Synthesis Of Analogues Research Articles

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.

Synthesis of phosphinic structural analogue of Met-Glu-His-Phe

The synthesis of a phosphinic structural analogue of the tetrapeptide Met-Glu-γ-His-Phe by adding the dipeptide component His-Phe to the adamantyl ester of the phosphinic pseudo-Met-[P]-Glu-peptide in the form of cyclic glutamate anhydride is proposed. The conditions for the interaction of phosphinic pseudo-Met-[P]-Glu-anhydride with His-Phe in free form to form phosphinic Met-[P]-Glu-γ-His-Phe tetrapeptide have been found. A chromatographic mass-spectrometry study, including MS2, and NMR of the phosphinic tetrapeptide on 1H, 13C, 31P nuclei was carried out using the methods of two-dimensional 1H–1H COSY, 1H–13C HSQC and 1H–13C HMBC NMR spectroscopy.

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.

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.

Open-vessel polymerization of N-carboxyanhydride (NCA) for polypeptide synthesis.

Synthetic polypeptides, also known as poly(α-amino acids), have the same polyamide backbone structures as natural proteins and peptides. As an important class of biomaterials, polypeptides have been widely used because of their biocompatibility, bioactivity and biodegradability. Ring-opening polymerization of N-carboxyanhydride (NCA) is a classical and widely used method for the synthesis of polypeptides. The dominantly used primary amine-initiated NCA polymerization can yield well-defined polymers and complex macromolecular architectures, but the reaction is slow and sensitive to moisture, making it necessary to use anhydrous solvents and a glovebox. One solution is to use lithium hexamethyldisilazide (LiHMDS) as the initiator, as described in this protocol. LiHMDS-initiated NCA polymerization is less sensitive to moisture and can be carried out in an open vessel outside the glovebox. It is also very fast; the reaction can be complete within 5 min to produce 30-mer polypeptides. In this protocol, poly(γ-benzyl-L-glutamate) is prepared as an example, but the protocol can easily be adapted to the synthesis of other polypeptides by generating NCAs from different amino acids, making it particularly suitable for the efficient parallel synthesis of polypeptide libraries. We provide detailed procedures for NCA synthesis and purification, the method of polymer end-group modification and measurement of polymerization kinetics and reactivity ratio. The procedure for synthesis of monomers and polymerization to form polypeptides requires <1 d. The superfast and open-vessel NCA polymerization method described here will probably enable a wide range of applications in the synthesis and functional study of polypeptide biomaterials.

Selenium(II)-Nitrogen Exchange (SeNEx) Chemistry: A Good Chemistry Suitable for Nanomole-Scale Parallel Synthesis, DNA-encoded Library Synthesis and Bioconjugation.

The continuous development of click reactions with new connecting linkage is crucial for advancing the frontiers of click chemistry. Selenium-nitrogen exchange (SeNEx) chemistry, a versatile chemistry in click chemistry, represents an all-encompassing term for nucleophilic substitution events that replace nitrogen at an electrophilic selenium(II) center, enabling the flexible and efficient assembly of linkages around a Se(II) core. Several SeNEx chemistries have been developed inspired by the biochemical reaction between Ebselen and cysteine residue, and demonstrated significant potential in on-plate nanomole-scale parallel synthesis, selenium-containing DNA-encoded library (SeDEL) synthesis, as well as peptide and protein bioconjugation. This concept aims to present the origins, advancements, and applications of selenium(II)-nitrogen exchange (SeNEx) chemistry while also outlining the potential directions for future research in this field.

Adjuvants restore colistin sensitivity in mouse models of highly colistin-resistant isolates, limiting bacterial proliferation and dissemination.

Antimicrobial resistance (AMR) has led to a marked reduction in the effectiveness of many antibiotics, representing a substantial and escalating concern for global health. Particularly alarming is resistance in Gram-negative bacteria due to the scarcity of therapeutic options for treating infections caused by these pathogens. This challenge is further compounded by the rising incidence of resistance to colistin, an antibiotic traditionally considered a last resort for the treatment of multi-drug resistant (MDR) Gram-negative bacterial infections. In this study, we demonstrate that adjuvants restore colistin sensitivity in vivo. We previously reported that the salicylanilide kinase inhibitor IMD-0354, which was originally developed to inhibit the human kinase IKKβ in the NFκB pathway, is a potent colistin adjuvant. Subsequent analog synthesis using an amide isostere approach led to the creation of a series of novel benzimidazole compounds with enhanced colistin adjuvant activity. Herein, we demonstrate that both IMD-0354 and a lead benzimidazole effectively restore colistin susceptibility in mouse models of highly colistin-resistant Klebsiella pneumoniae and Acinetobacter baumannii-induced peritonitis. These novel adjuvants show low toxicity in vivo, significantly reduce bacterial load, and prevent dissemination that could otherwise result in systemic infection.

6603 Impact of the Monocarbonyl Analogs of Curcumin, C66 and B2BrBC, on the Protein Expression of Epithelial and Mesenchymal Markers in MCF-7 Breast Cancer Cells

Abstract Disclosure: R. Stojchevski: None. A. Lavi: None. J. Bogdanov: None. N. Hadzi-Petrushev: None. M. Mladenov: None. L. Poretsky: None. D.B. Avtanski: None. The synthesis of monocarbonyl analogs of curcumin (MACs) presents a solution to the challenges posed by curcumin, a natural polyphenol extracted from the roots of the turmeric plant (Curcuma longa), which is known for its antioxidant and anti-inflammatory properties. The limitations of curcumin, including poor stability, low bioavailability, and rapid metabolism, hinder its application, and MACs, designed without a β-diketone moiety, address these drawbacks and exhibit enhanced stability and bioavailability. This study aimed to assess the effects of two monocarbonyl analogs of curcumin, (2E,6E)-2,6-bis[(2-trifluoromethyl)benzylidene]cyclohexanone (C66) and (2E,6E)-2,6-bis(2-bromobenzylidene)cyclohexanone (B2BrBC), on epithelial-to-mesenchymal transition (EMT) in MCF-7 breast cancer cells using western blot analysis. Our previous findings indicated that these analogs can potentially affect EMT by modulating the epithelial and mesenchymal gene expression. MCF-7 cells were cultured in complete medium supplemented with EMT-inducing factors for two days, followed by C66 and B2BrBC administration (100 µM) for three additional days. After the experiments, proteins were extracted, and western blot analyses were performed to measure the expression levels of various epithelial and mesenchymal markers (E-cadherin, N-cadherin, SNAI1, and Claudin-1). The results revealed that both C66 and B2BrBC increased the protein levels of the epithelial marker E-cadherin and suppressed those of the mesenchymal marker N-cadherin. Moreover, C66 and B2BrBC decreased the protein expression of the transcription factor SNAI1 and transmembrane protein Claudin-1. Between the two MACs, B2BrBC showed a more pronounced effect on N-cadherin expression, while C66 was more potent in suppressing SNAI1 protein expression. Our findings demonstrate that C66 and B2BrBC counteract EMT, contributing to the potential therapeutic applications of MACs in managing breast cancer progression. Presentation: 6/3/2024

6603 Impact Of The Monocarbonyl Analogs Of Curcumin, C66 And B2BrBC, On The Protein Expression Of Epithelial And Mesenchymal Markers In MCF-7 Breast Cancer Cells

Abstract Disclosure: R. Stojchevski: None. A. Lavi: None. J. Bogdanov: None. N. Hadzi-Petrushev: None. M. Mladenov: None. L. Poretsky: None. D.B. Avtanski: None. The synthesis of monocarbonyl analogs of curcumin (MACs) presents a solution to the challenges posed by curcumin, a natural polyphenol extracted from the roots of the turmeric plant (Curcuma longa), which is known for its antioxidant and anti-inflammatory properties. The limitations of curcumin, including poor stability, low bioavailability, and rapid metabolism, hinder its application, and MACs, designed without a β-diketone moiety, address these drawbacks and exhibit enhanced stability and bioavailability. This study aimed to assess the effects of two monocarbonyl analogs of curcumin, (2E,6E)-2,6-bis[(2-trifluoromethyl)benzylidene]cyclohexanone (C66) and (2E,6E)-2,6-bis(2-bromobenzylidene)cyclohexanone (B2BrBC), on epithelial-to-mesenchymal transition (EMT) in MCF-7 breast cancer cells using western blot analysis. Our previous findings indicated that these analogs can potentially affect EMT by modulating the epithelial and mesenchymal gene expression. MCF-7 cells were cultured in complete medium supplemented with EMT-inducing factors for two days, followed by C66 and B2BrBC administration (100 µM) for three additional days. After the experiments, proteins were extracted, and western blot analyses were performed to measure the expression levels of various epithelial and mesenchymal markers (E-cadherin, N-cadherin, SNAI1, and Claudin-1). The results revealed that both C66 and B2BrBC increased the protein levels of the epithelial marker E-cadherin and suppressed those of the mesenchymal marker N-cadherin. Moreover, C66 and B2BrBC decreased the protein expression of the transcription factor SNAI1 and transmembrane protein Claudin-1. Between the two MACs, B2BrBC showed a more pronounced effect on N-cadherin expression, while C66 was more potent in suppressing SNAI1 protein expression. Our findings demonstrate that C66 and B2BrBC counteract EMT, contributing to the potential therapeutic applications of MACs in managing breast cancer progression. Presentation: 6/3/2024

Design, Synthesis, Docking Studies, and Biological Activity of Novel Analogs of Cyclophosphamide as Potential Anticancer Agents.

This study aimed to present the synthesis and characterization of four novel analogs of cyclophosphamide (2, 3, 4, 7) and their related precursors (1, 5, 6) and assess their anticancer activity against breast cancerous (MCF-7) and normal (HUVEC) cells. Notably, 2-(bis(2-chloroethyl)amino)-1,3,2-diazaphospholidine 2-oxide ((2)) and 2-(bis(2-hydroxyethyl)amino)-1,3,2-diazaphospholidine 2-oxide ((7)) exhibited concentration- dependent cytotoxicity against the MCF-7 cell line, with IC50 values of 8.98 and 28.74 μM, respectively. Annexin V/PI staining and ROS assays demonstrated reduced cell viability and mitochondrial dysfunction. in silico studies involving DFT-D optimization and Molegro virtual docking against B-DNA dodecamer and STAT3 receptors revealed enhanced interactions for certain compounds compared to cyclophosphamide. Importantly, the in silico and in vitro results corroborated each other, supporting the potential anticancer efficacy of these novel analogs.

Total Synthesis of Ryanodane Diterpenoids Garajonone and 3-epi-Garajonone.

Ryanodane diterpenes are structurally complex natural products that are well-known for their high degree of oxidation and the challenges associated with synthesizing them within the terpene class. Herein, we present a two-stage synthetic strategy that draws inspiration from the broad biosynthesis of terpenes, allowing us to successfully achieve the first chemical synthesis of garajonone, a ryanodane diterpenoid that occurs naturally at low abundance, as well as its epimer, 3-epi-garajonone. The key to this success lies in the rapid construction of the carbon framework of target molecule by employing an early-stage palladium-catalyzed Heck/carbonylative esterification cascade annulation, followed by successive late-stage selective redox manipulation to establish the desired oxidation state of the molecule. This research not only showcases the synthesis of garajonone and its epimer but also provides a platform for the chemical synthesis of other members and analogs within this complex diterpenoid family.

Synthesis of New Indazole Analogs of Curcumin as Antioxidant and Anti-inflammatory Candidates: An &lt;i&gt;In Vitro&lt;/i&gt; Investigation

The development of analog curcumin compounds by modifying the structure of monocarbonyl into an analog indazole of curcumin (AIC) is recognized to have a great potential. Still, only a few reports have been available. Rarely occurring in nature, indazole molecules are typically created through chemical synthesis. Therefore, this study aimed to synthesize six new AIC compounds with a particular focus on testing in vitro antioxidant activity using the DPPH and FRAP methods, as well as anti-inflammatory activity using the protein denaturation method. The results showed that the compounds formed had high anti-inflammatory activity but low antioxidant activity. All synthesis products produced higher anti-inflammatory activity than standard diclofenac sodium and curcumin compounds. Specifically, compound 3a showed the highest anti-inflammatory activity with an IC50 = 0.548 ± 0.062 μM. Therefore, it was concluded that compound 3a has the potential to be further studied for anti-inflammatory activity.