Innovative cascade reaction for 2H-indazole derivative synthesis.

In the realm of synthetic organic chemistry, by using a one-pot sequential combination of MCR, it is possible to manufacture chemical commodities (fine chemicals, agrochemicals, and pharmaceutical substances) that enhance our quality of life while generating less waste materials and increasing economic advantages. With this motivation, using a "one-pot" method with multiple components, we present a relatively simple way to make stereoselective substitute 2H-indazole analogues for this study. Firstly, functionalised 3-bromo-4-((methylthio)methyl) derivatives were produced using DMSO as both a carbon source and a solvent, in conjunction with TMSOTf as the Lewis acid promoter. These derivatives were then utilised in the synthesis of 2-H-indazole derivatives with an up to 80% yield using t-Bu3PHBF4 as the ligand and Cs2CO3 as the base, in the presence of a Pd catalyst at 100°C in an airtight tube. The phenyl ring is endowed with an electron-releasing group situated at position C-6, which efficiently synthesises several 2-H-indazol derivatives with cost-efficient and noteworthy yields by using this method. A comparative analysis of a number of halogen derivatives was also undertaken, using a variety of solvents that were classified according to their halogen group. To confirm the structures of the synthesised target compounds, spectrometric analysis (1H NMR, 13C NMR, and LCMS) was performed.

Palladium(0)-catalyzed aryne annulation: a powerful strategy for the synthesis of thio-bridged compounds.

A method for the construction of various thio-bridged compounds is developed using readily available o-(trimethylsilyl)aryl triflates as a source of aryne precursor, catalyzed by simple Pd(dba)2/dppe complex. This operationally simple and modular protocol allows thio-bridged compound via C(sp2)-C(sp2) and C(sp2)-C(sp3) bond formation in promising yields with a broad substrate scope. The key part is in situ generation of an aryne from o-(trimethylsilyl)aryl triflates and their subsequent intermolecular annulation.

First-row transition metal for isocyanide-involving multicomponent reactions (IMCR).

First-row transition metal catalyzed transformations that are able to construct complex molecules from simple, readily obtainable feedstocks have become a keystone of modern synthetic organic chemistry. Particularly, the multicomponent reaction (MCR) involving carbon-carbon (C-C) as well as carbon-heteroatom (C-X) bond formation plays an essential role in many chemical conversions, and insurgencies in these reactions powerfully improve the overall synthetic efficiency. Recently, MCRs emerges rapidly because of its greener sides like eco-friendly nature, swift and straightforward execution, high atom/step economy, and construction of aimed product with lowest or no by-product, usually in quantitative yield. Curiously, the exceptional divalent carbon atoms of isocyanides make them predominantly useful components in multicomponent reactions. As a result of widespread research over the past few decades, numerous well-designed and effective procedures for the first-row TM-catalyzed MCR to afford the various entities have been reported. These aspects are summarized in this review article. A particular focus on comparative discussion of various first-row transition-metal catalyzed isocyanide-based multicomponent reactions through mechanistic details included in the review article.

Iron-catalyzed intermolecular cross-dehydrogenative C(sp3)-H/C(sp)-H coupling of pyrimidine bearing 4-thiazolidinones with terminal alkynes.

A novel, simple and efficient protocol for the Fe-catalyzed, intermolecular cross-dehydrogenative coupling of pyrimidine bearing 4-thiazolidinones systems and terminal alkynes was established. This methodology offers a high yielding, straightforward, and one-pot approach towards the synthesis of alkynylated 4-thiazolidinones without prior activation of C(sp3)-H and C(sp)-H. The results of control experiments indicated that this conversion might proceed via a radical process.

Comparative biological study between quinazolinyl-triazinyl semicarbazide and thiosemicarbazide hybrid derivatives.

Practical synthesis and biological activities of quinazolinyl-triazinyl semicarbazides (10a-j) and quinazolinyl-triazinyl thiosemicarbazides (11a-j) have been described. The novel semicarbazides and thiosemicarbazides were prepared by condensation of different nucleophiles like isocyanate and isothiocyanate by the displacement of chlorine atoms on the basis of functionality concept on varying conditions. The synthesized quinazolinyl-triazinyl semicarbazide and thiosemicarbazide derivatives were evaluated for their expected antimicrobial activity. All the final synthesized derivatives were characterized by their melting point, mass spectra, 1H NMR and 13C NMR as well as elemental microanalysis. The final analogues were then analyzed for their in vitro antimicrobial activity against bacteria (Gram positive and negative) and fungus using the agar streak dilution method as well as in vitro anti-HIV activity against two types of viral strains, viz. HIV type I (IIIB) and type II (ROD) by using MTT assay method. SAR and HOMO-LUMO studies were also carried out for proving the structural biological activity. Among them, compounds 10e, 10f, 11h and 11j gave best results as their energy gap is very low which makes their activity higher.

Palladium-catalyzed acid-free Fujiwara-Moritani alkenylation of 4-thiazolidinones.

Herein, we report a facile method for the alkenylation of a 4-thiazolidinone motif without using external acid and high-pressure gas, which are required in conventional Fujiwara-Moritani reactions. Mild reaction conditions, one-pot synthesis, and utilization of an oxidant made this process more feasible in comparison with previously reported methods. Functionalization of the slightly more acidic [Formula: see text] C-H bond with the less acidic [Formula: see text] C-H bond yielded the alkenylated motif. This pathway opens new possibilities for organic synthesis.

Facile synthesis of benzonitrile/nicotinonitrile based s-triazines as new potential antimycobacterial agents.

A common strategy to synthesize 4/6-(4-(4-methylpiperazin-1-yl)-6-(4-(4-oxo-2-phenylthiazolidin-3-yl)phenyl)-1,3,5-triazin-2-yloxy)benzonitriles/nicotinonitriles was developed by applying an efficient palladium-catalyzed C-C Suzuki coupling. Moreover, the synthesized compounds were also tested for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv using BACTEC MGIT and Lowenstein-Jensen MIC methods. Several compounds displayed profound antimycobacterial activity in combination with low toxicity towards mammalian cells. The best results were observed amongst the nicotinonitrile substituted s-triazine analogs and it could be a potential starting point to develop new lead compounds in the fight against M. tuberculosis H37Rv. The newly synthesized compounds were characterized by IR, (1)H NMR, (13)C NMR, MS and elemental analysis.

Privileged s-triazines: structure and pharmacological applications.

This review summarizes recent reports on s-triazine and its respective analogs from the medicinal chemistry angle. Due to its high reactivity and binding characteristic towards various enzymes, s-triazine has attracted attention. This is combined with facile synthesis and interesting pharmacology. The triazine class demonstrates wide biological applications - including antimicrobial, antituberculosis, anticancer, antiviral and antimalarial. In this article the library of s-triazine-based molecular designs has been collated with respective bioactivity. Compounds are further compared with other heterocyclic/nontriazine moieties to correlate the efficiency of privileged s-triazine. We hope this article may assist chemists in their drug design and discovery efforts.

Design, synthesis, antimicrobial activity and anti-HIV activity evaluation of novel hybrid quinazoline-triazine derivatives.

A series of novel hybrid quinazoline-triazine derivatives was designed and synthesized from cyanuric chloride and anthranilic acid through sequential reactions, which contain different pharmacophores like quinazoline and substituted diaryl triazine (DATA) linked with ethylene diamine. All the newly synthesized compounds were characterized by infrared, (1)H-NMR, (13)C-NMR, MS and elemental analysis. Further, we evaluated the in vitro anti-HIV activity of the newly synthesized compounds against HIV-1 (IIIB) and HIV-2 (ROD) viral strains and as well as in vitro antimicrobial activity against four bacteria (Staphylococcus aureus, Bacillus cereus, Pseudomonas aeruginosa, Klebsiella pneumoniae) and two fungi (Aspergillus clavatus, Candida albicans) using the paper agar streak dilution method. The bioassay results indicate that four compounds namely 7d, 7n, 7r and 7s could be considered as possible potential agents.

New quinolinyl-1,3,4-oxadiazoles: synthesis, in vitro antibacterial, antifungal and antituberculosis studies.

In order to generate hybrid antimicrobial remedies with novel mode of action, two series of quinoline based 1,3,4-oxadiazole derivatives condensed with N-aryl/benzothiazolyl acetamides were synthesized and the MIC values of the compounds towards eight reference bacterial strains (S. aureus, B. cereus, E. coli, P. aeruginosa, K. pneumoniae, S. typhi, P. vulgaris, S. flexneri), four fungi (A. niger, A. fumigatus, A. clavatus, C. albicans) and Mycobacterium tuberculosis H37Rv were assayed in vitro. Quinoline-6-carboxlic acid was treated with thionyl chloride in refluxing methanol to obtain the corresponding ester derivative to be hydrazinolyzed by 99% hydrazine hydrate in ethanol to produce carbohydrazide intermediate. The carbohydrazide precursor underwent cyclization by carbon disulfide and ethanolic KOH to construct 5-quinolinyl-6-yl-1,3,4-oxadiazol-2-thiol. Substituted 2-chloro-N-phenyl(benzothiazolyl)aceta-mide derivatives were then condensed to 1,3,4-oxadiazole nucleus via sulphur linkage to yield the desired products. Target products bearing N-benzothiazolyl-2-chloroacetamides displayed good inhibitory potential. The biological screening identified that many final analogues exhibited a significant inhibition of the growth of microorganisms at 3.12-25 µg/mL of MIC, which were comparable to control drugs. The influence of the presence of various functional groups to the phenyl/benzothiazolyl ring on activity profiles was investigated. The proposed structures of the newly prepared products were confirmed with the aid of IR, 1H NMR, 13C NMR spectroscopy and elemental analysis. These results may provide new insights in the design of a novel pool of bioactive templates.

Design, synthesis, biological evaluation, and molecular modeling of coumarin-piperazine derivatives as acetylcholinesterase inhibitors.

Acetylcholinesterase (AChE) is an important drug target for the treatment of Alzheimer's disease. A novel series of coumarin-piperazine derivatives were synthesized and their potency to inhibit human AChE enzyme (hAChE) was studied. All the final compounds were characterized by infrared, (1)H NMR, (13)C NMR, and elemental analysis. Docking experiments of the designed coumarin-piperazine derivatives were carried out in order to compare the theoretical and experimental binding affinities toward hAChE, to delineate the inhibitory mechanism. Subsequently, a structure-activity relationship (SAR) study using the molecular field method showed that the hydrophobic field and positive charge center conferred by the coumarin and piperazine moieties demonstrated an inhibitory mechanism. Among the compounds tested, 3f, 3j, and 3m were found to be the most potent inhibitors of hAChE.

Synthesis and evaluation of novel 4-substituted styryl quinazolines as potential antimicrobial agents.

In an attempt to afford possible antibacterial and anti-human immunodeficiency virus (HIV) agents, a series of 22 novel styryl quinazoline-based heterocyclic entities were designed and synthesized. Various substituted aryl urea and thiourea cores were incorporated at position 4 of quinazoline, followed by styrylation of position 2, aiming at an augmented biological potential. The synthesized compounds were well characterized through IR, (1) H NMR, (13) C NMR and elemental analyses. All compounds were screened for their in vitro anti-HIV activity against the HIV-1 (IIIB) and HIV-2 (ROD) strains. The antibacterial activity was also evaluated against various pathogenic Gram-positive and Gram-negative bacterial strains.

Antimicrobial, anti-TB, anticancer and anti-HIV evaluation of new s-triazine-based heterocycles.

BACKGROUND: The acquirement of resistance by microorganisms to the antimicrobial arsenal is a threat to public health. A recent WHO report estimated that 1.3 million HIV-negative people and 0.38 million HIV-positive people died from TB in 2009. Various forms of cancer account for a high percentage of deaths in both women (breast cancer) and men (prostate cancer). RESULTS & DISCUSSION: In vitro activity assessment of newly constructed s-triazines against a panel of microorganisms including bacteria, fungi and Mycobacteria demonstrated that the compounds are of immense attraction for impending drug discovery. They were further examined for in vitro activity against breast cancer and prostate cancer cell lines, as well as HIV-1 (III(B)) and HIV-2 (ROD) viral strains. Proposed structural confirmation studies by IR, (1)H NMR, (13)C NMR, (19)F NMR spectroscopy and elemental analysis were in accordance. CONCLUSION: Activity profiles of the products may contribute considerably to future drug-discovery studies.

Microwave assisted synthesis and determination of in-vitro antimicrobial efficacy of well characterized s-triazinyl piperazines and piperidines.

An easy and convenient microwave-assisted synthesis of a library of s-triazinyl piperazines and piperidines, which, in addition to 4-aminobenzonitrile contain 8-hydroxyquinoline is described. The newly synthesized analogues were then subjected to determine their efficacy against some human pathogenic bacterial and fungal strains as 3 Gram negative bacteria (K. pneumoniae, S. typhi, P. vulgaris), 1 Gram positive bacteria (B. cereus) and 2 fungal species (A. clavatus, A. fumigatus) with an intent to develop novel class of antimicrobial agents. Microwave irradiation method was adopted for the final nucleophilic reactions, facilitates the condensation of piperazine and piperidine substituents to the s-triazine core. The results of bioassay showed that some of the newly synthesized s-triazines emerged as lead molecules with excellent MIC (mg/mL) values against the full array of bacterial and fungal pathogens comparable to the commercial antibiotics. The structure of final scaffolds has been affirmed on the basis of IR, 1H NMR, 13C NMR, 19F NMR and elemental analyses.

Synthesis of benzimidazolyl-1,3,4-oxadiazol-2ylthio-N-phenyl (benzothiazolyl) acetamides as antibacterial, antifungal and antituberculosis agents.

To affiliate multiple bioactivities in a compact heteronuclei, two series of benzimidazole based 1,3,4-oxadiazoles were synthesized and assessed in vitro for their efficacy as antimicrobial agents against eight bacteria (Staphylococcus aureus, Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella typhi, Proteus vulgaris, Shigella flexneri), four fungi (Aspergillus niger, Aspergillus fumigatus, Aspergillus clavatus, Candida albicans) and Mycobacterium tuberculosis H37Rv and best results were observed amongst the N-benzothiazolyl aetamide series. The lipophilicity (LogP) influence on the biological profile (MICs) of the prepared products was also discussed. Upon biological screening, it was observed that the majority of the compounds were found to possess a significant broad spectrum antimicrobial (3.12-25 µg/mL of MIC) and antitubercular (6.25-25 µg/mL of MIC) potential. The structural assignments of the new products were done on the basis of IR, (1)H NMR, (13)C NMR spectroscopy and elemental analysis.

Design, synthesis & biological evaluation of some novel quinazolinone scaffolds.

In an effort to discover new candidates with improved antimicrobial activities, we synthesized and studied invitro antimicrobial activities of various series of 3-((thiophen-2-yl)-ethyl)-2-(styryl)-quinazolin-4(3H)-one (3a-3g) and N1-(substituted aryl)-N3-[3-((3,4-dimethoxy phenyl-2-yl)-ethyl)-4(3H)-quinazolone-2-yl]-acetonyl semicarbazides (7a-7j) with an intent to overcome multiple drug resistance to the pathogenic strains and to retain psychological action to develop novel class of antibacterial agents. The structure of newly synthesized scaffolds has been affirmed on the basis of FTIR, 1H NMR, 13C NMR, mass and elemental analysis. All the final scaffolds have been subjected to in vitro antimicrobial screening against two Gram (+Ve) bacteria (S. aureus, B. subtilis), two Gram (-Ve) bacteria (E. coli, S.typhi) and two fungal strains (C. albicans, A. niger) using the broth micro-dilution method.

A new class of 2-(4-cyanophenyl amino)-4-(6-bromo-4-quinolinyloxy)-6-piperazinyl (piperidinyl)-1,3,5-triazine analogues with antimicrobial/antimycobacterial activity.

This study presents the synthesis and in vitro pharmacological evaluations of novel 2-(4-cyanophenyl amino)-4-(6-bromo-4-quinolinyloxy)-6-piperazinyl (piperidinyl)-1,3,5-triazines. The title compounds were assayed for their in vitro antimicrobial activity against eight bacteria (Staphylococcus aureus, Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella typhi, Proteus vulgaris, Shigella flexneria) and four fungi (Aspergillus niger, Aspergillus fumigatus, Aspergillus clavatus, Candida albicans) using paper disc diffusion and agar streak dilution method as well as against Mycobacterium tuberculosis H37Rv strain using BACTEC MGIT and Lowenstein-Jensen MIC method. The bioassay results indicate that nine compounds namely 5d, 5h, 5n, 5p, 5q, 5r, 5s, 5t and 5u could be considered as possible potential agents with dual antimicrobial and antimycobacterial activities. The structures of the compounds were elucidated with the aid of IR, (1)H NMR, (13)C NMR, (19)F NMR spectroscopy and CHN analysis.

Fluorinated s-triazinyl piperazines as antimicrobial agents.

A series of 1,3,5-triazine derivatives that contain 4-amino-2-trifluoromethyl-benzonitrile, 8-hydroxyquinoline, and different piperazines as substituents at the carbon atoms of the triazine ring have been synthesized by a simple and efficient synthetic protocol. The chemical structures of the compounds were elucidated with the aid of IR, 1H NMR and 13C NMR spectroscopy, and elemental analysis. The antimicrobial activity of the compounds was tested against seven bacteria (Staphylococcus aureus MTCC 96, Bacillus cereus MTCC 619, Escherichia coli MTCC 739, Pseudomonas aeruginosa MTCC 741, Klebsiella pneumoniae MTCC 109, Salmonella typhi MTCC 733, Proteus vulgaris MTCC 1771) and four fungi (Aspergillus niger MTCC 282, Aspergillus fumigatus MTCC 343, Aspergillus clavatus MTCC 1323, Candida albicans MTCC 183). The results indicate that some of the novel s-triazines have noteworthy activity in minimum inhibitory concentration as well as agar diffusion tests.

Synthesis and studies of novel 2-(4-cyano-3-trifluoromethylphenyl amino)-4-(quinoline-4-yloxy)-6-(piperazinyl/piperidinyl)-s-triazines as potential antimicrobial, antimycobacterial and anticancer agents.

A series of novel s-triazine analogs were synthesized and characterized by IR, (1)H NMR, (13)C NMR, (19)F NMR spectroscopy and elemental analysis. Preliminary screening of target compounds against eight bacteria (Staphylococcus aureus, Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella typhi, Proteus vulgaris, Shigella flexneria), four fungi (Aspergillus niger, Aspergillus fumigatus, Aspergillus clavatus, Candida albicans) and Mycobacterium tuberculosis H37Rv indicated that 5d, 5h, 5n, 5p, 5q, 5r, 5s, 5t and 5u were the most active compounds among twenty one studied. Thus, they were further subjected to in vitro biological evaluation against human prostate cancer cell line (DU-145) and the results indicate that two compounds 5n and 5s were markedly active.

Synthesis and Antimycobacterial Activity of Various 1-(8-Quinolinyloxy)-3-piperazinyl(piperidinyl)-5-(4-cyano-3-trifluoromethylphenylamino)-s-triazines.

This study presents the synthesis of novel 1-(8-quinolinyloxy)-3-piperazinyl(piperidinyl)-5-(4-cyano-3-trifluoromethylphenyl amino)-s-triazines. The synthetic route to final piperazinyl s-triazines consists of two nucleophilic substitution reactions of 4-amino-2-trifluoromethylbenzonitrile and 8-hydroxyquinoline with 2,4,6-trichloro-1,3,5-triazine resulting in 2,4-disubstituted-6-chloro-1,3,5-triazine derivatives to introduce the piperazinyl or piperidinyl functionality. The structures of the compounds were elucidated with the aid of IR, 1H NMR, 19F NMR, mass spectroscopy and elemental analysis. The title compounds were then investigated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv strain by using BACTEC MGIT and Lowenstein-Jensen MIC method. Compound 4-[4-(3,5-dimethylpiperidin-1-yl)-6-(quinolin-8-yloxy)-1,3,5-triazin-2-ylamino]-2-trifluoromethylbenzonitrile (5n) was the most potent one among the tested compounds. It was as potent as ethambutol to inhibit M. tuberculosis H37Rv completely (99%) at the minimum inhibitory concentration (MIC) of 3.12 µg/mL. Compounds 5p, 5s and 5u have shown equal potency to that of pyrazinamide at the minimum inhibitory concentration (MIC) of 6.25 mg/mL to inhibit (99%) M. tuberculosis H37Rv.