A microwave-assisted bismuth nitrate-catalyzed unique route toward 1,4-dihydropyridines.

The classical Hantzsch reaction is one of the simplest and most economical methods for the synthesis of biologically important and pharmacologically useful 1,4-dihydropyridine derivatives. Bismuth nitrate pentahydrate under microwave irradiation is proven to act as a very efficient catalyst for a one-pot, three-component synthesis of 1,4-dihydropyridines in excellent yields from diverse amines/ammonium acetate, aldehydes and 1,3-dicarbonyl compounds within 1-3 min under solvent-free conditions. The present environmentally benign procedure for the synthesis of 1,4-dihydropyridines is suitable for library synthesis and it will find application in the synthesis of potent biologically active molecules. The excellent yield and extreme rapidity of the method is due to a concurrent effect of the catalyst and microwave irradiation.

An expeditious iodine-catalyzed synthesis of 3-pyrrole-substituted 2-azetidinones.

2-Azetidinones and pyrroles are two highly important classes of molecules in organic and medicinal chemistry. A green and practical method for the synthesis of 3-pyrrole-substituted 2-azetidinones using catalytic amounts of molecular iodine under microwave irradiation has been developed. Following this method, a series of 3-pyrrole- substituted 2-azetidinones have been synthesized with a variety of substituents at N-1 and at C-4. The procedure is equally effective for mono- as well as polyaromatic groups at the N-1 position of the 2-azetidinone ring. The C-4 substituent has no influence either on the yield or the rate of the reaction. Optically pure 3-pyrrole-substituted 2-azetidinones have also been synthesized following this methodology. No deprotection/rearrangement has been identified in this process, even with highly acid sensitive group-containing substrates. A plausible mechanistic pathway has also been suggested based on the evidence obtained from ¹H-NMR spectroscopy. The extreme rapidity with excellent reaction yields is believed to be the result of a synergistic effect of the Lewis acid catalyst (molecular iodine) and microwave irradiation.

Role of imine isomerization in the stereocontrol of the Staudinger reaction between ketenes and imines.

Computational-experimental analysis has allowed determining that the stereochemistry of the Staudinger reaction between ketenes and imines is strongly associated with the nature of the imine, which affects the two steps of the reaction. The first step, namely the nucleophilic attack of the sp2-hybridized nitrogen atom of the imine on the sp-hybridized carbon atom of the ketene, is affected by the energetically accessible in situ isomerization patterns of the imine. The second step consists of a conrotatory electrocyclization of the zwitterionic intermediate formed in the previous step. This latter pericyclic step depends on the inward/outward torquoelectronic effects generated by the substituents of the imine. The impact of these factors on the stereochemistry of this reaction has been analyzed kinetically by numerical methods. The results of these simulations are compatible with the experimental results and support these conclusions.

Drug Repurposing Strategy (DRS): Emerging Approach to Identify Potential Therapeutics for Treatment of Novel Coronavirus Infection.

Drug repurposing is also termed as drug repositioning or therapeutic switching. This method is applied to identify the novel therapeutic agents from the existing FDA approved clinically used drug molecules. It is considered as an efficient approach to develop drug candidates with new pharmacological activities or therapeutic properties. As the drug discovery is a costly, time-consuming, laborious, and highly risk process, the novel approach of drug repositioning is employed to increases the success rate of drug development. This strategy is more advantageous over traditional drug discovery process in terms of reducing duration of drug development, low-cost, highly efficient and minimum risk of failure. In addition to this, World health organization declared Coronavirus disease (COVID-19) as pandemic globally on February 11, 2020. Currently, there is an urgent need to develop suitable therapeutic agents for the prevention of the outbreak of COVID-19. So, various investigations were carried out to design novel drug molecules by utilizing different approaches of drug repurposing to identify drug substances for treatment of COVID-19, which can act as significant inhibitors against viral proteins. It has been reported that COVID-19 can infect human respiratory system by entering into the alveoli of lung via respiratory tract. So, the infection occurs due to specific interaction or binding of spike protein with angiotensin converting enzyme-2 (ACE-2) receptor. Hence, drug repurposing strategy is utilized to identify suitable drugs by virtual screening of drug libraries. This approach helps to determine the binding interaction of drug candidates with target protein of coronavirus by using computational tools such as molecular similarity and homology modeling etc. For predicting the drug-receptor interactions and binding affinity, molecular docking study and binding free energy calculations are also performed. The methodologies involved in drug repurposing can be categorized into three groups such as drug-oriented, target-oriented and disease or therapy-oriented depending on the information available related to quality and quantity of the physico-chemical, biological, pharmacological, toxicological and pharmacokinetic property of drug molecules. This review focuses on drug repurposing strategy applied for existing drugs including Remdesivir, Favipiravir, Ribavirin, Baraticinib, Tocilizumab, Chloroquine, Hydroxychloroquine, Prulifloxacin, Carfilzomib, Bictegravir, Nelfinavir, Tegobuvir and Glucocorticoids etc to determine their effectiveness toward the treatment of COVID-19.

An expeditious synthesis of N-substituted pyrroles via microwave-induced iodine-catalyzed reactions under solventless conditions.

An expeditious synthesis of N-substituted pyrroles has been developed by reacting 2,5-dimethoxy tetrahydrofuran and several amines using a microwave-induced molecular iodine-catalyzed reaction under solventless conditions.

An effective microwave-induced iodine-catalyzed method for the synthesis of quinoxalines via condensation of 1,2-diamines with 1,2-dicarbonyl compounds.

A microwave-induced iodine-catalyzed simple, rapid and convenient synthesis of different types of quinoxalines via condensation of 1,2-diamines with 1,2-dicarbonyl compounds has been accomplished with an excellent yield.

A highly efficient bismuth salts-catalyzed route for the synthesis of α-aminophosphonates.

A convenient synthesis of different types of α-amino phosphonates via one-pot solvent-free three component reactions of aldehydes, amines and phosphites catalyzed by bismuth salts has been investigated. Bismuth triflate is found to be the most effective catalyst for this reaction.

Remarkable iodine-catalyzed synthesis of novel pyrrole-bearing N-polyaromatic beta-lactams.

Because of their interesting biological properties various methods for the synthesis of substituted pyrroles are described in the literature. However, synthesis of pyrroles fused with a beta-lactam ring has not been reported. Our group has demonstrated synthesis and biological evaluation of various beta-lactams as anticancer agents. The anticancer activities of these compounds have prompted us to study the synthesis of pyrroles bound to the beta-lactams. We have identified an expeditious synthetic method for the preparation of pyrroles fused with beta-lactams by reacting 3-amino beta-lactams with acetonylacetone in the presence of catalytic amounts (5 mol%) of molecular iodine at room temperature. It has also been discovered that the reaction gives products under domestic and automated microwave oven irradiation. To our knowledge, there are no other prior reports that describe the synthesis of pyrrole-substituted beta-lactams.

Metal-Free Cross-Dehydrogenative Coupling (CDC): Molecular Iodine as a Versatile Catalyst/Reagent for CDC Reactions.

The development of ecofriendly methods for carbon-carbon (C-C) and carbon-heteroatom (C-Het) bond formation is of great significance in modern-day research. Metal-free cross-dehydrogenative coupling (CDC) has emerged as an important tool for organic and medicinal chemists as a means to form C-C and C-Het bonds, as it is atom economical and more efficient and greener than transition-metal catalyzed CDC reactions. Molecular iodine (I2 ) is recognized as an inexpensive, environmentally benign, and easy-to-handle catalyst or reagent to pursue CDCs under mild reaction conditions, with good regioselectivities and broad substrate compatibility. This review presents the recent developments of I2 -catalyzed C-C, C-N, C-O, and C-S/C-Se bond-forming reactions for the synthesis of various important organic molecules by cross-dehydrogenative coupling.

Synthesis of Medicinally Privileged Heterocycles through Dielectric Heating.

BACKGROUND: Heterocyclic compounds are intriguing part of modern drug discovery research. Ecofriendly syntheses of heterocycles, following green techniques, are privileged routes to protect Mother nature. Microwave-assisted synthesis of chemical compounds is considered as a major greener pathway, both in academia and industry. METHODS: A total of 106 publications (including a few authentic web links) have been reviewed mainly to discuss (i) mechanism of microwave irradiation, (ii) abundance of commercial heterocyclic drugs, (iii) various synthetic procedures, and (iv) medicinal activity of the synthesized molecules. RESULTS: This review summarizes the potential application of microwave irradiation (dielectric heating) to synthesize biologically important heterocyclic small molecules in the recent past. A huge number of heterocyclic compounds are present in various natural sources like plant, marine microbe or other organisms and many of them possess unique biological activity. In addition to nature-derived heterocyclic compounds, a large number of synthetic heterocycles are being used as medicines. This review describes the relevant recent examples of microwave irradiation to accomplish various chemical transformations accelerated by a variety of catalysts which include, but not limited to, Lewis acids, other metal containing catalysts, organocatalysts, heterogeneous catalysts, phase-transfer catalysts, solid-supported catalysts, inorganic catalysts (bases, acids and salts) and so on. Although there are an increasing number of reports on application of dielectric heating in various other fields, this review is focused on a large number of new and novel strategies related to synthetic organic chemistry. The discussion is mostly organized by the disease type although some reactions/molecules can certainly be placed in multiple sections. Since green chemistry is an extremely emerging and comparatively new field of research, attempts to stimulate more activities on green medicinal chemistry are provided. Discussion related to the concurrent effect of microwaves, catalysts and/or solvents, supports to constitute expeditious and general route for the syntheses of medicinally important heterocyclic compounds and pharmacophores has also been included. CONCLUSION: The dielectric heating procedure to produce novel medicinally privileged heterocyclic scaffolds/ compounds is extremely promising and challenging. As a result, this green technique has been gaining increasing interest from the pharmaceutical world. A recent update has been presented. While every effort has been made to include all pertinent reports in this field, any omission is unintentional.

Microwave-induced Bismuth Salts-mediated Synthesis of Molecules of Medicinal Interests.

BACKGROUND: Bismuth salts-mediated reactions have become a powerful tool for the synthesis of diverse medicinally-significant compounds because of their low-toxicity (non-toxic) and Lewis acidic capacity. In fact, LD50 of bismuth nitrate is lower than table salt. On the other hand, microwave-induced chemical synthesis is considered as a major greener route in modern chemistry. METHODS: A total of 139 publications (including a few authentic web links) have been reviewed mainly to discuss bismuth salts-induced electrophilic aromatic substitution, protection-deprotection chemistry of carbonyl compounds, enamination, oxidation, carbohydrate chemistry, hydrolysis, addition-elimination route, Paal-Knorr reaction, Clauson-kaas synthesis, Michael addition, aza-Michael addition, Hantzsch reaction, Biginelli reaction, Ferrier rearrangement, Pechmann condensation, Diels-Alder and aza-Diels- Alder reactions, as well as effects of microwave irradiation in a wide range of chemical transformations. RESULTS: Bismuth salts-mediated reactions are developed for the synthesis of diverse organic molecules of medicinal significance. Reactions conducted with bismuth salts are environmentally benign, economical, rapid and high yielding. Microwave irradiation has accelerated these reactions significantly. It is believed that bismuth salts released corresponding acids in the media during the reaction. However, a coordination of bismuth salt to the electronegative atom is also observed in the NMR study. Bismuth has much less control (less attractive forces) over anions (for example, halides, nitrate, sulfate and triflates) compared to alkali metals. Therefore, it forms weak bond with electronegative atoms more readily and facilitates the reactions significantly. Many products obtained via bismuth salts-mediated reactions are medicinally active or intermediate for the synthesis of biologically active molecules including antifungal, anti-parasitic, anticancer and antibacterial agents, as well as agents to prevent Leishmaniosis and Chagas' diseases. CONCLUSION: Bismuth salts are able to (i) generate mineral acids in the reaction media and (ii) coordinate with electronegative atoms to facilitate the reaction. When the reagents and the catalyst (bismuth salt) are subjected to microwave irradiation, microwave passes through the (glass) walls of the reaction vessel and heat only the reactants avoiding local overheating at the wall of the vessel. Accordingly, the possibility of side reaction and subsequent by-product formation are reduced abruptly which in turn increases the yield of the desired product. The extreme rapidity with excellent yield of the product can be rationalized as a synergistic effect of the bismuth salts and microwave irradiation.

Polysaccharides from Dolichos biflorus Linn and Trachyspermum ammi Linn seeds: isolation, characterization and remarkable antimicrobial activity.

Polysaccharides are structurally complex and essential constituents of life, and therefore, studies directed to these kinds of molecules have received scientific attention. Despite an easy availability of Dolichos biflorus Linn and Trachyspermum ammi (Linn) seeds isolation, characterization and antimicrobial studies of polysaccharides derived from these two natural sources have not been investigated. Therefore, we report here isolation of polysaccharides, their purification and characterization from Dolichos biflorus Linn and Trachyspermum ammi (Linn) seeds. Gel permeation chromatography, GC-MS, SEM, XRD, EDX and FT-IR analyses show the presence of three pentose sugar such as D-ribose, D-arabinose, D-xylose and hexose sugar such as D-mannose, D-galactose and D-glucose. Unprecedented antimicrobial activity of these polysaccharides against Gram positive bacteria such as Staphylococcus aureus and Bacillus subtilis and Gram negative bacteria such as Escherichia coli and Pseudomonas aeruginosa are established.

A Practical Green Synthesis and Biological Evaluation of Benzimidazoles Against Two Neglected Tropical Diseases: Chagas and Leishmaniasis.

Antimicrobial resistance is an ever-increasing problem throughout the world and has already reached severe proportions. Two very common neglected tropical diseases are Chagas' disease and leishmaniasis. Chagas' disease is a severe health problem, mainly in Latin America, causing approximately 50000 deaths a year and millions of people are infected. About 25-30% of the patients infected with Trypanosoma cruzi develop the chronic form of the disease. On the other hand, Leishmaniasis represents complex diseases with an important clinical and epidemiological diversity. It is endemic in 88 countries 72 of which are developing countries and it has been estimated that are 12 million people infected and 350 million are in areas with infection risk. On this basis, research on organic compounds that can be used against these two diseases is an important target. A very simple, green, and efficient protocol is developed in which bismuth nitrate pentahydrate is employed as a Lewis acid catalyst in aqueous media under microwave irradiation for the synthesis of various 2-aryl substituted benzimidazoles from aldehydes and o-phenylenediamine. Other salient features of this protocol include milder conditions, atom-economy, easy extraction, and no wastes. Nine 1H-benzimidazole derivatives (1-9) with substituents at positions 2 and 5 were synthesized and the structure of the compounds was elucidated by spectroscopic methods. The compounds were screened to identify whether they posses pharmacological activity against Chagas' disease and leishmaniasis. Compound 8 showed better activity than the control Nifurtimox against INC-5 Trypanosoma cruzi strain whereas compounds 3 and 9 have demonstrated potent leshmanicidal activity. A systematic green synthetic procedure and in vitro biological evaluation of nine 1H-benzimidazoles are described.

Apoptotic-inducing activity of novel polycyclic aromatic compounds in human leukemic cells.

Persistent but relatively limited research has been devoted to the use of compounds related to polycyclic aromatic hydrocarbons (PAH) as anticancer agents. In previous reports, we have described the cytotoxicity of a number of new and novel PAH against human cancer cell lines. However, the involved molecular mechanisms of inducing cell death were not elucidated. In the current study, we describe the apoptotic pathway as apparently playing a crucial role in induced cell death in human leukemia Jurkat T cells by several diamide and diamine PAH that contain chrysene as their core aromatic ring system. Structure-activity relationships were analyzed. Importantly, no effect was demonstrated in a normal, non-transformed line of human natural killer cells. These results provide additional evidence for the potential chemotherapeutic use of PAH.

A selective, expeditious and sustainable entry en route to benzopyrazines and bis-benzopyrazines.

A convenient green synthesis of benzopyrazines and bis-benzopyrazines has been performed by the condensation of diversely substituted diamines and dicarbonyl compounds in water using indium powder as catalyst under controlled microwave exposure. The effects of microwave power, and temperature on this reaction are investigated in detail to identify the best condition. A wide range of diversely substituted diamines and dicarbonyl compounds produce excellent yield of the corresponding benzopyrazines and bis-benzopyrazines. A comparative study has also been made between microwave-induced procedure and conventional method. The present method is atom-economical, environmentally friendly, and affords synthetically useful and challenging products very rapidly.

Design, synthesis and biological evaluation of novel pyrenyl derivatives as anticancer agents.

Polycyclic aromatic hydrocarbons are widespread in nature with a toxicity range from non-toxic to extremely toxic. A series of pyrenyl derivatives has been synthesized following a four-step strategy where the pyrene nucleus is attached with a basic heterocyclic moiety through a carbon linker. Virtual screening of the physicochemical properties and druggability has been carried out. The cytotoxicity of the compounds (1-8) have been evaluated in vitro against a small panel of human cancer cell lines which includes two liver cancer (HepG2 and Hepa 1-6), two colon cancer (HT-29 and Caco-2) and one each for cervical (HeLa) and breast (MCF-7) cancer cell lines. The IC50 data indicate that compound 6 and 8 are the most effective cytotoxic agents in the present set of pyrenyl derivatives, suggesting that having a 4-carbon linker is more effective than a 5-carbon linker and the presence of amide carbonyl groups in the linker severely reduces the efficacy of the compound. The compounds showed selectivity toward cancer cells at lower doses (<5 µM) when compared with the normal hepatocytes. The mechanism of action supports the cell death through apoptosis in a caspase-independent manner without cleavage of poly (ADP-ribose) polymerase (PARP), even though the compounds cause plasma membrane morphological changes. The compounds, whether highly cytotoxic or mildly cytotoxic, localize to the membrane of cells. The compounds with either a piperidine ring (6) or an N-methyl piperazine (8) in the side chain were both capable of circumventing the drug resistance in SKOV3-MDR1-M6/6 ovarian cancer cells overexpressing P-glycoprotein. Qualitative structure-activity relationship has also been studied.

Stereoselective synthesis of beta-lactams with polyaromatic imines: entry to new and novel anticancer agents.

We present herein stereoselective synthesis of novel beta-lactams using polyaromatic imines following the Staudinger reaction. Consistent mechanisms for these results have been advanced. As a measure of cytotoxicity, some of these compounds have been assayed against nine human cancer cell lines. Structure-activity study has revealed that 1-N-chrysenyl and 1-N-phenanthrenyl 3-acetoxy-4-aryl-2-azetidinones have potent anticancer activity. The presence of the acetoxy group at C(3) of the beta-lactams has proven to be obligatory for their anticancer activity.

Polycyclic aromatic compounds as anticancer agents: synthesis and biological evaluation of methoxy dibenzofluorene derivatives.

Synthesis of a new methoxy dibenzofluorene through alkylation, cyclodehydration and aromatization in a one-pot operation is achieved for the first time. Using this hydrocarbon, a few derivatives are prepared through aromatic nitration, catalytic hydrogenation, coupling reaction with a side chain and reduction. The benzylic position of this hydrocarbon with the side chain is oxidized and reduced. Some of these derivatives have demonstrated excellent antitumor activities in vitro. This study confirms antitumor activity depends on the structures of the molecules.

An expeditious green route toward 2-aryl-4-phenyl-1H-imidazoles.

BACKGROUND: Azaheterocycles are an important class of compounds because of their highly potent medicinal activities, and the imidazole subcategory is of special interest in regard to drug discovery research. FINDINGS: An expeditious synthetic protocol of 2-aryl-4-phenyl-1H-imidazoles has been accomplished by reacting phenylglyoxal monohydrate, ammonium acetate, and aldehyde under sonication. Following this green approach a series of 2-aryl-4-phenyl-1H-imidazoles has been synthesized using diversely substituted aldehydes. CONCLUSIONS: A rapid and simple synthetic procedure to synthesize diversely substituted 2-aryl-4-phenyl-1H-imidazoles has been reported. Other salient features of this protocol include milder conditions, atom-economy, easy extraction, and minimum wastes. The present procedure may find application in the synthesis of biologically active molecules. Graphical Abstract An expeditious synthetic protocol of 2-aryl-4-phenyl-1H-imidazoles has been accomplished by reacting phenylglyoxal monohydrate, ammonium acetate, and diversely substituted aldehydes under sonication.