Substituted Benzoyl Chlorides Research Articles

Abstract 3102: Synthesis of N-benzoylamino-tetrahydropyridine analogues as selective COX-2 inhibitors and anti-breast cancer agents

Abstract The World Health Organization confirms breast cancer as the most common cancer globally, as of 2021, tallying 12% of new annual cancer cases. Female breast cancer is the second leading cancer in incidence rates among women after lung cancer. It is also more deadly amongst Black and Hispanic women as mortality rates increase by 40% compared to their caucasian counterparts. Hence, there is a dire need to design and develop novel molecules as effective anticancer agents. Rational design-based drug discovery has led to advancements in developing novel small molecules as effective anticancer agents. Chronic inflammation is directly related to cancer. Literature testifies to the presence and overexpression of cyclooxygenase-2 (COX-2) in various inflammation-based ailments, diseases, and many cancers. Therefore, it is imperative to investigate the relevance of cyclooxygenase-2 inhibition in cancer therapy. The tetrahydropyridine structure has been documented in several natural products. They display biological properties including antioxidant, anti-inflammatory, and chemotherapeutic. Substituted benzoylamino-5-ethyl-1,2,3,6-tetrahydropyridine analogues have been designed as COX-2 inhibitors. This project aims to synthesize thirteen novel THP analogues using a 4-step synthesis. The synthesis of these 1,2,3,6-THP analogues primarily involves the hydrolysis of ethyl-o-(mesitylenesulfonyl) acethydroxymate to render O-(mesitylsulfonyl)hydroxylamine (MSH). MSH then acts as an aminating agent as it reacts with 3-ethyl pyridine. This amination reaction affords the mesitylene salt, 1-amino-3-ethylpyridin-1-ium. Next, the salt product undergoes acylation with various substituted benzoyl chlorides to generate stable N-ylide products. Finally, the partial reduction of the ylides yields the desired final tetrahydropyridine products. Purification was completed by flash chromatography. The novel THP analogues were characterized using nuclear magnetic resonance, infrared spectroscopy, and elemental analysis. Computer-aided drug design studies provided the preliminary data constituting that the likelihood of the THP moiety generating more effective COX-2 inhibitors is dependent on suitable modifications to the structure. Further studies include testing the novel THP analogues as cyclooxygenase-2 inhibitors using COX-2 inhibition assays, and lastly, determining their anti-breast cancer activity in MDA-MD-231, MCF-7 and Ishikawa cell lines to assess their antiproliferative effects. This research was supported by the National Institute on Minority Health and Health Disparities of the National Institutes of Health under Award Number U54 MD007582. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Citation Format: Shasline Gedeon, Madhavi Gangapuram, Kinfe K. Redda, Tiffany Ardley. Synthesis of N-benzoylamino-tetrahydropyridine analogues as selective COX-2 inhibitors and anti-breast cancer agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3102.

Synthesis and Evaluation of Amide and Thiourea Derivatives as Carbonic Anhydrase (CA) Inhibitors.

Series of sulfonamide-substituted amide (9-11), benzamide (12-15), and 1,3-disubstituted thiourea (17-26) derivatives were synthesized from a common precursor, i.e., substituted benzoyl chlorides. Structures of all of the synthesized compounds were characterized by spectroscopic techniques (1H nuclear magnetic resonance (NMR),13C NMR, and Fourier transform infrared spectroscopy (FTIR)). All of the amide (9-15) and thiourea (17-26) derivatives were screened against human carbonic anhydrases, hCA-II, hCA IX, and hCA-XII. Sulfonamide-substituted amides 9, 11, and 12 were found to be excellent selective inhibitors with IC50 values of 0.18 ± 0.05, 0.17 ± 0.05, and 0.58 ± 0.05 μM against hCA II, hCA IX, and hCA XII, respectively. Compound 9 was found to be highly selective for hCA II and about 6-fold more potent as compared to the standard antagonist, acetazolamide. Safe toxicity profiling of the most potent and selective compounds was determined against normal BHK-21 and HEK-293 T cells. Molecular docking studies were performed, which described the type of interactions between the synthesized compounds and enzyme proteins. In addition, in silico absorption, distribution, metabolism, and excretion (ADME) studies were performed, which showed that all of the synthesized molecules fulfilled the druggability criteria.

Isoeugenol Ester Derivatives as Future Potential Drug

Abstract: Isoeugenol has wide medical applications. It is used in manufacturing perfumeries, flavorings, essential oils (odour description: Clove, spicy, sweet, woody) and in medicine (local antiseptic and analgesic). Its analogues also show various biological activities which prompted us to synthesize few more analogues for their future applications as bioactive molecules. These were synthesized by coupling isoeugenol with benzoyl chloride / substituted benzoyl chloride / acetyl chloride using pyridine as a base in dichloromethane as a solvent at 150C to RT for 8hrs. These synthesized analogues were unambiguously characterized by 1H NMR, elemental analysis and Mass spectral data. Few of them showing promising antibacterial activity.

Synthesis of trans N-Substituted Pyrrolidine Derivatives Bearing 1,2,4- triazole Ring.

1,2,4-triazoles scaffolds display significant biological activities due to hydrogen bonding, solubility, dipole character, and rigidity. The core motif of 1,2,4-triazoles plays a vital role in clinical drugs such as Rizatriptan (antimigraine), Ribavirin (antiviral), anastrozole (anticancer), etizolam (anxiolytic), estazolam (anticonvulsant), alprazolam (anti-hypnotic), letrozole (aromatase inhibitor), loreclezole (anticonvulsant), trazadone (antidepressant) etc. Methods: Epoxide ring opening of tert-butyl 6-oxa-3-azabicyclo [3.1.0] hexane-3-carboxylate followed by methylation under basic conditions and de-protection gave the corresponding trans 1-(4- methoxypyrrolidin-3-yl)-1H-1,2,4-triazole hydrochloride salt as the precursor. This precursor on reaction with substituted benzoyl chlorides and benzyl bromides gave the desired amide and amine products. A library of 14 N-substituted pyrrolidine derivatives i.e. trans3-methoxy-4-(1H-1,2,4-triazol- 1-yl) pyrrolidin-1-yl) (phenyl)methanone and trans 1-benzyl-4-methoxypyrrolidin-3-yl)-1H-1,2,4- triazole were prepared. Eight novel amides (6a-h) and six amines (8a-f) derivatives were synthesized using 1-(4- methoxypyrrolidin-3-yl)-1H-1,2,4-triazole 4 salt with substituted benzoyl chlorides and benzyl bromides.

Synthesis, characterization and anti HIV1 screening of some novel clubbed benzimidazole derivatives

A humble and a competent technique was improved in production of novel substituted benzimidazole derivatives by the condensation of various diamines with 2-amino-benzoic acid and many substituted benzoyl chloride reactions have demonstrated the benefits of classical reactions; convenient operation, and good yields. Finally, it has treated with phosphorous pentachloride and sodiumazide reaction to yield benzimidazole clubbed with tetrazole moiety compounds which were established by an Elemental analysis, IR, 1H NMR, 13C NMR and Mass spectra and screening of various biological studies also recorded.

Ultrasound-Promoted Sustainable Synthesis and Antimicrobial Evaluation of 2-Aryl Benzimidazoles Catalyzed by BPAE at Room Temperature

Background: Present-day chemists are more interested in developing and using green chemistry protocol for various organic transformations, which employ natural feedstock extracts, and solvent-free, and greener catalysts; they are well known for their non-hazardous nature and have replaced many organic and inorganic based catalysts. In literature, the reported homogenous catalytic approaches have been employed for various bioactive heterocycle syntheses, which follow the green chemistry principle established for various organic transformations catalyzed by WERSA, BFE, WEPPA, WEMFSA, WEMPA, and Eichhorniacrassipes. Among them, 2-aryl benzimidazole derivatives have emerged as prominent molecules with a wide variety of applications in biological and material science. Methods: The agro-waste sourced from the banana peel is utilized for the preparation of BPAE catalyst, which is employed for the synthesis of 2-aryl benzimidazole derivatives under ultrasound waves at room temperature. Results: Here, 2-Aryl benzimidazoles synthesized through the reaction of a substituted o-phenylene diamine with substituted benzoyl chloride catalyzed by BPAE under ultrasound waves at room temperature are described. Furthermore, catalyst BPAE is characterized by flame emission spectrometry, SEM-EDX, and XRD techniques. Conclusion: The present work established an eco-friendly, sustainable and novel approach for the synthesis of 2-aryl benzimidazoles using natural feedstock BPAE. The major merits of BPAE include its use as an agro-waste-derived catalyst. It is also highly abundant, inexpensive, yields faster reactions, has a simple workup, and does not require the use of column chromatography.

New Bioactive Fused Triazolothiadiazoles as Bcl-2-Targeted Anticancer Agents.

A series of 3-(6-substituted phenyl-[1,2,4]-triazolo[3,4-b]-[1,3,4]-thiadiazol-3-yl)-1H-indoles (5a–l) were designed, synthesized and evaluated for anti-apoptotic Bcl-2-inhibitory activity. Synthesis of the target compounds was readily accomplished through a reaction of acyl hydrazide (1) with carbon disulfide in the presence of alcoholic potassium hydroxide to afford the corresponding intermediate potassium thiocarbamate salt (2), which underwent cyclization reaction in the presence of excess hydrazine hydrate to the corresponding triazole thiol (3). Further cyclisation reaction with substituted benzoyl chloride derivatives in the presence of phosphorous oxychloride afforded the final 6-phenyl-indol-3-yl [1,2,4]-triazolo[3,4-b]-[1,3,4]-thiadiazole compounds (5a–l). The novel series showed selective sub-micromolar IC50 growth-inhibitory activity against Bcl-2-expressing human cancer cell lines. The most potent 6-(2,4-dimethoxyphenyl) substituted analogue (5k) showed selective IC50 values of 0.31–0.7 µM against Bcl-2-expressing cell lines without inhibiting the Bcl-2-negative cell line (Jurkat). ELISA binding affinity assay (interruption of Bcl-2-Bim interaction) showed potent binding affinity for (5k) with an IC50 value of 0.32 µM. Moreover, it fulfils drug likeness criteria as a promising drug candidate.

Ultrasound-assisted a domino three-component reaction to polycyclic selenopyrans synthesis

A novel and efficient three-component reaction of substituted benzoyl chlorides, potassium selenocyanate and vinyl malononitriles was developed for the synthesis of polycyclic selenopyrans via an ultrasound-assisted domino vinylogous nucleophilic reaction/intramolecular selenocyclization/imine-enamine tautomerization reaction. Introducing a simple one-step method and use of available starting materials and mild reaction conditions are the most important advantages of this strategy.

The synthesis and biological evaluation of A- and B-ring fluorinated flavones and their key intermediates

An efficient three-step method for the synthesis of new polyfluoroflavones has been proposed using substituted benzoyl chlorides and 2-hydroxyacetophenone to form the initial 2-(polyfluoroaroyloxy)acetophenones, which are transformed into 1,3-diaryl-1,3-diketones as a result of the Baker-Venkataraman rearrangement. The ability of these 1,3-diketones to undergo keto-enol and ring-chain tautomerism was found, depending on the nature of the solvent. Under acid- or base-catalyzed conditions the alternative cyclization routes of fluorine-containing 1,3-diaryl-1,3-diketones into A- and B-ring halogenated flavones have been reported. The anti-influenza and fungistatic effects of the synthesized compounds were evaluated, and products with promising antimicrobial properties were found.

Synthesis of 3-aryl-1-phosphinoimidazo[1,5-a]pyridine ligands for use in Suzuki-Miyaura cross-coupling reactions.

3-Aryl-1-phosphinoimidazo[1,5-a]pyridine ligands were synthesized from 2-aminomethylpyridine as the initial substrate via two complementary routes. The first synthetic pathway underwent the coupling of 2-aminomethylpyridine with substituted benzoyl chlorides, followed by cyclization, iodination and palladium-catalyzed cross-coupling phosphination reactions sequence to give our phosphorus ligands. In the second route, 2-aminomethylpyridine was cyclized with aryl aldehydes, followed by the iodination and palladium-catalyzed cross-coupling phosphination reactions to yield our phosphorus ligands. The 3-aryl-1-phosphinoimidazo[1,5-a]pyridine ligands were evaluated in palladium-catalyzed sterically-hindered biaryl and heterobiaryl Suzuki–Miyaura cross-coupling reactions.

Development of structurally extended benzosiloxaboroles - synthesis and in vitro biological evaluation.

The synthesis of potassium 6-hydroxy-7-chloro-1,1-dimethyl-3,3-difluorobenzo-1,2,3-siloxaborolate 5b from readily available 4-bromo-2-chlorophenol was developed. This compound proved useful in various derivatizations resulting in a wide range of O-functionalized benzosiloxaboroles. Reactions of 5b with selected substituted benzoyl chlorides gave rise to a series of respective derivatives with 6-benzoate side groups attached to the benzosiloxaborole core. Furthermore, treatment of 5b with substituted benzenesufonyl chlorides afforded several benzosiloxaboroles bearing functionalized benzenesulfonate moieties at the 6 position. The synthesis of related chloropyridine-2-yloxy substituted benzosiloxaboroles was accomplished by a standard approach involving silylation/boronation of appropriate heterodiaryl ethers. Investigation of biological activity of obtained compounds revealed that some benzoate and most benzenesulfonate derivatives exhibit high activity against Gram-positive cocci such as methicillin-sensitive Staphylococcus aureus ATCC 6538P as well as methicillin-resistant S. aureus ATCC 43300 with the MIC values in the range of 0.39–3.12 mg L−1. Some benzenesulfonate derivatives showed also potent activity against Enterococcus faecalis ATCC 29212 and E. faecium ATCC 6057 with MIC = 6.25 mg L−1. Importantly, for the most promising cocci-active benzenesulfonate derivatives the obtained MIC values were far below the cytotoxicity limit determined with respect to human normal lung fibroblasts (MRC-5). For those derivatives, the obtained IC50 values were higher than 12.3 mg L−1. The results of antimicrobial activity and cytotoxicity indicate that the tested compounds can be considered as potential antibacterial agents.

Synthesis, antibacterial activities, binding mode analysis and predictive ADME studies of novel 1-(aryl)-2-(1H-imidazol-1-yl)methanones

Introduction: In the present study a novel series of twelve 1-(aryl)-2-(1H-imidazol-1-yl)methanones 3(a-l) were synthesized and characterised by physicochemical and spectral analysis,viz. elemental analysis, IR spectroscopy, NMR spectroscopy. The antibacterial property of the compounds were examined, in order to develop new broad spectrum antibiotics. Methods: The compounds 3(a-l) were synthesised by reacting the corresponding 2-(aryl)-1H-imidazoles 2 with substituted benzoyl chlorides. Binding mode analysis of the most active compound was carried out. Predictive ADME studies were carried out for all the compounds. Results and Discussions: Among the synthesized compounds, (2-(3-nitrophenyl) (2,4-dichlorophenyl) -1Himidazol-1-yl)methanone 3i exhibited highest antibacterial activity. Binding mode analysis of the highest active compound was carried out in the active site of glucosamine-6-phosphate synthase (2VF5).

A Highly Active Catalyst 2,4,6‐Tris (di‐4‐chlorobenzamido)‐1,3,5‐triazine Palladium (II) Chloride for the Green Synthesis of Substituted Dihydrobenzo[b]thiophene in Ionic Liquid

AbstractThe palladium‐metallodendrimer (Pd‐MD) 2,4,6‐tris (di‐4‐chlorobenzamido)‐1,3,5‐triazine palladium (II) chloride was synthesized by the reaction of substituted triazine, substituted benzoyl chloride, and (Ph3P)2PdCl2 in DMF at 100 °C. This Pd‐MD was characterized by FTIR, 1H NMR, 13C NMR, Scanning Electron Microscopy (SEM), Energy Dispersive X‐ray (EDX), mass spectrometry, X‐ray photoelectron spectroscopy (XPS), elemental analysis, Thermogravimetric analysis (TGA), and Differential scanning calorimetry (DSC) methods. This catalyst was successfully applied for the green synthesis of different substituted alkyl 2,3‐dihydrobenzo[b]thiophene‐2‐carboxylates in ionic liquid tetra‐n‐butylammonium bromide (TBAB) solution at 120 °C for 2.5 hours with a good to an excellent percentage of yields (75 % to 96 %). Importantly, this homogeneous catalytic system was easily recoverable and reusable at least five times without a significant loss of activity.

Design, Synthesis of Some New N-(2-fluoro-4-morpholin-4-yl-phenyl)-Substituted-Benzamide Derivatives and Screening of Their Microbial Activities

In the present work, we are reporting efficient synthesis of a series of novel fluorinated Morpholine containing benzamide derivatives and their microbial activities. In the reaction between 2-fluoro-4-morpholinobenzenamine and different substituted benzoyl chloride in presence of toluene solvent at reflux temperature to give desired products in pure form. The compounds are characterized by spectral technique like 1H NMR, IR, mass, and elemental analysis. Yields of synthesized compounds are good to excellent as well as the synthetic process is rapid. The synthetic process was shown to have advantageous such as low cost, short reaction time, mild reaction conditions, and eco-friendly. Some of the synthesized compounds exhibit potent antifungal and antibacterial activity as compared with standard drug molecules as Gentamycin, Ampicillin, Chloramphenicol, Iprofloxacin, Norfloxacin, Nystatin, and Greseofulvin.

Synthesis, Characterization, Antitubercular and Anti-Inflammatory Activity of New Pyrazolo[3,4-d]Pyrimidines.

Copious proinflammatory cytokines including TNF-α and IL-1β are involved in progression of inflammation in human body. Inhibition of signaling mediated by proinflammatory cytokines offer effective in the treatment of inflammatory diseases. The treatment of dreadful infectious disease mycobacterium tuberculosis still remains a challenge owing to resistance to multiple drugs hence an urgent need for newer drugs. Pyrazolo[3,4-d]pyrimidines have been disclosed to possess numerous pharmacological activities including anti-inflammatory, antimicrobial and antitubercular activities. Here in we report the synthesis of pyrazolo[3,4-d]pyrimidines for anti-inflammatory and antitubercular activities. The targeted compounds having pyrazolo[3,4-d]pyrimidine scaffold 8a-m were synthesized in three step reactions with the formation of key intermediate 5-amino-4-- cyno-1-phenyl pyrazole which upon cyclization resulted in 4-amino pyrazolo[3,4-d]pyrimidine for subsequent benzoylation with substituted benzoyl chlorides to form 8a-m. Antiinflammatory activity of 8a-m was assessed at 25 mg/Kg dose and minimum inhibitory concentration against gram positive, gram negative and mycobacteria was also performed. Binding interactions were also measured in binding pocket of p38 kinase. Four compounds 8a, 8b, 8e and 8i significant anti-inflammatory activity in rat paw edema model induced by carrageenan and among all 8b was potent with 80.6% activity. Numerous compounds exhibited potent activity against fungal strains than bacterial strains, compound 8k was most potent against gram negative bacteria Klebsiella pneumoniae. Compounds 8d, 8e and 8f exhibited antitubercular activity with MIC value of 6.25 μg/mL. Substituted N-benzoylated amino pyrazolo[3,4-d]pyrimidines endowed significant and potent anti-inflammatory and antimicrobial activities. Molecular docking studies also revealed favorable interactions in active site of p38 kinase.

Three-Component Reaction between 2-Aminobenzamide, Aroyl Chlorides and Potassium Selenocyanate: Synthesis of 2-[3-(Aroyl)-Selenoureido])-Benzamide

A simple, one-pot and green synthesis of six 2-[3-(aroyl)-selenoureido])-benzamide and 2-arylquinazolin-4(3H)-ones has been achieved in moderate to good yields via a three-component condensation of 2-aminobenzamide, variously substituted benzoyl chlorides and potassium selenocyanate under solvent-free conditions and in the presence of triethylamine.

Design, Synthesis and Characterization of Some Novel benzamide derivatives and it's Pharmacological Screening

The new series of substituted N-(phenylcarbamothioyl)benzamide derivatives (2a-2f) was designed, development and synthesized by using conventional and microwave method. In present work 6 different N-(phenylcarbamothioyl)benzamide were synthesized. Substituted benzoyl chloride is converted into benzoyl isothiocyanate by esterification. Benzoyl isothiocyanate is converted into Substituted (phenylcarbamothioyl)benzamide by treating with different types of substituted aniline. Confirmation of the chemical structure of the synthesized was substantiated by TLC, IR, 1H NMR, MS spectroscopy.Novel synthesized compounds screened for their in vivo and in-vitro anti-inflammatory studies and compound 2f shows promising anti-inflammatory activity.

Synthesis of 5-aryl-2-ethylsulfanyl-[1,3,4]thiadiazolo[3,2,a][1,3,5] triazine-7-selones via a three-component condensation of 5-ethylsulfanyl-[1,3,4]thiadiazol-2-ylamine, potassium selenocyanate and an acyl chloride

A simple, one-pot synthesis of seven 5-aryl-2-ethylsulfanyl-[1,3,4]thiadiazolo[3,2,a][1,3,5] triazine-7-selones has been achieved in moderate to good yields via a three-component condensation of 5-ethylsulfanyl-[1,3,4]thiadiazol-2-ylamine, potassium selenocyanate and variously substituted benzoyl chlorides in acetone at room temperature.

Facile Synthesis of Novel Benzoylthiophene C-Nucleoside Analogues via Coupling of Sugar Alkynes, Aroyl Chlorides, and 1,4-Dithiane-2,5-diol

Concise synthesis of novel benzoylthiophene C-nucleoside analogues has been achieved by the reaction of various terminal sugar alkynes with substituted benzoyl chlorides and 1,4-dithiane-2,5-diol, and subsequent dilute HCl-promoted dehydration in one pot. The sugar alkynes include pyranosides, furanosides, and acyclic sugar. The benzoyl chloride has various substituents. Twenty-eight examples are given. The desired products are obtained in 70–89% yields, and the mechanism has been clarified by isolation of the intermediate.

Synthesis of 4-aryl-7-methoxy-9-thia-[1,3,4a]triazafluorene-2-selones via a three-component condensation of 6-methoxybenzothiazol-2-ylamine, potassium selenocyanate and an acyl chloride

A simple, one-pot synthesis of six 4-aryl-7-methoxy-9-thia-[1,3,4a]triazafluorene-2-selones has been achieved in moderate to good yields via a three-component condensation of 6-methoxybenzothiazol-2-ylamine, potassium selenocyanate and variously substituted benzoyl chlorides in acetone at room temperature.