Synthesis of novel scaffolds based on thiazole or triazolothiadiazine linked to benzofuran or benzo[d]thiazole moieties as new hybrid molecules

Abstract

A synthesis of novel hybrid molecules containing thiazole or bis(thiazoles) each bearing benzofuran and/or benzo[d]thiazole moieties by the reaction of the appropriate thioamide derivatives with the corresponding bis-bromoacetyl derivatives is reported. Mono- and bis(triazolothiadiazine) derivatives based on benzofuran or benzo[d]thiazole moieties were also synthesized in good yields by the reaction of the appropriate bis(bromoacetyl) derivatives with each of 4-amino-5-mercapto-1,2,4-triazoles and their corresponding bis-derivatives.     

Regioselective synthesis and biological evaluation of novel dispiropyrrolidine derivatives via one-pot four-component reaction

Abstract

A new series of regioselective dispiropyrrolidine analogs via efficient one-pot four-component tandem reaction has been discovered. The reaction was carried out in the presence of four common reactants and magnesium silicate nanoparticles (NPs) in ethanol under microwave irradiation. The reaction proceeds rapidly and can be completed within 60–90?min. This methodology offers several significant advantages such as high yield, mild catalyst, and easy to perform. The synthesized compound was further screened for antibacterial and antiproliferative activities. The results showed that compound 5c and 5a were potent antibacterials against Gram-positive and Gram-negative bacteria. Further, 5a showed best antiproliferative activity against tested cell lines.     

Synthesis,cytotoxicity, in-vitro antibacterial screening and in-silico study of novel thieno[2,3-b]pyridines as potential pim-1 inhibitors

Abstract

A novel series of thieno[2,3-b]pyridines was prepared via an one-step protocol in excellent yields. The protocol involved the reaction of pyridine-2(1H)-thiones with the appropriate halogen containing reagents in ethanolic sodium ethoxide solution under stirring at 80?°C for 2?h. The new thienopyridines were screened against different bacterial and fungal strains. Thieno[2,3-b]pyridine-2-carboxylate 9a showed the most effective antibacterial activities against each of Staphylococcus aureus and Escherichia coli with MIC/MBC values of 9.9/19.8 and 19.8/39.5?µM, respectively, when compared with Ciprofloxacin. 9a was the most effective compound against MRSA with inhibition zone of 16.2?±?0.6?mm, when compared with Gentamicin. Moreover, 9a exhibited the best cytotoxic activity against each of HEPG2 and MCF-7 cell lines with IC₅₀ values of 25.7 and 30.53?µM, respectively, when compared with Doxorubicin. The in-silico study was performed to predict the capability of new thienopyridines as potential inhibitors of pim-1 kinase.     

N-Mannich bases of benzimidazole as a potent antitubercular and antiprotozoal agents: Their synthesis and computational studies

Abstract

This article dealing with the microwave assisted synthesis of N-Mannich bases of pyridine clubbed with two different benzimidazole cores with their micromolar biological potency. All the synthesized compounds were evaluated for their in-vitro antibacterial, antimycobacterial and antiprotozoal potency. One of the final compound was found to be most active against M. tuberculosis (MIC = 3.125?µM) in the primary screening. N-Mannich bases of benzimidazole with pyridine-3-amine and 5-methyl-pyridine-2-amine showed potency against L. mexicana and T. cruzi respectively with IC₅₀ value 0.25 and 1.02?µg/mL. Compound 4a showed good binding energy in the active pocket of receptor (PDB: 4cod) with ?11.013 docking score. The stability of docked complex was validated by performing Molecular dynamics (MD) up to 20?ns simulation time. In silico ADME parameters and toxicity predicted that the active compounds belong to the Class IV GHS with LD₅₀ value 1360?mg/kg and hence found to be mildly toxic.     

N'-(1-([1,1'-biphenyl]-4-yl)ethylidene)-2-cyanoacetohydrazide as scaffold for the synthesis of diverse heterocyclic compounds as prospective antitumor and antimicrobial activities

In this article, the main target was to study the antitumor and antimicrobial efficacy of new heterocycles conjugated with biphenyl moiety in-vitro. This was implemented by utilizing N'-(1-([1,1'-biphenyl]-4-yl)ethylidene)-2-cyanoacetohydrazide 3 as a material for the synthesis of various heterocyclic compounds. Among of them, some compounds were selected and assayed against two antitumor cell lines as (HepG2) and (HCT-116). Conspicuously, the achieved results showed that compounds 6, 13, and 23 possess significant potency against both cancer cell lines. Particularly, compound 13 exhibited a remarkable efficacy, similar to the standard anticancer drug (doxorubicin), against both cancer cell lines. Noteworthy, compound 13 may serve as a potential anticancer therapeutic drug in the future. On the other hand, In-vitro antifungal and antibacterial activities of selected compounds were assayed and the results indicated that the compound 6 exhibited significant potency against Candida albicans, while compounds 6 and 8 displayed spectacular results for the antibacterial study.     

Triarylimidazo[1,2-a]pyridine-8-carbonitriles: solvent-free synthesis and their anti-cancer evaluation

In this study, we have presented the synthesis of novel 2,5,7-triarylimidazo[1,2-a]pyridine-8-carbonitriles from 2-amino-4,6-diarlypyridine-3-carbonitrile and nitrostyrene using FeCl₃ (20?mol%) as Lewis acid under solvent-free conditions. A library of compounds with diverse substitutions have also been synthesized and screened for in-vitro anti-cancer activity against various cell lines such as A549 (Lung), HCT-116 (Colon), SW-620 (Colon), and MIAPACA (Pancreas).     

Green chemistry approach to the synthesis of 3-substituted-quinazolin-4(3H)-ones and 2-methyl-3-substituted-quinazolin-4(3H)-ones and biological evaluation

ABSTRACT

A synthesis of two series of 3-substituted quinazolinones was performed utilizing a green chemistry approach, deep eutectic solvents and microwaves, namely. 2-Methyl-3-substituted-quinazolin-4(3H)-one derivatives were synthesized in a two-step reaction, using choline chloride:urea deep eutectic solvent (DES). 3-Substituted-quinazolin-4(3H)-ones were synthesized in one-pot one-step reaction of anthranilic acid, amines and orthoester in a microwave reactor. For the synthesis of 2-methyl-3-substituted-quinazolin-4(3H)-ones, first conventional synthesis of benzoxazinone, as an intermediate, was performed. Further, benzoxazinone in reaction with corresponding amines, in choline choline:urea deep eutectic solvent, furnished desired compounds. These procedures are based on green principles with the aim of developing synthetic routes for the potential antitumor agents. All compounds were characterized by LC/MS, ¹H NMR and ¹³C NMR spectral techniques. Compound 1 bearing trifluoromethoxyphenyl group showed promising activity against HuT-78 cell line with IC₅₀ of 51.4?±?5.1?µM.     

Pinus wallichiana-synthesized silver nanoparticles as biomedical agents: in-vitro and in-vivo approach

ABSTRACT

The current study aims to assess the aqueous extract of Pinus wallichiana stem for the synthesis of small spherical-shaped (10–30?nm) silver nanoparticles (AgNPs) and their in-vitro and in-vivo biomedical applications. The biosynthesized AgNPs were nonmutagenic and safe at all test doses as per Ames and acute toxicity assay (20, 40, 60, and 80?mg/kg). The percent writhing inhibitory effect generated by AgNPs was 42.51, 50.84, and 59.06 at test doses of 10, 20, and 30?mg/kg, respectively. The percent decreased in gastrointestinal tract motility observed was 41.34%, 32.69%, and 28.48% at 10, 20, and 30?mg/kg, respectively. They also showed a significant antipyretic effect after 1, 2, and 3?h in comparison to normal saline. The AgNPs of P. wallichiana showed good antibacterial activity against Acinetobacter baumannii (60% with MIC₅₀?=?2.36?mg/ml and MBC?=?5.0?mg/ml). These nanoparticles also possessed good antioxidant activity of 61.77?±?0.828% and 70.25?±?0.56% at 400 and 500?µg/ml, respectively and lack phytoagglutinin potential. Because of their high potency as biomedical agents, these nanoparticles can be a good alternative to the currently available drugs and approaches.     

Efficient and Rapid Synthesis of Highly Functionalized Novel Symmetric 1,4-Dihydropyridines Using Glacial Acetic Acid as Solvent

A new series of 1,4-dihydropyridines bearing a pyrazole moiety in the 4-position were synthesized by a variation of the classical Hantzsch synthesis. The reaction of 1,3-diphenyl-1H-pyrazole-4-carbaldehyde 4a–n with 3-amino crotononitrile in the presence of glacial acetic acid afforded novel 3,5-dicyano-2,6-dimethyl 1,4-dihydropyridines 5a–n. The procedure has short reaction time (15–20 min), easy workup, and good yield of product. The structures of all synthesized compounds were well characterized by mass, infrared, ¹H and ¹³C NMR, and elemental analysis.     

Synthesis and biological activities of benzothiazole derivatives bearing a 1,3,4-thiadiazole moiety

A series of benzothiazole derivatives bearing a 1,3,4-thiadiazole moiety were designed, synthesized and evaluated for their antibacterial, antifungal and antiviral activities. The bioassay results indicated that most of target compounds showed good antiviral activities against tobacco mosaic virus (TMV) and antibacterial activities against Xanthomonas oryzae pv. oryzae (Xoo) and Ralstonia solanacearum (Rs). Especially, the anti-Xoo effect of title compounds 5k (N-(5-methoxybenzo[d]thiazol-2-yl)-2-((5-(2-tolyl)-1,3,4-thiadiazol-2-yl)thio)acetamide) and the anti-Rs effect of title compounds 5a (N-(5-nitrobenzo[d]thiazol-2-yl)-2-((5-(4-(trifluorom ethyl)phenyl)-1,3,4-thiadiazol-2-yl)thio)acetmide) respectively reached 52.4% and 71.6% at 100?µg/mL, which are superior to that of bismerthiazol (32.0% and 52.3%). In addition, the protective and inactivation activities of title compound 5i (N-(5-methoxybenzo [d]thiazol-2-yl)-2-((5-(4-nitrophenyl)-1,3,4-thiadiazol-2-yl)thio)acetamide) against TMV were 79.5% and 88.3%, respectively, which are better than that of ningnanmycin (76.4% and 86.8%). The above research showed that benzothiazole derivatives bearing a 1,3,4-thiadiazole moiety may be used as potential molecular templates in searching for highly-efficient antiviral and antibacterial agents.     

Design,synthesis and biological evaluation of novel N1,N8-bis(((4-((5-aryl-1,3,4-oxadiazol-2-yl)methoxy)phenyl)amino)oxy)-1-naphthamide derivatives

A new series of 1,8-bis(4-((5-phenyl-1,3,4-oxadiazol-2-yl) methoxy)-substituted aryl) naphthalene-1,8-dicarboxamide derivatives (6a–j) were synthesized in the presence of POCl₃ and obtained good yields. All the synthesized novel compounds were characterized by IR, ¹H NMR, ¹³C NMR, HRMS spectroscopic data and elemental analysis. All the synthesized compounds evaluated for their antibacterial and antifungal activities. The antibacterial activity screened against Gram-positive bacteria Staphylococcus aureus and Gram-negative bacteria Escherichia coli and used standard reference drug ciprofloxacin. The antifungal activity screened against two pathogenic fungal strains Aspergillus niger and Candida albicans used a reference standard drug Voriconazole. All these compounds (6a–j) demonstrate good antibacterial and antifungal activity. Among them, compounds 6h and 6c show highest antibacterial and antifungal activity.     

Synthesis and biological evaluation of novel fused indolo [3, 2-c] [1,8] naphthyridine derivatives as potential antibacterial agents

Nine novel fused indolo [1,8] naphthyridine derivatives were synthesized using the Povarov reaction, in a one-pot system, and were fully characterized by spectroscopic techniques such as FT-IR, NMR, TOF-MS, and elemental analysis. Furthermore, their antibacterial activities against six bacterial strains were assessed. The results of the bioassay demonstrated that compounds 4a, 4c, and 4i showed good inhibitory effect with a MIC value ranging from 0.04687 to 0.09375?µM against Bacillus cereus and Staphylococcus aureus. The toxicity of 4a–i, evaluated through mutagenicity test against Salmonella typhimurium TA 98 and TA100 strains, revealed that there was no significant increase in the number of revertant colonies in comparison with the control, sodium azide.     

Microwave Assisted Green Synthesis of Pyrazole, 1, 2, 3‐ Triazole Based Novel Benzohydrazones and Their Antibacterial Activities

A series of novel pyrazole, triazole based benzohydrazones ( 7a‐l ) were synthesized via conventional and microwave methods in the presence of acetic acid catalyst. Microwave method provided green and economical approach towards the synthesis of novel Schiff bases ( 7a‐l ). Some intermediates and all the final compounds were characterized by NMR, mass, and elemental analysis. The compounds were screened for their in vitro antibacterial activity against Gram‐negative bacteria (Escherichia coli and Pseudomonas aeruginosa) and Gram‐positive bacteria (Staphylococcus aureus and Bacillus cereus). Compounds 7e and 7g showed good antibacterial activity.     

One-pot synthesis,theoretical study and antimicrobial activity of 5,5′-(1,4-phenylenebis-(methanylylidene))Bis(3-Aryl(Alkyl)-2-thioxoimidazolidin-4-one) derivatives

A simple, facile, and convenient practical method for the one-pot synthesis of pharmaceutically interesting 5,5`-(1,4-phenylenebis-(methanylylidene))bis-thiohydantoins via a three-component condensation reaction of terephthalaldehyde, α-amino acids and isothiocyanates had been developed. The S-alkylated derivatives 6a and 6b were obtained by the alkylation of the bis-thiohydantoins 4a with methyl iodide and/or benzyl chloride in a basic media. The molecular structures of the synthesized compounds were confirmed by their elemental analyses and spectral data (IR, ¹H, ¹³C NMR and MS). The assignment of more stable Z- or E-isomers as the major form of 4a, 6a, and 8a was investigated by DFT calculations at B3LYP/6-31+G* level. Some of the prepared compounds were screened for their in-vitro antimicrobial activity. Compounds 4a, 6 b, 8 b and 8c exhibited low antibacterial activity against gram-positive bacteria Bacillus cereus. (5Z,5′Z)-5,5′-(1,4-Phenylenebis(methanylylidene))bis(3-benzyl-2-thioxoimidazolidin-4-one) (4b) exhibited good fungicidal activity against Fusarium oxysporum.     

Bis-Thiourea Bearing Aryl and Amino Acids Side Chains and Their Antibacterial Activities

Abstract

A series of symmetrical 1,3-bis thiourea 1a–e and 1,4-bis thiourea derivatives 2a–e have been successfully synthesized from the reactions of amines with 3-acetylbenzoyl isothiocyanate and 4-acetylbenzoyl isothiocyanate, respectively. All the synthesized compounds were characterized by FT-IR spectroscopy and ¹H and ¹³C NMR spectroscopy. The compounds were screened for their antibacterial activity by turbidimetric method using gram-negative bacteria (E. coli ATCC 8739) using turbidimetric method. The newly synthesized bis-thiourea derivatives bearing aryl side chains showed good antibacterial activity against E. coli. The effect of the molecular structure of the synthesized compounds on the antibacterial activity is discussed.     

Design,Synthesis and Molecular Modeling of Nonsteroidal Anti‐inflammatory Drugs Tagged Substituted 1,2,3‐Triazole Derivatives and Evaluation of Their Biological Activities

A novel series of 1,4‐disubstituted‐1,2,3‐triazole derivatives 3a – l and 5a – i were one‐pot synthesized via CuAAC‐alkyne click chemistry and evaluated for their antibacterial activity against four organisms and screened for their anticancer activity against human colon cancer cell line HT‐29 and human lung cancer cell line HTB‐29. These hybrid molecules structure elucidation has been performed by IR, ¹H‐NMR, ¹³C‐NMR, and mass spectral analysis. Synthesized nonsteroidal anti‐inflammatory drugs‐triazoles evaluated for their antibacterial activities against bacterial microorganisms Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, and Klebsiella pneumonia. Final compounds 3i , 3c , and 5b showed magnificent broad spectrum activity against P. aeruginosa, K. pneumonia, E. coli, and S. aureus with zone of inhibition values of 20, 15, 17, and 16 mm, respectively. Among the series of compound, 3j showed the best antibacterial activity against all the strains. Further, the compounds 3i and 5a were more cytotoxic than cisplatin against all tested two human cancer cell lines, with 50.8%, and 52.3% and 73.4% and 75.3% of growth, respectively. The synthesized compounds were tested for kinase inhibitory activity against glycogen synthase kinase‐3 protein kinases, in addition, for cytotoxic activity against two different human cancer cell lines.     

Staudinger ketene–imine [2+2] cycloaddition of novel azomethines to synthesize biologically active azetidinone derivatives and their in vitro antimicrobial studies

Since considerable intrigue has been focused on azetidinone (β-lactam) compounds for their wide range antimicrobial activity, the present study focuses on the synthesis of new series of azetidinone compounds. The reaction between the novel azomethine and α-haloester in the presence of Zn impetus and benzene resulted into the formation of desired azetidinone derivative by [2+2] cycloaddition involving imine–ketene. The reaction has also been studied in the presence of diverse Lewis acids such as Zn(OTf)₂, ZnCl₂, Cu(OTf)₂, TiCl₄, and BF₃.Et₂O. The effect of such Lewis acids also enhance the yield of the desired product. Moreover, the structure of the isolated products was also affirmed by spectral analysis (Fourier-transform infrared [FT-IR] spectroscopy, proton nuclear magnetic resonance [¹H NMR], carbon-13 nuclear magnetic resonance [¹³C NMR], and high-resolution mass spectrometry [HRMS]). Furthermore, the antibacterial activity of synthesized compounds has been screened in vitro against different pathogenic bacterial and fungus species. Inspection of the results uncovered that all of the newly synthesized compounds individually display varying degrees of inhibitory impacts on the development of the tested bacterial species, thus, they might be considered as medication possibility for bacterial pathogens. The azomethine exhibited an expansive range of antibacterial activity against Gram-negative Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumonia, and Acinetobacter baumannii and Gram-positive Staphylococcus aureus bacterial strains and antifungal activity against Candida albicans, Candida tropicalis, and Candida parapsilosis bacterial strain. The result demonstrated that the β-lactam subordinates have good antibacterial and antifungal activities on microscopic organisms.     

Synthesis,molecular docking,antibacterial, antioxidant,and cytotoxicity activities of novel pyrido-cyclopenta[b]indole analogs

Abstract

A series of new pyrido-cyclopenta[1,2-b]indole derivatives were synthesized via Knoevenagel reaction and followed by reflux with dimethylformamide dimethyl acetal. Their structures were investigated by spectral techniques and elemental analysis. In vitro antibacterial assessment against seven selected microorganisms evidenced that the compounds with halogen substituent have strong inhibitory action than that of the reference drugs. The antioxidant results were apparent that the compounds 5b, 5c, and 6c manifested explicit activity when compared with Butylhydroxyanisole and Vitamin-C. Cytotoxic activity analysis toward HeLa and MCF-7 cell lines was also assessed. Analogs 6c (IC₅₀ values 15.1?μM and 18.6?μM) and 6d (IC₅₀ values 17.4?μM and 20.7?μM) illustrated the interesting cytotoxicity activity. Molecular docking studies against p38 MAP kinase displayed a potential binding affinity with the receptor. Furthermore, in silico pharmacokinetic studies articulated the drug-likeness nature of the target compounds.     

Isocoumarin Thioanalogues as Potential Antibacterial Agents

A series of 3-substituted-1H-isochromene-1-thiones (3) were prepared by the reaction of 3-substituted isocoumarins (2) with Lawesson's reagent in the presence of toluene under a nitrogen atmosphere. The antimicrobial activities of the newly synthesized products were measured using Gram-negative (Escherichia coli, Salmonella typhi, and Proteus mirabilis) and Gram-positive bacteria (Staphylococcus aureus and Bacillus cereus). Synthesized thioanalogue of isocoumarins showed good antibacterial activity against Proteus mirabilis.     

Synthesis and antimicrobial activity of some benzoxazinoids derivatives of 2-nitrophenol and 3-hydroxy-2-nitropyridine

Benzoxazinoids (BXs), alkaloids frequently found in Gramineae species, are natural defensives that can potentially be exploited to the development of novel antimicrobial agents. Here, BXs analogs were synthesized from 2-nitrophenol (benzoxazinone series) and 3-hydroxy-2-nitropyridine (pyridoxazinone series) and tested against fungal and bacteria of medical interest. The starting materials were submitted to adequate nucleophilic substitution in order to functionalize of analogs, followed by a reductive cyclization catalyzed by palladium on carbon. Next, the biological assays showed that pyridoxazinone serie has a good antibacterial activity, especially against Enterococcus faecalis (Minimum inhibitory concentration—MIC: 7.8-15.6?μg.mL^?1) and Acinetobacter baumannii (MIC 31.25-125?μg.mL^?1). Antifungal activity, in turn, was related to compound 2e which showed a MIC of 62.5?μg.mL^?1 against Candida albicans, Candida glabrata, and Candida tropicalis. All analogs complied with Lipinski's rules and were predicted to have a low toxicity.