Recent Advances in Metal-Catalyzed Approaches for the Synthesis of Quinazoline Derivatives.

Quinazolines are an important class of heterocyclic compounds that have proven their significance, especially in the field of organic synthesis and medicinal chemistry because of their wide range of biological and pharmacological properties. Thus, numerous synthetic methods have been developed for the synthesis of quinazolines and their derivatives. This review article briefly outlines the new synthetic methods for compounds containing the quinazoline scaffold employing transition metal-catalyzed reactions.

Role of Glycation in Type 2 Diabetes Mellitus and Its Prevention through Nymphaea Species.

The dysregulation of glucose metabolism that includes the modification of biomolecules with the help of glycation reaction results in the formation of advanced glycation end products (AGEs). The formation of AGEs may activate receptors for advanced glycation end products which induce intracellular signaling, ultimately enhancing oxidative stress, a well-known contributor to type 2 diabetes mellitus. In addition, AGEs are possible therapeutic targets for the treatment of type 2 diabetes mellitus and its complications. This review article highlights the antioxidant, anti-inflammatory, and antidiabetic properties of the Nymphaea species, and the screening of such aquatic plants for antiglycation activity may provide a safer alternative to the adverse effects related to glucotoxicity. Since oxidation and glycation are relatively similar to each other, therefore, there is a possibility that the Nymphaea species may also have antiglycating properties because of its powerful antioxidant properties. Herbal products and their derivatives are the preeminent resources showing prominent medicinal properties for most of the chronic diseases including type 2 diabetes mellitus. Among these, the Nymphaea species has also shown elevated activity in scavenging free radicals. This species has a load of phytochemical constituents which shows various therapeutic and nutritional value including anti-inflammatory and antioxidant profiles. To the best of our knowledge, this is the first article highlighting the possibility of an antiglycation value of the Nymphaea species by inhibiting AGEs in mediation of type 2 diabetes mellitus. We hope that in the next few years, the clinical and therapeutic potential may be explored and highlight a better perspective on the Nymphaea species in the inhibition of AGEs and its associated diseases such as type 2 diabetes mellitus.

Exploration of artemisinin derivatives and synthetic peroxides in antimalarial drug discovery research.

Malaria is a life-threatening infectious disease caused by protozoal parasites belonging to the genus Plasmodium. It caused an estimated 405,000 deaths and 228 million malaria cases globally in 2018 as per the World Malaria Report released by World Health Organization (WHO) in 2019. Artemisinin (ART), a "Nobel medicine" and its derivatives have proven potential application in antimalarial drug discovery programs. In this review, antimalarial activity of the most active artemisinin derivatives modified at C-10/C-11/C-16/C-6 positions and synthetic peroxides (endoperoxides, 1,2,4-trioxolanes, 1,2,4-trioxanes, and 1,2,4,5-tetraoxanes) are systematically summarized. The developmental trend of ART derivatives, and cyclic peroxides along with their antimalarial activity and how the activity is affected by structural variations on different sites of the compounds are discussed. This compilation would be very useful towards scaffold hopping aimed at avoiding the unnecessary complexity in cyclic peroxides, and ultimately act as a handy resource for the development of potential chemotherapeutics against Plasmodium species.

Antimalarial application of quinones: A recent update.

Atovaquone belongs to a naphthoquinone class of drugs and is used in combination with proguanil (Malarone) for the treatment of acute, uncomplicated malaria caused by Plasmodium falciparum (including chloroquine-resistant P. falciparum/P. vivax). Numerous quinone-derived compounds have attracted considerable attention in the last few decades due to their potential in antimalarial drug discovery. Several semi-synthetic derivatives of natural quinones, synthetic quinones (naphtho-/benzo-quinone, anthraquinones, thiazinoquinones), and quinone-based hybrids were explored for their in vitro and in vivo antimalarial activities. A careful literature survey revealed that this topic has not been compiled as a review article so far. Therefore, we herein summarise the recent discovery (the year 2009-2020) of quinone based antimalarial compounds in chronological order. This compilation would be very useful towards the exploration of novel quinone-derived compounds against malarial parasites with promising efficacy and lesser side effects.

Metronidazole-conjugates: A comprehensive review of recent developments towards synthesis and medicinal perspective.

Nitroimidazoles based compounds remain a hot topic of research in medicinal chemistry due to their numerous biological activities. Moreover, many clinical candidates based on this chemical core have been reported to be valuable in the treatment of human diseases. Metronidazole (MTZ) derived conjugates demonstrated a potential application in medicinal chemistry research over the last decade. In this review, we summarize the synthesis, key structure-activity-relationship (SAR) and associated biological activities such as antimicrobial, anticancer, antidiabetic, anti-inflammatory, anti-HIV and anti-parasitic (Anti-trichomonas, antileishmanial, antiamoebic and anti-giardial) of explored MTZ-conjugates. The molecular docking analysis is also presented simultaneously, which will assist in developing an understanding towards designing of new MTZ-conjugates for target-based drug discovery against multiple disease areas.

Phenyliodine(III) Diacetate-Mediated 1,2-ipso-Migration in Mannich Bases of Imidazo[1,2-a]pyridines: Preparation of N-Acetoxymethyl/Alkoxymethyl-N-arylimidazo[1,2-a]pyridine-3-amines.

Phenyliodine(III) diacetate -mediated 1,2-ipso-migration of an imidazo[1,2-a]pyridine ring via the formation of an aziridine intermediate in Mannich bases derived from imidazo[1,2-a]pyridines, 2-pyridylamines or arylamines, and formaldehyde is reported. The imidazo[1,2-a]pyridines bearing different substituents showed excellent migratory aptitude and resulted in corresponding N-acetoxymethyl-, N-alkoxymethyl-, and N-hydroxymethyl-N-arylimidazo[1,2-a]pyridine-3-amine derivatives in moderate to excellent (42 examples; 35-93%) yields. Radical trapping experiments confirmed the involvement of a non-radical intermediate. The developed protocol is amenable for a scale-up reaction, and synthetic utility of N-acetoxymethyl products was demonstrated by transforming them to corresponding N-(pyridin-2-yl)imidazo[1,2-a]pyridin-3-amines.

Dual Role of Glyoxal in Metal-Free Dicarbonylation Reaction: Synthesis of Symmetrical and Unsymmetrical Dicarbonyl Imidazoheterocycles.

A practical and efficient method has been developed for the dicarbonylation of imidazoheterocycles using glyoxals as dicarbonyl precursors under metal-free conditions in acetic acid. A series of symmetrical and unsymmetrical dicarbonyl imidazoheterocycles was synthesized in good yields. Aryl and alkyl glyoxals also demonstrated excellent reactivity under similar reaction conditions and delivered corresponding dicarbonyl imidazoheterocycles in high yields. It is believed that the glyoxal plays a dual role both as a dicarbonyl source and as an oxidant in this transformation. A probable mechanistic pathway has been proposed based on control experiments and electrospray ionization high-resolution mass spectrometry analysis.

A straightforward TBHP-mediated synthesis of 2-amidobenzoic acids from 2-arylindoles and their antimicrobial activity.

A simple and highly efficient strategy has been developed for the synthesis of 2-amidobenzoic acids through the tert-butyl hydroperoxide (TBHP)-mediated oxygenation and sequential ring opening of 2-arylindoles in a one-pot fashion under metal-free aerobic conditions. The developed synthetic protocol is operationally simple, tolerates a wide range of functional groups, and is amenable to the gram-scale. Radical trapping experiments revealed that the reaction involves a radical pathway. The synthesized compounds (2a-s) were tested for in vitro antimicrobial activity. Among all screened compounds, 2d showed the maximum antibacterial activity against P. aerugunosa (ZOI = 17 mm, MIC = 32 µg mL-1) and compounds 2d and 2p showed the maximum (32 µg mL-1) antifungal activity against A. flavus and C. albicans.

Pyranocarbazole derivatives as potent anti-cancer agents triggering tubulin polymerization stabilization induced activation of caspase-dependent apoptosis and downregulation of Akt/mTOR in breast cancer cells.

A series of new pyranocarbazole derivatives were synthesized via semi-synthetic modification of koenimbine (1a) and koenidine (1b) isolated from the leaves of Murraya koenigii. Among all, compound 3bg displayed significant anti-cancer activity against MDA-MB-231, DU145 and PC3 cell lines with the IC50 values of 3.8, 7.6 and 5.8 µM, respectively. It was also observed that the halogenated-benzyl substitution at N-9 position, C-3 Methyl and C-7 methoxy group on carbazole motif are favoured for anti-cancer activity. The detailed investigation was carried out with compound 3bg and its SEDDS (self-emulsifying drug delivery systems) formulation 3bgF. The in vivo drug release behavior study showed that the formulation enhanced slow release and better bioavailability at a tumor site. Compound 3bg and its formulation (3bgF) significantly inhibited cell proliferation and colony formation, induced G2/M arrest, reduced cellular ROS generation and induced caspase-dependent apoptosis in MDA-MB-231 cells. 3bg also induced significant alteration of Bax/Bcl expression ratio suggesting involvement of mitochondrial apoptosis. Additionally, 3bg caused down-regulation of mTOR/Akt survival pathway. 3bg do not bind to DNA, but interacts with tubulin as observed with in silico molecular docking studies. This interaction results in stabilization of tubulin polymerization similar to paclitaxel as detected in cell-free assay. Oral administration of 3bgF for 30 days at dose rate of 10 and 20 mg/kg body weight significantly reduced tumor growth in syngenic rat LA-7 mammary tumor model. These results indicated that the pyranocarbazole natural product based N-substituted analogues can act as potential anti-cancer lead.

Metal-free synthesis of aminomethylated imidazoheterocycles: dual role of tert-butyl hydroperoxide as both an oxidant and a methylene source.

A novel and efficient aminomethylation approach has been developed for the regioselective functionalization of imidazoheterocycles under metal-free conditions. A wide range of imidazoheterocycles and 2/4-aminoazaheterocycles successfully provided corresponding aminomethylated imidazoheterocycles in moderate to excellent (33-80%) yields. The isotopic labelling study suggested that TBHP played a dual role as both an oxidant and a methylene source in this transformation. The developed protocol follows a radical pathway which is supported by radical trapping experiments.

Design and Synthesis of Imidazo/Benzimidazo[1,2-c]quinazoline Derivatives and Evaluation of Their Antimicrobial Activity.

A new class of fused quinazolines has been designed and synthesized via copper-catalyzed Ullmann type C-N coupling followed by intramolecular cross-dehydrogenative coupling reaction in moderate to good yields. The synthesized compounds were tested for in vitro antibacterial activity against three Gram negative (Escherichia coli, Pseudomonas putida, and Salmonella typhi) and two Gram positive (Bacillus subtilis, and Staphylococcus aureus) bacteria. Among all tested compounds, 8ga, 8gc, and 8gd exhibited promising minimum inhibitory concentration (MIC) values (4-8 µg/mL) for all bacterial strains tested as compared to the positive control ciprofloxacin. The synthesized compounds were also evaluated for their in vitro antifungal activity against Aspergillus niger and Candida albicans and compounds 8ga, 8gc, and 8gd having potential antibacterial activity also showed pronounced antifungal activity (MIC values 8-16 µg/mL) against both strains. The bactericidal assay by propidium iodide and live-dead bacterial cell screening using a mixture of acridine orange/ethidium bromide (AO/Et·Br) showed considerable changes in the bacterial cell membrane, which might be the cause or consequence of cell death. Moreover, the hemolytic activity for most potent compounds (8ga, 8gc, and 8gd) showed their safety profile toward human blood cells.

Anti-colon cancer activity of Murraya koenigii leaves is due to constituent murrayazoline and O-methylmurrayamine A induced mTOR/AKT downregulation and mitochondrial apoptosis.

In recent years, many alkaloids of plant origin have attracted great attention due to their diverse range of biological properties including anti-hyperglycemic, anti-oxidant, anti-inflammatory, anti-diabetic and anti-tumor activity. Herein, the pyranocarbazole alkaloids were isolated from leaves of Murraya koenigii and their anti-cancer potential was investigated in different cancer cell lines. Among all tested compounds, murrayazoline and O-methylmurrayamine A demonstrated potent anti-cancer activity against DLD-1 colon cancer cells with the IC50 values of 5.7µM and 17.9µM, respectively, without any non-specific cytotoxicity against non-cancer HEK-293 and HaCaT cells. Further, studies of pure compounds revealed that the anti-cancer activity of compounds corresponds with altered cellular morphology, cell cycle arrest in G2/M phase, reactive oxygen species level and mitochondrial membrane depolarization of colon cancer cells. In addition, these compounds activated caspase-3 protein and upregulated Bax/Bcl-2 protein expression ratio leading to induction of caspase-dependent apoptosis in DLD-1 cells. These event induced by carbazole alkaloids also coincides with downregulation of Akt/mTOR suggesting downstream targeting of cell survival pathway. Thus, our in vitro studies not only provided scientific basis of the use of M. koenigii leaves in the traditional Indian Ayurveda medicines, but also expands possibilities of medicinal uses of M. koenigii leaves against colon cancer. Particularly, these findings will help in further investigating murrayazoline and O-methylmurrayamine A or their improvised derivatives as new therapeutics for the treatment of colon cancer.

Antileishmanial Activity of Pyrazolopyridine Derivatives and Their Potential as an Adjunct Therapy with Miltefosine.

A series of pyrazolo(dihydro)pyridines was synthesized and evaluated for antileishmanial efficacy against experimental visceral leishmaniasis (VL). Among all compounds, 6d and 6j exhibited better activity than miltefosine against intracellular amastigotes. Compound 6j (50 mg/kg/day) was further studied against Leishmania donovani/BALB/c mice via the intraperitoneal route for 5 days and displayed >91 and >93% clearance of splenic and liver parasitic burden, respectively. Combination treatment of 6j with a subcurative dose of miltefosine (5 mg/kg) in BALB/c mice almost completely ameliorated the disease (>97% inhibition) by augmenting nitric oxide generation and shifting the immune response toward Th1. Furthermore, investigating the effect of 6j on Leishmania promastigotes revealed that it induced molecular events, such as a loss in mitochondrial membrane potential, externalization of phosphatidylserine, and DNA fragmentation, that ultimately resulted in the programmed cell death of the parasite. These results along with pharmacokinetic studies suggest that 6j could be a promising lead for treating VL as an adjunct therapy with miltefosine.

H2O2/DMSO-Promoted Regioselective Synthesis of 3,3'-Bisimidazopyridinylmethanes via Intermolecular Oxidative C(sp(2))-H Bond Activation of Imidazoheterocycles.

In the past decade, metal-free approaches for C-C bond formation have attracted a great deal of attention due to their ease of use and low cost. This report represents a novel and metal-free synthesis of 3,3'-bisimidazopyridinylmethanes via intermolecular oxidative C(sp(2))-H bond functionalization of imidazo[1,2-a]pyridines with dimethyl sulfoxide as the carbon synthon (CH2) using H2O2 as a mild oxidant under air. A library of 3,3'-bis(2-arylimidazo[1,2-a]pyridin-3-yl)methanes has been achieved in good to excellent yields. The present methodology has been successfully applied to imidazo[2,1-b]thiazoles and imidazo[2,1-b]benzothiazoles. Furthermore, the current approach was also extended for the synthesis of unsymmetrical 3,3'-bisimidazopyridinylmethanes under optimized reaction conditions. A mechanistic pathway is proposed on the basis of experiments with radical scavengers and DMSO-d6 and ESI-MS observations.

Naturally Occurring Carbazole Alkaloids from Murraya koenigii as Potential Antidiabetic Agents.

This study identified koenidine (4) as a metabolically stable antidiabetic compound, when evaluated in a rodent type 2 model (leptin receptor-deficient db/db mice), and showed a considerable reduction in the postprandial blood glucose profile with an improvement in insulin sensitivity. Biological studies were directed from the preliminary in vitro evaluation of the effects of isolated carbazole alkaloids (1-6) on glucose uptake and GLUT4 translocation in L6-GLUT4myc myotubes, followed by an investigation of their activity (2-5) in streptozotocin-induced diabetic rats. The effect of koenidine (4) on GLUT4 translocation was mediated by the AKT-dependent signaling pathway in L6-GLUT4myc myotubes. Moreover, in vivo pharmacokinetic studies of compounds 2 and 4 clearly showed that compound 4 was 2.7 times more bioavailable than compound 2, resulting in a superior in vivo efficacy. Therefore, these studies suggested that koenidine (4) may serve as a promising lead natural scaffold for managing insulin resistance and diabetes.

Substrate Controlled Synthesis of Benzisoxazole and Benzisothiazole Derivatives via PhI(OAc)2-Mediated Oxidation Followed by Intramolecular Oxidative O-N/S-N Bond Formation.

A phenyliodine(III) diacetate (PIDA)-mediated, highly efficient and tandem approach for the synthesis of aryldiazenylisoxazolo(isothiazolo)arenes from simple 2-amino-N'-arylbenzohydrazides has been developed. The reaction proceeds via formation of (E)-(2-aminoaryl)(aryldiazenyl)methanone as the key intermediate, followed by intramolecular oxidative O-N/S-N bond formation in one pot at room temperature. The quiet different reactivity of the substrate is due to the formation of a diazo intermediate which encounters a nucleophilic attack by carbonyl oxygen on the electrophilic amine to produce isoxazole products, as compared to the previous reportsa,b,4 in which an N-acylnitrenium ion intermediate is intramolecularly trapped by an amine group.