Facile Synthesis of 5-Aryl-N-(pyrazin-2-yl)thiophene-2-carboxamides via Suzuki Cross-Coupling Reactions,Their Electronic and Nonlinear Optical Properties through DFT Calculations

Synthesis of 5-aryl-N-(pyrazin-2-yl)thiophene-2-carboxamides (4a–4n) by a Suzuki cross-coupling reaction of 5-bromo-N-(pyrazin-2-yl)thiophene-2-carboxamide (3) with various aryl/heteroaryl boronic acids/pinacol esters was observed in this article. The intermediate compound 3 was prepared by condensation of pyrazin-2-amine (1) with 5-bromothiophene-2-carboxylic acid (2) mediated by TiCl₄. The target pyrazine analogs (4a–4n) were confirmed by NMR and mass spectrometry. In DFT calculation of target molecules, several reactivity parameters like FMOs (E_HOMO, E_LUMO), HOMO–LUMO energy gap, electron affinity (A), ionization energy (I), electrophilicity index (ω), chemical softness (σ) and chemical hardness (η) were considered and discussed. Effect of various substituents was observed on values of the HOMO–LUMO energy gap and hyperpolarizability. The p-electronic delocalization extended over pyrazine, benzene and thiophene was examined in studying the NLO behavior. The chemical shifts of ¹H NMR of all the synthesized compounds 4a–4n were calculated and compared with the experimental values.     

Arylation of halogenated thiophene carboxylate via Suzuki–Miyaura reaction: Anti-bacterial study against clinically isolated extensively drug resistant Escherichia coli sequence type 405 and computational investigation

In present study, Pd(0) catalysed Suzuki-Miyaura cross coupling reaction was used to synthesize 2,4-biarylphenyl-5-arylthiophene-2-carboxylate (7a–7f) and 2-aryl-4-chlorophenyl-5-arylthiophene-2-carboxylate derivatives (8a–8l) in moderate to good yields. While 2,4-dibromophenyl-5-bromothiophene-2-carboxylate (4) and 2-bromo-4-chlorophenyl-5-bromothiophene-2-carboxylate (5) were synthesized via Steglich esterification of 5-bromothiophene-2-carboxylic acid (1) with 2,4-dibromo phenol (2) and 2-bromo-4-chlorophenol (3) in the presence of N, N?-dicyclohexylcarbodiimide (DCC) and 4-(dimethylamino)pyridine (DMAP). ¹H and ¹³C NMR were used to confirm all of the compounds. To screen out the most active lead compounds, binding interactions of all synthesized compounds with MurD and MurE Escherichia coli proteins were evaluated theoretically via molecular docking studies indicating the good binding affinities. DFT calculations were performed out by using DFT-B3LYP/3-21g and structural and reactivity parameters were calculated. Compounds 5, 8b, 8e, 8h, and 8j have demonstrated potential reactivities and charge distributions that indicate their efficiency towards biological targets. These chemicals were tested in vitro for antibacterial activity against Gram-negative bacteria (Escherichia coli) at different concentrations based on theoretical results. The total results were quite close to the theoretical predictions and compound 8j was found to be having the greatest potential value, strongest binding affinities, and a promising antibacterial agent with MIC value of 50 mg/ml against Escherichia coli.     

Chiral supramolecular thiophene fluorophore consisting of thiophenecarboxylic acid derivatives

Solid-state chiral supramolecular thiophene fluorophore has been successfully prepared by using chiral (R)-1-(2-naphthyl)ethylamine and 5-bromothiophene-2-carboxylic acid. This chiral supramolecular thiophene fluorophore is formed by assembling chiral 2₁-helical columnar network structures composed of (R)-1-(2-naphthyl)ethylamine and 5-bromothiophene-2-carboxylic acid. This supramolecular organic fluorophore exhibits circularly polarized luminescence (CPL) even in the solid state.     

Synthesis,Characterization, and Antimicrobial Studies of Some Quinolines Containing 1,3-Thiazines

6/8-Substituted-2-chloroquinoline-3-carboxylic acids, upon reaction with 3-(p-substituted aryl)-4H-5-mercapto-1,2,4-triazoles in the presence of sodium acetate and an acetic anhydride medium, afforded a novel series of 2-(p-substituted aryl)-s-triazolo[5,1-b]-6/8-substituted quinolino [1,3] thiazin-9(H)-ones. The structures of the new compounds were elucidated by IR, ¹H NMR, and mass spectral studies. All the newly synthesized compounds have been screened for their antibacterial and antifungal activities. Most of them showed significant activity comparable with that of the standards Furacin and Flucanazol.     

Synthesis of novel 5-chloro-2-(thiophen-2-yl)-7,8-dihydroquinoline-6-carboxamides as potent inhibitors of Mycobacterium tuberculosis

A series of novel 5-chloro-2-(thiophen-2-yl)-7,8-dihydroquinoline-6-carboxamides was designed, synthesized, and evaluated for antitubercular activity. The required 5-chloro-2-(thiophen-2-yl)-7,8-dihydroquinoline-6-carboxylic acid intermediate was prepared by oxidizing the respective aldehyde with sodium chlorite and 30% H2O2. Further, the acid was coupled with various aryl, alkyl, and heterocyclic amines using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and hydroxybenzotriazole to give the desired 5-chloro-2-(thiophen-2-yl)-7,8-dihydroquinoline-6-carboxamides in excellent yields. All the new compounds were characterized by their NMR and mass spectral analysis. Screening of all new compounds for in vitro antimycobacterial activity against M. tuberculosis H37Rv (Mtb) resulted in five analogs with MIC 3.12 µg/cm3 as promising antitubercular agents with lower cytotoxicity profiles.     

Stereoselective Synthesis of the Di-Spirooxindole Analogs Based Oxindole and Cyclohexanone Moieties as Potential Anticancer Agents

A new series of di-spirooxindole analogs, engrafted with oxindole and cyclohexanone moieties, were synthesized. Initially, azomethine ylides were generated via reaction of the substituted isatins 3a–f (isatin, 3a, 6-chloroisatin, 3b, 5-fluoroisatin, 3c, 5-nitroisatin, 3d, 5-methoxyisatin, 3e, and 5-methylisatin, 3f, and (2S)-octahydro-1H-indole-2-carboxylic acid 2, in situ azomethine ylides reacted with the cyclohexanone based-chalcone 1a–f to afford the target di-spirooxindole compounds 4a–n. This one-pot method provided diverse structurally complex molecules, with biologically relevant spirocycles in a good yields. All synthesized di-spirooxindole analogs, engrafted with oxindole and cyclohexanone moieties, were evaluated for their anticancer activity against four cancer cell lines, including prostate PC3, cervical HeLa, and breast (MCF-7, and MDA-MB231) cancer cell lines. The cytotoxicity of these di-spirooxindole analogs was also examined against human fibroblast BJ cell lines, and they appeared to be non-cytotoxic. Compound 4b was identified as the most active member of this series against prostate cancer cell line PC3 (IC₅₀ = 3.7 ± 1.0 µM). The cyclohexanone engrafted di-spirooxindole analogs 4a and 4l (IC₅₀ = 7.1 ± 0.2, and 7.2 ± 0.5 µM, respectively) were active against HeLa cancer cells, whereas NO₂ substituted isatin ring and meta-fluoro-substituted (2E,6E)-2,6-dibenzylidenecyclohexanone containing 4i (IC₅₀ = 7.63 ± 0.08 µM) appeared to be a promising agent against the triple negative breast cancer MDA-MB231 cell line. To explore the plausible mechanism of anticancer activity of di-spirooxindole analogs, molecular docking studies were investigated which suggested that spirooxindole analogs potentially inhibit the activity of MDM2.     

Retinoidal pyrimidinecarboxylic acids. Unexpected diaza-substituent effects in retinobenzoic acids

Several pyridine- and pyrimidine-carboxylic acids were synthesized as ligand candidates for retinoid nuclear receptors, retinoic acid receptors (RARs) and retinoic X receptors (RXRs). Although the pyridine derivatives, 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]pyri dine-3-carboxylic acid (2b) and 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido]py ridine-3-carboxylic acid (5b) are more potent than the corresponding benzoic acid-type retinoids, Am80 (2a) and Am580 (5a), the replacement of the benzene ring of Am580 (5a), Am555 (6a), or Am55 (7a) with a pyrimidine ring caused loss of the retinoidal activity both in HL-60 cell differentiation assay and in RAR transactivation assay using COS-1 cells. On the other hand, pyrimidine analogs (PA series, 10 and 11) of potent RXR agonists (retinoid synergists) with a diphenylamine skeleton (DA series, 8 and 9) exhibited potent retinoid synergistic activity in HL-60 cell differentiation assay and activated RXRs. Among the synthesized compounds, 2-[N-n-propyl-N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)a mino]pyrimidine-5-carboxylic acid (PA013, 10e) is most active retinoid synergist in HL-60 assay.     

Synthesis,characterization and antimicrobial evaluation of 2,5-disubstituted-4-thiazolidinone derivatives

In the present study novel derivatives of 4-thiazolidinone were prepared from biphenyl-4-carboxylic acid and evaluated for their in vitro antimicrobial activity against two Gram negative strains (Escherichia coli and Pseudomonas aeruginosa) and two Gram positive strains (Bacillus subtilis and Staphylococcus aureus) and fungal strain Candida albicans and Aspergillus niger. The newly synthesized compounds were characterized by IR, ¹H NMR and C, H, N analyses. The results revealed that all synthesized compounds have a significant biological activity against the tested microorganisms. Among the synthesized derivatives 4g (biphenyl-4-carboxylic acid [2-(3-bromophenyl)-5-(3-nitrobenzylidene)-4-oxo-thiazolidin-3-yl]-amide) and 4i (biphenyl-4-carboxylic acid [5-(3-bromobenzylidene)-2-(3-bromophenyl)-4-oxo-thiazolidin-3-yl]-amide) were found to be most effective antimicrobial compounds.     

Design,synthesis and screening of some novel benzoxazole based 1,3,4-oxadiazoles as potential antimicrobial agents

A series of novel 2-(5-substituted-[1,3,4]oxadiazol-2-yl)-benzoxazoles (7a–h) were synthesized in good yields in two different directions by involving benzoxazole-2-carboxylic acid (1) as raw material and benzoxazole-2-carbonyl chloride (2), benzoxazole-2-carboxylic acid methyl ester (3), benzoxazole-2-carboxylic acid hydrazide (4), benzoxazole-2-carboxylic acid N′-acetyl hydrazide (5a–d) and benzoxazole-2-carboxylic acid-ethylidene-hydrazides (6a–d) as reactive intermediates. The chemical structures of all the synthesized compounds were elucidated by their IR, ¹H NMR and ¹³C NMR and mass spectral data. Further, the target compounds were screened for their antimicrobial activity against various Gram-positive and Gram-negative bacteria.     

Ionic immobilization, diversification, and release: application to the generation of a library of methionine aminopeptidase inhibitors

Development of an ionic immobilization, diversification, and release method for the generation of methionine aminopeptidase inhibitors is reported. This method involves the immobilization of 5-bromofuran-2-carboxylic acid and 5-bromothiophene-2-carboxylic acid onto PS-BEMP, followed by Suzuki reaction on a resin-bound intermediate and subsequent release to provide products in moderate yields and excellent purities. Compound potencies were evaluated on the Co(II), Mn(II), Ni(II), and Fe(II) forms of Escherichia coli MetAP1. The furoic-acid analogs were found to be Mn(II) selective with IC 50 values in the low micromolar range. Qualitative SAR analysis, supplemented by molecular modeling studies, provides valuable information on structural elements responsible for potency and selectivity.     

Synthesis of 3-aminomethyl-substituted pyrazoles and isoxazoles

A series of new 3-(aminomethyl)pyrazoles and 3-(aminomethyl)isoxazoles was synthesized along a route involving the formation as key intermediates of esters of 5-substituted 1H-pyrazole-3-carboxylic and 1H-isoxazole-3-carboxylic acids. All compounds obtained were characterized by physicochemical constants, IR, ¹H, ¹³C NMR, and mass spectra.     

Synthesis and cytotoxicity of new 2-oxo-7-phenyl-2,3-dihydrothiazolo[4,5-b]pyridine-5-carboxylic acid amides

Abstract

The synthesis and anticancer activity evaluation of new thiazolo[4,5-b]pyridine-5-carboxylic acid amides is described. The structures of the synthesized compounds were confirmed by spectroscopic data and a single crystal X-ray diffraction analysis for 2.4. The synthesized compounds were screened for their in vitro anticancer activity according to US NCI protocols. The most active 7-(4-fluorophenyl)-2-oxo-2,3-dihydrothiazolo[4,5-b]pyridine-5-carboxylic acid (4-chlorophenyl)amide 2.2 and 7-(4-chlorophenyl)-2-oxo-2,3-dihydrothiazolo[4,5-b]pyridine-5-carboxylic acid (4-chlorophenyl)amide 2.5 were screened for their cytotoxicity effects on C6 Rat glioma cells and U373 Human glioblastoma astrocytoma cells which revealed promising results comparable to temozolamide as reference control according MTT assay data.     

Design, synthesis and in vitro evaluation of phenylbenzamidine derivatives as SSRIs

A series of phenylbenzamidine analogs were synthesized and tested for their biological activities of inhibiting the reuptake of 5- HT. All of them were new compounds, and their structures were confirmed by 1HNMR, MS and XRD.     

Synthesis,DNA-binding,and cytotoxic studies on three copper(II) complexes of unsymmetrical synthetic analogues of curcumin

Copper(II) chelates of three unsymmetrical synthetic analogs of curcumin, namely (2E)-2-(4-hydroxy-3-methoxybenzylidene)-5-((E)-3-(4-hydroxy-3-methoxyphenyl)acryloyl)cyclopentanone(1), (2E)-2-(3,4-dihydroxybenzylidene)-5-((E)-3-(3,4-dihydroxyphenyl)acryloyl)cyclopentanone(2), and (2E)-2-(3,4-dimethoxybenzylidene)-5-((E)-3-(3,4-dimethoxyphenyl)acryloyl)cyclopeantanone(3) have been synthesized and characterized by physicochemical and spectroscopic methods. The ligands were in their enolic form and metal complexes have 1 : 2 metal:ligand stoichiometry. The DNA-binding properties of the ligands and their metal complexes were studied by absorption titrations, fluorescence quenching experiments, and viscosity measurements with calf-thymus DNA. The interactions of copper(II) complexes were higher than that of free ligands. The observed intrinsic binding constants reveal moderate interaction of copper(II) complexes with calf-thymus DNA. The binding involves intercalative mode through non-covalent interactions and produced conformational changes in the structure of DNA. The compounds were investigated for their possible cytotoxic and antitumor activities. All the compounds were cytotoxic towards Dalton’s lymphoma ascites cells. It was found that copper chelates are remarkably active compared to free curcumin analogs. Concentrations needed for 50% cell death were 10–22 μg mL^?1 for copper complexes and 27–52 μg mL^?1 for curcumin analogs. Copper complex of 2 with two hydroxyl groups in the phenyl ring was most active towards Dalton’s lymphoma ascites cells (increase in life span 77.91%). Copper(II) complex of 3, which possesses methoxy groups in the phenyl ring system, showed the lowest activity towards increase in lifespan of tumor-bearing mice (increase in lifespan 60.14%). Copper chelates of all curcuminoid analogs showed a significant reduction in solid tumor volume in mice.     

Design,synthesis, and in vitro anticancer screening of novel pyrazolinyl-pyrazole/1, 2, 3-triazole hybrids

Novel hybrids, pyrazolinylpyrazoles, and pyrazolinyltriazoles were designed, synthesized, and screened for their anticancer activity. Eleven compounds were selected by the National Cancer Institute (NCI)/USA for anticancer screening at single high dose (10⁻⁵ M) in full NCI 60 cell panels. Two compounds: 4-aminopyrazole-5-carbonitrile, 5c (NSC-747630/1) and ethyl 4-aminopyrazole-5- carboxylate, 7d (NSC-747634/1) were the most active candidates of the series and were selected for further evaluation at five dose screening as they displayed significant growth inhibition with full panel median growth inhibition (GI₅₀) 5.47 and 2.24 μM, respectively. Both 5c and 7d hybrids exhibited broad spectrum antitumor activity; however 7d showed moderate selectivity (selectivity ratio 3.6) toward leukemia.     

Synthesis of new polydentate tweezers ligands of amido-amine type

A series of new tweezers amido-amine ligands containing pyrrole, bipyrrole, and dipyrrolylmethane fragments were synthesized by reaction of 2-thioxothiazolidin-3-yl derivatives of α-pyrrolecarboxylic acids {5-[1-(5-carboxy-3-methyl-4-phenyl-1H-pyrrol-2-yl)-1-methylethyl]-4-methyl-3-phenyl-1H-pyrrole-2-carboxylic acid, 5-[(5-carboxy-3-methyl-4-phenyl-1H-pyrrol-2-yl)phenylmethyl]-4-methyl-3-phenyl-1H-pyrrole-2-carboxylic acid, 5-(5-carboxy-3-methyl-4-phenyl-1H-pyrrol-2-yl)-4-methyl-3-phenyl-1H-pyrrole-2-carboxylic acid, and 3,4-dimethyl-pyrrole-2,5-dicarboxylic acid} with o-phenylenediamine. All compounds obtained were characterized by elemental analysis, NMR and mass spectra.     

Synthesis of 5-arylisoxazole- and 4,5-dichloroisothiazole-3-carboxylates derived from natural alcohols,thymol, and its synthetic analogs

Esters derived from 5-phenyl-, 5-(4-methylphenyl)-, and 5-(2,5-dimethylphenyl)-1,2-oxazole-3-carboxylic and 4,5-dichloro-1,2-thiazole-3-carboxylic acids and some natural alcohols (L-menthol, grosshemin), thymol, and synthetic analogs of the latter (4-tert-butylphenol, 4-tert-octylphenol, 2-tert-butyl-4-methylphenol) were synthesized by reactions of the corresponding alcohols with acid chlorides.     

Synthesis and Antimicrobial Studies of Novel Imidazole Containing Bisazetidinones and Bisthiazolidinone Derivatives

A simple, practical, and efficient approach to new series of imidazole containing bisazetidinones ( 7a , 7b , 7c , 7d , 7e , 7f , 7g , 7h , 7i , 7j and 9a , 9b , 9c , 9d , 9e , 9f , 9g , 9h , 9i , 9j ) was prepared by Staudinger [2 + 2] cycloaddition reaction, and bisthiazolidinones ( 8a , 8b , 8c , 8d , 8e , 8f , 8g , 8h , 8i , 8j and 10a , 10b , 10c , 10d , 10e , 10f , 10g , 10h , 10i , 10j ) were obtained by cyclization of bisimines with thioglycolic acid. The bisimines ( 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i , 5j and 6a , 6b , 6c , 6d , 6e , 6f , 6g , 6h , 6i , 6j ) were synthesized by the condensation of 3‐(1‐(3‐aminobenzyl)‐4, 5‐dihydro‐1H‐imidazol‐2‐yl) aniline ( 3 , 4 ) with a series of different substituted aromatic aldehydes. All the newly synthesized target compounds were evaluated for their in vitro antimicrobial activity against two Gram‐positive bacteria and two Gram‐negative bacteria. Additionally, these synthesized compounds were tested for their antifungal activities. Few compounds showed very good antibacterial and antifungal activity.     

Design,synthesis and biological evaluation of 5-(2-(4-(substituted benzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)indolin-2-one and 5-(2-(4-substitutedpiperazin-1-yl)acetyl)indolin-2-one analogues as novel anti-tubercular agents

A series of thirty-six novel 5-(2-(4-(benzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)indolin-2-one and 5-(2-(4-substitutedpiperazin-1-yl)acetyl)indolin-2-one analogues were synthesized, characterized and screened for their in vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain. These compounds exhibited minimum inhibitory concentration between 1.56 and 50 μg/mL. Among these derivatives, compounds 10c, 10d, 10j, 10o and 10v (MIC 6.25 μg/mL) displayed moderate activity, while compounds 10e, 10l, 10q, 10w,10x, 12d, 12e and 12i (MIC 3.12 μg/mL) showed good anti-tubercular activity and compounds 10f, 10k, 10p, 10r, 12f, 12j and 12k (MIC 1.56 μg/mL) exhibited excellent anti-tubercular activity. In addition, MTT assay was accomplished on the active analogues of the series against mouse macrophage (RAW 264.7) cells to evaluate the cytotoxic effect of the newly synthesized compounds and selectivity index of the compounds was determined.