Letters in Organic Chemistry - Volume 15, Issue 1, 2018

Background: The quaternary ammonium compounds (QAC) are the important group of chemical individuals with widespread usage in many fields of industry or science. The surface-active cationic surfactants are well known disinfection agents. Its effectivity against gram-positive, gramnegative bacteria, yeasts and some viruses is already used in many preparations. On the other hand, the emergence of resistance is the cause of an increasing necessity of new substances. Methods: The series of 5-alkyl-7-hydroxy-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-5-ium bromides has been synthesized as a novel potential antimicrobial agent. Reaction of the nucleophilic substitution type has been used. The novel compounds have been tested as disinfection agents against bacteria and fungi. The microdilution broth method was utilized for antimicrobial evaluation. Standard MTT test was used for cytotoxic evaluation. Results: We have prepared 5 new compounds based on 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-ol with different length of lipophilic alkyl chain on the quaternary nitrogen (C10-18). The compounds were characterized with analytical data (NMR, HRMS) and evaluated as wide spectrum antimicrobial agents against pathogenic fungal and bacterial strains. We have observed the efficacy towards microbial cells of C12 and C14 compounds for only several antimicrobial strains (Staphylococcus aureus, Candida krusei, Candida glabrata, Trichophyton mentagrophytes). Conclusion: We report on the preparation and characterization of a set of novel cationic surfactant-like compounds based on 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-ol. The novel compounds have been evaluated as wide spectrum antimicrobial agents against pathogenic fungal and bacterial strains. Only two compounds with alkyl chain C12 and C14 showed significant activity against microbes. So, these two compounds should be considered as the potential disinfectants with the selective effect against certain bacterial and fungal strains, not as wide spectra antimicrobial agents.

Background: Tenofovir alafenamide (TAF) is an oral antiviral prodrug of tenofovir (TFV), we have developed a facial and efficient method for the synthesis and chiral resolution of TAF. Method: The practical synthetic route of a mixed two diastereomers at phosphorous could start from (R)-9-[2-(Phosphonomethoxy)propyl]adenine (PMPA), the esterification reaction between PMPA and phenol occurred under the catalysis of dicyclohexylcarbodiimide (DCC) in 1-methyl-2-pyrrolidinone (NMP) at the temperature of 100°C to afforded 1. Phosphonochloridate was synthesized from 1 by chloride acetylation with thionyl chloride, and then react with an excess of L-Alanine isopropyl ester hydrochloride to give the diastereomer mixture of 9-[(R)-2-[[(R,S)-[[(S)-1-(isopropoxycarbonyl)ethyl] amino]-phenoxyphosphinyl]methoxy]propyl]adenine (2). The antipodes of 2 were separated in a satisfactory yield and diastereomeric excess (99% de) by resolution via formation diastereoisomer salt or inclusion complex to afford the more potent diastereomer (3). Tenofovir Alafenamide hemifumarate could be afforded by 3 and fumaric acid in a 1:0.5 ratio. Results: The diastereomeric excess of 3 could reach to 99% de. Conclusion: In a word, we have developed an efficient and chromatography-free route for the preparation of TAF. In consideration of the expensive equipment and higher operation cost of SMBC, we chose a traditional resolution route to obtain chiral phosphorus.

Background: The recent emergence of multidrug-resistant strains of M. tuberculosis that are resistant to two major effective drugs, viz. isoniazid and rifampicin, stimulated us to make an attempt for the development of a new class of potent antitubercular agents by modifying the structures of existing drugs. Aiming this, an efficient synthesis of glucose linked-isonicotinoyl-1,3,4-thiadiazolidines has been carried out. Method: The title compounds have been synthesized through cyclocondensation reaction of 1- isonicotinoyl-4-aryl thiosemicarbazides with N-tetra-O-acetyl-β-D-glucopyranosyl isocyanodichloride. The structures of newly synthesized compounds were verified by IR, 1H NMR, 13C NMR, mass spectrometry and elemental analyses. The title compounds were evaluated for their in vitro antitubercular potency against M. tuberculosis H37Rv strain using Lowenstein-Jensen method. Results: A few title compounds were found to be equipotent with the reference drug rifampicin, while moderately potent, when compared with the reference drug isoniazid. These compounds were subjected to molecular docking studies and their results were found to be in agreement with the in vitro studies. Conclusion: We reported simple and efficient protocol for the synthesis of series of bioactive glucoselinked isonicotinoyl-1,3,4-thiadiazolidines by utilizing N-tetra-O-acetyl-β-D-glucopyranosyl isocyanodichloride as a suitable reagent for glycosylation. This approach is a valuable addition to the fastdeveloping field of glucose-linked heterocycles and might be used to develop new potential drugs. We demonstrated the introduction of isonicotinoyl and glucosyl moieties in single molecular framework which may prove beneficial for developing new class of antitubercular agents.

Background: Tuberculosis is one of the top ranked airborne infectious diseases caused by the bacillus Mycobacterium tuberculosis with high mortality rate from a single infectious agent. In the present article, we aimed to synthesize oxadiazole-coumarin-triazole based small molecules and evaluate for their possible anti-mycobacterial activity. Method: Herein, we describe the facile synthesis of 5-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)-1,3,4- oxadiazole-2-thiol-tethered substituted 4-(bromomethyl)-7-methyl-2H-chromen-2-one derivatives and evaluated for their anti-mycobacterial activity against H37Rv strain of M. tuberculosis. We also evaluated the cytotoxic effect of new compounds on normal cells. Results: Among the 14 novel oxadiazole-coumarin-triazole derivatives, 4-((5-((1H-benzo[d][1,2,3]triazol-1- yl)methyl)-1,3,4-oxadiazol-2-ylthio)methyl)-6-methoxy-2H-chromen-2-one (5f) displayed good antimycobacterial activity towards M. tuberculosis with an MIC value of 15.5 μM. Pyrazinamide was used as reference drug. Our investigation also revealed that, 5f is not cytotoxic to normal cells. Conclusion: In summary, the findings suggested that novel 1,3,4-oxadiazole coumarin-triazole hybrids are promising antimycobacterial agents against M. tuberculosis.

Background: In the recent years, various bis-heterocyclic compounds are reported for their varied biological activities. Bis(indolyl)methanes and its derivatives are commonly present in over 3000 natural isolates and reported for its broad spectrum of biological activities. Though, there are so many methods reported for the synthesis of bis(indolyl)methanes, there is a need to develop a green and ecofriendly synthetic protocol which in turn is important for economic and synthetic point of view. Method: The supramolecular chemistry approach was efficiently used for the synthesis of bis(indolyl)methane derivatives 3(a-o) by the condensation reaction of indole 1 (2.0 mmol) and substituted aldehydes 2(a-o) (1.0 mmol) at 60°C using β-cyclodextrin in water. The progress of the reaction was monitored by TLC using ethyl acetate:hexane (7:3) as a mobile phase. The identity and purity of the products were confirmed by MASS, 1H NMR, and 13C NMR. Results: This report describes supramolecular synthesis of bis(indolyl)methanes 3(a-o) using β-cyclodextrin (1.0 mol%) in water at 60°C. The synthesized compounds 3(a–o) were obtained in excellent yields (80-92 %) in less reaction time (20-40 min). The hydrophobic binding of β-cyclodextrin with one of the reactants is explained by 1H NMR. The rate of the reaction is accelerated if electron withdrawing groups like Cl and F are present on the aromatic ring. Conclusion: We have efficiently synthesized bis(indolyl)methanes 3(a–o) via threecomponent one-pot condensation reaction of indole with substituted aldehydes using β-cyclodextrin as a supramolecular catalyst in aqueous medium. β-cyclodextrin is biodegradable, recoverable and purely environmentally benign. This method has several advantages over existing catalytic protocols as it has simple and green experimental procedures, use of green reaction media (water), lower reaction time, high reaction rate and avoids cumbersome work-up.

An efficient and eco-friendly procedure for the synthesis of 2,3-dihydroquinazolin-4(1H)- ones and spiroquinazolinones in the presence of sulfuric acid functionalized silica-coated magnetite nanoparticles under solvent-free conditions has been described. The reactions are completed in short times, and the products are obtained in high isolated yields without any undesirable side reaction. This method has several advantages, including short reaction time, facile operation, easy work-up, ecofriendly reaction conditions, high isolated yields, and reusability of the catalyst. The catalyst could be easily separated and recovered from the reaction mixture by an external magnet and reused in subsequent reactions with no considerable loss in activity.

Background: Pyrano[3,2-c]chromenes are important frameworks of various natural products and have attracted much attention due to their biological activities. These properties include spasmolytic, anti microbial, anti coagulant, anti tumor and central nervous system activities. Methods: we described a convenient method for the preparation of functionalized pyrano[3,2-c] chromenes from the reaction of malononitrile, activated alkynes and 4-hydroxycoumarin in the presence of Et3N in EtOH at reflux condition. Result: Five pyrano[3,2-c]chromene derivatives were synthesized in high yield and their structures were completely characterized by spectroscopic techniques and elemental analysis. These products have potential applications in medicinal chemistry and in organic synthesis. Conclusion: A practical procedure one pot, three component reaction of readily available starting materials to give pyrano[3,2-c]chromene compounds has been developed. This method has some advantages like mild reaction condition, experimental simplicity, easy purification of products and does not require any metal-catalyst.

Background: Cancer is one of the major health diseases worldwide with an approximately 14 million new cases of cancer and 8.2 million cancer related death tolls were reported in 2012. The major complications associated with chemotherapy are limited efficacy, selectivity, safety as well as higher cost, emergence of drug resistant cancer, and genotoxicity. Today we need more effective and safer cytotoxic agents to combat cancer. Method: Two new series of N-(2,6-dimethylphenyl)-5-aryl-1,3,4-oxadiazol-2-amine (4a–g) and N-{[5- aryl-1,3,4-oxadiazol-2-yl]methyl}-2,6-dimethylaniline (4h-n) were designed and synthesized based on the structure of IMC-038525 (tubulin polymerization inhibitor) and NSC 777948 as cytotoxic agents. The cytotoxicity of eight compounds was carried out as per National Cancer Institute (NCI US) protocol on nearly 60 cancer cell lines, while the cytotoxicity of five compounds was carried out as per Sulforhodamine B assay on two breast cancer cell lines. The molecular docking studies implying tubulin inhibition were also carried out to observe the binding mode of new oxadiazoles. Results: N-(2,6-Dimethylphenyl)-5-(4-chlorophenyl)-1,3,4-oxadiazol-2-amine (4b) showed significant cytotoxicity with comparatively higher sensitivity towards colon cancer (HT29), melanoma (LOX IMVI), leukemia (RPMI-8226), and melanoma (M14), with percent growth inhibitions (% GIs) of 80.99, 75.05, 63.25, and 62.19 respectively. Compound 4b showed better cytotoxicity than the standard drug imatinib. Further compound 4b showed maximum docking score and was found to have different binding mode than the rest of the compounds at the colchicine binding site of tubulin enzyme with a hydrogen bonding between NH with carbonyl oxygen of Thr353 (bond length = 3.05A). The hydrophilicity of compound 4b was another parameter that might play a major role and made it most effective when compared to the rest of the compounds. Conclusion: The oxadiazoles reported herein are cytotoxic agents. These findings may be helpful in future drug design of more potent cytotoxic agents.

Green chemistry emphasizes the development of environmentally benign chemical processes and technologies. Pseudo-multicomponent synthesis of 2-aryl-1-arylmethyl-1H-benzimidazoles using o-phenylenediamine and aromatic aldehydes is carried out by Bronsted acid type bio-surfactant as a catalyst. The green features of this method include the use of biodegradable catalyst obtained from renewable resource i.e. Citrus Limonium extract as bio-surfactant type Bronsted acid, which provides a micellar media for effective cyclocondensation. The critical micellar concentration (cmc) of biosurfactant was determined by conductivity method and visualized by light microscopy measurement. Identity of all pure compounds was ascertained on the basis of FT-IR, 1H NMR and 13C NMR spectroscopic techniques.

Background: Oxadiazoles are privileged scaffolds in different areas of medicinal, pesticidal, polymer and material science. They act as anticancer, benzodiazepine receptor agonists, antimicrobial, analgesic, diuretic and tyrosinase inhibitors etc. A number of compounds containing an oxadiazole moiety are in late stage clinical trials including zibotentan and furamizole. Despite numerous methods are reported, the majority of them suffer from major drawbacks such as the use of strong alkaline or acidic conditions, highly toxic and corrosive reagents and also involve the use of costly reagents, elevated temperatures and longer reaction times. Inspired by the potential application of hypervalent iodonium reagents in organic synthesis, we would like to explore the readily available IBX and KI reagents for the facile synthesis of 1,3,4-oxadiazoles. Method: Oxidative cyclization has successfully been developed for the synthesis of 2,5-disubstituted 1,3,4-oxadiazoles. Results: An efficient process for the one-pot synthesis of 2,5-disubstituted 1,3,4-oxadiazoles has been developed using IBX/KI system at 25°C. The reaction was successful with a wide range of substrates such as aromatic and heterocyclic aldehyde and arylhydrazides to afford the corresponding unsymmetrical 2,5-disubstituted 1,3,4-oxadiazoles. The mild reaction conditions, cost-effective reagents and short reaction time are noteworthy advantages of this methodology. Conclusion: We have developed a one-pot strategy for the synthesis of 1,3,4-oxadiazioles using a combination of IBX/KI at ambient temperature. This one-pot procedure proved to be quite general and worked well with a wide variety of aryl and heterocyclic aldehydes and variety of acylhydrazides. The advantage of this method lies in the simplicity of experimental procedure and the ready accessibility of the reagents, which render this, an experimentally attractive method for the preparation of unsymmetrical 1,3,4-oxadiazoles.

Aurones were synthesized through an oxidation-cyclization tandem reaction of 2-(1- hydroxyprop-2-ynyl)phenols catalyzed by copper nanoparticles (Cu NPs) with bipyridine as the ligand. In the reaction, oxygen worked as a green and mild oxidant to give the best results. Cu NPs were dually activated by bipyridine ligand and water, and showed highly efficient catalytic activities to the oxygen oxidation and the cylization to give aurones and flavonoids.