADME analysis

An approach towards the synthesis of novel isosteres of benzonaphthyridines and benzonaphthonaphthyridines from the condensation reaction between 4-chloro-2-methylquinolines/4-chloro-2-methylbenzo[h]quinoline and appropriate o-amino aromatic and heteroaromatic carboxylic acids by using solvent (ethanol)/solvent free (neat) condition to yield the intermediate followed by the cyclization with PPA. The intermediate yield has been slightly increased in neat (solvent-free) conditions compared to solvent conditions. Further, the target isosteres of benzonaphthyridines and benzonaphthonaphthyridines were achieved in the one-pot synthesis using a CuI catalyst with a higher yield than the stepwise method. Quantum chemical calculations of synthesized compounds are performed by using M06-2X with 6-311+G(d,p) basis set in water, DFT calculations of the molecular electrostatic potential (MEP), frontier molecular orbitals (FMOs), and the optimized geometry of the XRD values are compared with experimental values. All the synthesized novel isosteres molecules are investigated under molecular docking studies using MMP1 and MMP2 proteins, which showed all the molecules have the potential to heal pancreatic cancer. The most potent molecules among them are 3i and 3h due to their better docking scores. Furthermore, the molecules' pharmacokinetic (ADME) parameters have been observed to be effective in future biological evaluations of these compounds to be active.

Synthesis, Biological Evaluation and Molecular Modeling Studies of Novel Tribromo-substituted Imidazole Analogs

IntroductionWith the increasing rate of antimicrobial resistance, there is an urgent demand of developing newer antimicrobial agents. In the present study we report a novel series of eighteen 1-(aryl)-2-(2,4,5-tribromo-1H-imidazol-1-yl)ethan-1-ones, which were synthesized and their spectral characterization was performed. The in-vitro studies of the compounds were carried out. Molecular modeling studies were performed on the most promising compound. The results obtained would help develop new compounds that may have broad-spectrum therapeutic effects. MethodsThe compounds were synthesized by reacting the corresponding bromo-imidazoles with substituted phenacyl bromides. The predictive ADME studies, MM-GBSA studies, and In-vitro studies were carried out for all the compounds. Binding mode analysis of the most active compounds was carried out. DFT investigations were also performed. Results and discussionsAll the synthesized compounds were found to be active against the different strains of microorganisms used in the in-vitro analysis. Binding mode analysis of the most active compounds were carried out in the active site of glucosamine-6-phosphate synthase (2VF5) and crystal structure of Mycobacterium tuberculosis InhA inhibited by PT70 (2X22). With the increasing global challenge of multi-drug resistance and the urgent need for new antimicrobial agents, these compounds show promising potential to meet emerging therapeutic demands in treating infectious diseases.

Synthesis of 6-dialkylaminopyrimidine carboxamide analogues and their anti-tubercular properties

AbstractTuberculosis (TB) continues to be a threat to global health stability. Pyrimidine carboxamides have demonstrated potent anti-tubercular properties against clinical Mycobacterium tuberculosis, the causative agent of TB. Herein, we report a follow-up study on the synthesis of pyrimidine carboxamide molecular analogues and their anti-TB evaluation. In total, a library consisting of 37 new compounds is reported. Seven compounds (7b, 7d, 7m, 7p, 7q, 7aa, and 7ah) demonstrated excellent in vitro activities with MIC90 values below 1.00 µM. Apart from compound 7ah, compounds with improved aqueous solubility properties had lower anti-TB potency. Preliminary mode of action studies using bioluminescence assays indicate that the active compounds do not affect the integrity of mycobacterial DNA or the cell wall. The active compounds were also found to be bactericidal against replicating H37Rv Mtb strain.

Design and Synthesis of Mycophenolic Acid Analogues for Osteosarcoma Cancer Treatment

Design and Synthesis of Mycophenolic Acid Analogues for Osteosarcoma Cancer Treatment

One‐Step Synthesis of Novel Erlotinib Analogs Catalyzed by Nano‐CuO as Potent Anticancer Agent

ABSTRACTTwenty new substituted erlotinib analogs with anticancer activity were produced with good to excellent yields through the one‐step reaction of erlotinib, aromatic aldehydes, and cyclic secondary amines such as piperidine, morpholine, pyrrolidine, N‐methylpiperazine, or imidazole using nano‐CuO in choline chloride: urea (ChCl:urea) solvent under ultrasound irradiation at 80°C. MTT protocol was applied to investigate the cytotoxicity of all produced substituted erlotinib analogs in A431 (human epidermoid carcinoma cell) and HU02 (foreskin fibroblast) cell lines. The results illustrated that at a concentration of less than 10 μM, the growth of A431 cells could be inhibited by the produced compounds. Compared to erlotinib as positive control, the highest cytotoxic activity with IC50 equal to 2.58 ± 0.57 μM belonged to compound 4c carrying 4‐fluorobenzene with piperidine substitution. All of the synthesized compounds showed significant cytotoxic activity on A431, while showing no apparent cytotoxicity to HU02. The reasons for the stronger cytotoxic activity 4c can be most probably attributed to the two phenomena of greater solubility of the fluoro derivative and the flexibility of piperidine. Based on this study, compound 4c is the most promising compound with anticancer properties.

Spasmolytic Activity and Anti-Inflammatory Effect of Novel Mebeverine Derivatives.

Background: Irritable bowel syndrome (IBS) has a major negative influence on quality of life, causing cramps, stomach pain, bloating, constipation, etc. Antispasmodics have varying degrees of efficacy. Mebeverine, for example, works by controlling bowel movements and relaxing the muscles of the intestines but has side effects. Therefore, more efficient medication is required. Methods: In the current study, we investigated the synthesis of novel mebeverine analogs and determined ex vivo their spasmolytic and in vitro and ex vivo anti-inflammatory properties. The ability to influence both contractility and inflammation provides a dual-action approach, offering a comprehensive solution for the prevention and treatment of both conditions. Results: The results showed that all the compounds have better spasmolytic activity than mebeverine and good anti-inflammatory potential. Among the tested compounds, 3, 4a, and 4b have been pointed out as the most active in all the studies conducted. To understand their mechanism of activity, molecular docking simulation was investigated. The docking analysis explained the biological activities with their calculated Gibbs energies and possibilities for binding both centers of albumin. Moreover, the calculations showed that molecules can bind also the two muscarinic receptors and interleukin-β, hence these structures would exert a positive therapeutic effect owed to interaction with these specific receptors/cytokine. Conclusions: Three of the tested compounds have emerged as the most active and effective in all the studies conducted. Future in vivo and preclinical experiments will contribute to the establishment of these novel mebeverine derivatives as potential drug candidates against inflammatory diseases in the gastrointestinal tract.

Friedel-Crafts Reactivity with Sulfondiimidoyl Fluorides for the Synthesis of Heteroaryl Sulfondiimines.

Sulfur functional groups are ubiquitous in molecules used in the pharmaceutical and agrochemical industries, and within these collections sulfones hold a prominent position. The double aza-analogues of sulfones, sulfondiimines, offer significant potential in discovery chemistry but to date their applications have been limited by the lack of convenient synthetic routes. The existing methods mainly rely on imination of low-valent-sulfur intermediates, or the combination of pre-formed organometallic reagents and electrophilic S(VI)-functionalities. Herein, we describe a Friedel-Crafts-type reaction of sulfondiimidoyl fluorides with (hetero)aryls. This new SuFEx reactivity benefits from broad functional group tolerance, mild reaction conditions, and does not require the use of pre-formed organometallic reagents. The efficient use of unprotected indoles and pyrroles, as well as furan, thiophene and carbocyclic aromatics, further demonstrates the advantages of these reactions. We show that the reactivity of the sulfondiimidoyl fluorides can be tuned by switching the N-substituents, allowing an expansion of the range of coupling partners. The utility of the transformation is exemplified by the synthesis of the sulfondiimine analogue of the HIV-I reverse transcriptase-inhibitor L-737,126.

P-Stereodefined morpholino dinucleoside 3',5'-phosphorothioates.

Here, we present for the first time the synthesis of P-stereodefined morpholino phosphorothioate analogs by using a modified 1,3,2-oxathiaphospholane method (OTP method) and provide valuable structural insights into their stereochemistry. N-(2-Thio-4,4-pentamethylene-1,3,2-oxathiaphospholane) derivatives of morpholino-type nucleosides (mU-OTPs) were synthesized, separated into pure P-diastereomers and used to prepare P-stereodefined morpholino dinucleoside 3',5'-phosphorothioates.

Friedel‐Crafts Reactivity with Sulfondiimidoyl Fluorides for the Synthesis of Heteroaryl Sulfondiimines

Sulfur functional groups are ubiquitous in molecules used in the pharmaceutical and agrochemical industries, and within these collections sulfones hold a prominent position. The double aza‐analogues of sulfones, sulfondiimines, offer significant potential in discovery chemistry but to date their applications have been limited by the lack of convenient synthetic routes. The existing methods mainly rely on imination of low‐valent‐sulfur intermediates, or the combination of pre‐formed organometallic reagents and electrophilic S(VI)‐functionalities. Herein, we describe a Friedel‐Crafts‐type reaction of sulfondiimidoyl fluorides with (hetero)aryls. This new SuFEx reactivity benefits from broad functional group tolerance, mild reaction conditions, and does not require the use of pre‐formed organometallic reagents. The efficient use of unprotected indoles and pyrroles, as well as furan, thiophene and carbocyclic aromatics, further demonstrates the advantages of these reactions. We show that the reactivity of the sulfondiimidoyl fluorides can be tuned by switching the N‐substituents, allowing an expansion of the range of coupling partners. The utility of the transformation is exemplified by the synthesis of the sulfondiimine analogue of the HIV‐I reverse transcriptase‐inhibitor L‐737,126.

Pin1 WW Domain Ligand Library Synthesized with an Easy Solid-Phase Phosphorylating Reagent.

Cell cycle regulatory enzyme Pin1 both catalyzes pSer/Thr-cis/trans-Pro isomerization and binds the same motif separately in its WW domain. To better understand the function of Pin1, a way to separate these activities is needed. An unnatural peptide library, R1CO-pSer-Pro-NHR2, was designed to identify ligands specific for the Pin1 WW domain. A new solid-phase phosphorylating reagent (SPPR) containing a phosphoramidite functional group was synthesized in one step from Wang resin. The SPPR was used in the preparation of the library by parallel synthesis. The final 315-member library was screened with our WW-domain-specific, enzyme-linked enzyme-binding assay (ELEBA). Four of the best hits were resynthesized, and the competitive dissociation constants were measured by ELEBA. NMR chemical-shift perturbations (CSP) of ligands with 15N-labeled Pin1 were used to measure Kd for the best four ligands directly, demonstrating that they were specific Pin1 WW domain ligands. Models of the ligands bound to the Pin1 WW domain were used to visualize the mode of binding in the WW domain.