Titanium-Catalyzed Selective N-Alkylation of Amines with Alcohols via Borrowing Hydrogen Methodology.

The N-alkylation of amines with alcohols using earth-abundant and nonprecious metal catalysts has gained considerable attention in the pharmaceutical industry. We described titanium-catalyzed synthetic protocol for N-alkylation of amines with alcohols via borrowing hydrogen or hydrogen autotransfer reactions. The methodology enables the selective monoalkylation of various substituted (hetero)aromatic amines in good to excellent yields (up to 97% yield). The importance of the protocol was further demonstrated by the applicability of earth-abundant metal catalysis and the synthesis of 32 N-alkylated amines. The work allows the utilization of titanium-based catalysts for various reactions to expand the nature blueprint in catalysis.

Heterogeneous V2O5/TiO2-Mediated Photocatalytic Reduction of Nitro Compounds to the Corresponding Amines under Visible Light.

The hydrogenation of nitro compounds to their corresponding amines is developed using a heterogeneous and recyclable catalyst (V2O5/TiO2) under irradiation of blue LED (9 W) at ambient temperature. Hydrazine hydrate is used as a reductant and ethanol is used as a solvent, facilitating green, sustainable, low-cost production. The synthesis of 32 (hetero)arylamines and their pharmaceutically relevant molecules (five) are described. Significant features of the protocol include catalyst recyclability, green solvent, ambient temperature, and gram-scale reactions. Among the other aspects studied are 1H-NMR-assisted reaction progress monitoring, control experiments for mechanistic studies, protocol applications, and recyclability studies. Furthermore, the developed protocol enabled wide functional group tolerance, chemo-selectivity, high yield, and low-cost, sustainable, and environmentally benign synthesis.

Synthesis of novel ciprofloxacin-avibactam conjugates for the development of second-generation non-ß-lactam-ß-lactamase inhibitors.

To overcome the antibiotic resistance challenge, we synthesized a novel class of conjugates based on ciprofloxacin and avibactam, covalently linked by diverse amino acids. In vitro studies of these conjugates have shown improved antibacterial efficacy of avibactam when used alone against some ESKAPE pathogens, i.e., S. aureus, E. coli, and A. baumannii. Further, ceftazidime was screened in combination with all conjugates and found to be less synergistically effective than avibactam-ceftazidime co-dosing against K. pneumoniae and E. coli bacterial strains. Subsequently, the top-ranked active conjugates were investigated against the commercially available ß-lactamase-II (Penicillinase from Bacillus cereus) through in vitro studies. These studies elucidated two conjugates i.e, 9 (IC50 = 1.69±0.35 nM) and 24b (IC50 = 57.37±5.39 nM), which have higher inhibition profile than avibactam (IC50 = 141.08±12.20 nM). These outcomes allude to avibactam integration with ciprofloxacin is a novel and fruitful approach to discovering clinically valuable next-generation non-ß-lactam-ß-lactamase inhibitors.

Recent progress in the homogeneous gold-catalysed cycloisomerisation reactions.

In the last two decades, interest in reactions catalysed by gold complexes has tremendously increased due to their ability to tolerate a variety of functional groups and their capability to activate various unsaturated groups. In this review, gold-catalysed cycloisomerisation reactions of ynamides, diynes and 1,n-enynes have been summarized. These gold-catalysed cycloisomerisation reactions open new opportunities for synthesising a range of new complex polycyclic chemical moieties in one step. Gold-catalysed cycloisomerisation is a valuable way for synthesising fused spiro carbocycles, BODIPY cores, bicyclo[3.2.1]oct-2-ene, dihydro benzo[b]thiepine, disubstituted furans, spiroindolines, bridged [n.2.1] skeletons, etc.

Mechanistic studies on polyphenol rich fractions of Kangra tea by HPTLC and NMR for their antioxidant activities.

Abstract: The antioxidant activity in tea is largely driven by its polyphenolic content, however, the antioxidant reaction mechanism and the compounds involved are not well characterized. Therefore, in this study, we performed in-depth profiling of the antioxidant reaction mechanism of Green Tea (GT), Black Tea (BT), and their polyphenolic fractions with free radical using state-of-the-art analytical techniques. The polyphenol enriched fractions from GT and BT were isolated using column chromatography. Catechins were isolated and characterized by diverse spectroscopic techniques. Samples were screened for their antioxidant activity by HPTLC and further evaluated using a spectrophotometer. The free radical reactions with GT, BT, enriched fractions viz, GT Polyphenols (GTP), BT Polyphenols (BTP), and isolated catechins were studied using the 13C NMR technique. The highest polyphenol content was found in GTP (795.4 ± 0.012 mg/g) whereas GT (321.0 ± 0.028 mg/g) showed maximum flavonoids content. Individual catechins isolated from GTP were EGCG, ECG, EGC, EC and C. Antioxidant activity followed the order EGCG > ECG > EGC > EC > GTP > C > BTP > GT > BT. In GT, the antioxidant reaction mechanism showed single electron and H-transfer in all catechins, which involved the transformation of the hydroxyl group to the carbonyl group. Whereas in BT theaflavins, conversion of the benzotropolone ring to the six-membered ring was observed. Supplementary Information: The online version contains supplementary material available at 10.1007/s13197-021-05297-w.

Tridecaptin M, a New Variant Discovered in Mud Bacterium, Shows Activity against Colistin- and Extremely Drug-Resistant Enterobacteriaceae.

The World Health Organization has categorized the Gram-negative superbugs, which are inherently impervious to many antibiotics, as critical priority pathogens due to the lack of effective treatments. The breach in our last-resort antibiotic (i.e., colistin) by extensively drug-resistant and pan-drug-resistant Enterobacteriaceae strains demands the immediate development of new therapies. In the present study, we report the discovery of tridecaptin M, a new addition to the family, and its potential against colistin-resistant Enterobacteriaceae in vitro and in vivo Also, we performed mode-of-action studies using various fluorescent probes and studied the hemolytic activity and mammalian cytotoxicity in two cell lines. Tridecaptin M displayed strong antibacterial activity (MICs of 2 to 8 µg ml-1) against clinical strains of Klebsiella pneumoniae (which were resistant to colistin, carbapenems, third- and fourth-generation cephalosporins, fluoroquinolones, fosfomycin, and other antibiotics) and mcr-1-positive Escherichia coli strains. Unlike polymyxins, tridecaptin M did not permeabilize the outer membrane or cytoplasmic membrane. It blocked ATP synthesis in bacteria by dissipating the proton motive force. The compound exhibited negligible acquired resistance, low in vitro cytotoxicity and hemolytic activity, and no significant acute toxicity in mice. It also showed promising efficacy in a thigh infection model of colistin-resistant K. pneumoniae Altogether, these results demonstrate the future prospects of this class of antibiotics to address the unmet medical need to circumvent colistin resistance in extensively drug-resistant Enterobacteriaceae infections. The work also emphasizes the importance of natural products in our shrunken drug discovery pipeline.

An eco-compatible strategy for the diversity-oriented synthesis of macrocycles exploiting carbohydrate-derived building blocks.

An efficient, eco-compatible diversity-oriented synthesis (DOS) approach for the generation of library of sugar embedded macrocyclic compounds with various ring size containing 1,2,3-triazole has been developed. This concise strategy involves the iterative use of readily available sugar-derived alkyne/azide-alkene building blocks coupled through copper catalyzed azide-alkyne cycloaddition (CuAAC) reaction followed by pairing of the linear cyclo-adduct using greener reaction conditions. The eco-compatibility, mild reaction conditions, greener solvents, easy purification and avoidance of hazards and toxic solvents are advantages of this protocol to access this important structural class. The diversity of the macrocycles synthesized (in total we have synthesized 13 macrocycles) using a set of standard reaction protocols demonstrate the potential of the new eco-compatible approach for the macrocyclic library generation.

Synthesis of skeletally diverse alkaloid-like molecules: exploitation of metathesis substrates assembled from triplets of building blocks.

A range of metathesis substrates was assembled from triplets of unsaturated building blocks. The approach involved the iterative attachment of a propagating and a terminating building block to a fluorous-tagged initiating building block. Metathesis cascade chemistry was used to "reprogram" the molecular scaffolds. Remarkably, in one case, a cyclopropanation reaction competed with the expected metathesis cascade process. Finally, it was demonstrated that the metathesis products could be derivatised to yield the final products. At each stage, purification was facilitated by the presence of a fluorous-tagged protecting group.

Novel 3-Methyleneisoindolinones Diversified via Intramolecular Heck Cyclization Induce Oxidative Stress, Decrease Mitochondrial Membrane Potential, Disrupt Cell Cycle, and Induce Apoptosis in Head and Neck Squamous Cell Carcinoma Cells.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer in the world and the most prevalent cancer of developing countries. Increased disease burden and a smaller number of approved targeted therapies are a growing concern worldwide. Isoindolinone motifs have been a central part of many pharmacological compounds, and their derivatives possess substantial anticancer potential. However, their anticancer potential against HNSCC has not been well investigated. In the current study, a series of 3-methyleneisoindolinones have been designed and synthesized and their late-stage intramolecular Heck cyclization was achieved to evaluate their anticancer potential against HNSCC cells. Additionally, in silico ADME profiling of synthesized compounds revealed their drug-likeness properties as potential drug candidates. Among the synthesized compounds, 3-bromo-5-methylpyridin-2-yl-3-methyleneisoindolin-1-one, i.e., 3n, with a pyridyl unit exhibited the most significant cytotoxicity against HNSCC cells. The cytotoxic potential of synthesized compounds varied depending on the nature of substituents present and has been well established with structure-activity relationship studies. Further, flow cytometric analysis showed that 3f, 3h, and 3n triggered intracellular oxidative stress, disrupted mitochondrial membrane potential, and interrupted the cell cycle of HNSCC cells in the S-phase and sub-G1 phase. Further, 3f, 3h, and 3n also exhibited pro-apoptotic potential and induced cellular apoptosis in the HNSCC cells. Overall, the findings of this study attributed 3-methyleneisoindolinone chemistry and efficacy evaluation and corroborated their anticancer potential against HNSCC. It will pave the way to further design and optimize novel 3-methyleneisoindolinone as effective antitumor agents, which may provide effective treatment modalities against HNSCC.

Recent Advances in the Discovery of Potent Proteases Inhibitors Targeting the SARS Coronaviruses.

Across the globe, countries are being challenged by the SARS-CoV-2 (COVID-19) pandemic in ways they have never been before. The global outbreak of SARS-CoV-2 with an uncertain fatality rate has imposed extreme challenges on global health. The World Health Organization (WHO) has officially declared the outbreak of COVID-19 a pandemic, after the disease caused by the new coronavirus spread to more than 100 countries. To date, various therapeutic approaches have been proposed and are being implemented to combat this pandemic, but unfortunately, no sovereign remedy has been established yet. Protease enzymes are important targets to develop therapies for the treatment of infections caused by SARS coronaviruses. In this review, an overview is given on recent advances in the discovery of potent protease inhibitors targeting the SARS coronaviruses. Different classes of natural product inhibitors targeting protease enzymes of SARS coronaviruses have been studied in detail along with their structure-activity relationship analysis. This study emphasized important covalent and non-covalent small molecule inhibitors, which effectively inhibited chymotrypsin- like cysteine protease (3CLpro) and papain-like protease (PLpro) of two SARS coronaviruses, i.e., SARS-CoV-1 and SARS-CoV-2. Repurposing of drugs has also been outlined in this study to understand their roles as quick-to-be-identified therapy to combat these zoonotic coronaviruses.

Recent advances in the discovery of potent RNA-dependent RNA-polymerase (RdRp) inhibitors targeting viruses.

WHO has declared COVID-19 a pandemic, which has affected the whole world and has caused unprecedented social and economic disruption. Since the emergence of the disease, several druggable targets have been suggested including 3-chymotrypsin-like protease (3CLpro), spike, RNA-dependent RNA polymerase (RdRp), and the papain-like protease (PLpro) computational approach. From the beginning, viral replication has been the main focus for any antiviral drug development for viral diseases, including HCV, influenza virus, zika virus, norovirus, measles, dengue virus, and coronaviruses. This review lists the nucleoside, nucleotide, and non-nucleoside RdRp inhibitor analogues of various viral diseases that may be evaluated for drug development to treat COVID-19.

Synthesis of Macrocyclic Lactones and Dilactones Using Olive Oil.

Macrocyclic lactones have redolent characteristics of muscones that originate from the rectal musk organs of the musk deer. These lactones are the primary raw material in the flavor and fragrance industry and are also found within the cyclic frameworks of various bioactive molecules. Due to great demand, many efforts have been made for their synthesis; however, strategies generating a large number of macrocyclic analogues from renewable resources have not been fully realized and are urgently required. Here, we outline a sustainable, straightforward, and eco-friendly approach to synthesize high-valued macrocyclic lactones utilizing olive oil under greener reaction conditions. The outlined method allows us to turn biomass into valuable 12- to 29-membered lactones and dilactones.

Heterogeneous vanadium-catalyzed oxidative cleavage of olefins for sustainable synthesis of carboxylic acids.

The development of green and sustainable processes to synthesize active pharmaceutical ingredients and key starting materials is a priority for the pharmaceutical industry. A green and sustainable protocol for the oxidative cleavage of olefins to produce pharmaceutically and biologically valuable carboxylic acids is achieved. The developed protocol involves 70% aq. TBHP as an oxidant over a heterogeneous vanadium catalyst system. Notably, the synthesis of industrially important azelaic acid from various renewable vegetable oils is accomplished. The catalyst could be recycled for up to 5 cycles without significant loss in yield and the protocol was successfully demonstrated at the gram-scale.

Synthesis of Bioactive Complex Small Molecule-Ciprofloxacin Conjugates and Evaluation of Their Antibacterial Activity.

Conjugates between pharmaceuticals and small molecules enable access to a vast chemical space required for the discovery of new lead molecules with modified therapeutic potential. However, the dearth of specific chemical reactions that are capable of functionalizing drugs and bioactive natural products presents a formidable challenge for preparing their conjugates. Here, we report a support-free CuI-nanoparticle-catalyzed strategy for conjugating electron-deficient and electron-rich terminal alkynes with a ciprofloxacin methyl ester. Our conjugation technique exploits the late-stage functionalization of bioactive natural products such as tocopherol, vasicinone, amino acids, and pharmaceuticals such as aspirin and paracetamol to provide conjugates in excellent yields under mild and green conditions. This protocol also enabled the synthesis of (hetero)arene-ciprofloxacin 1,4-disubstituted 1,2,3-triazoles in good yields and high regioselectivities. These synthesized ciprofloxacin conjugates were evaluated in vitro for their antibacterial activity against a panel of relevant bacteria. A significant number of conjugates showed comparable activity against Gram-positive and Gram-negative bacteria. Moreover, some conjugates exhibited less toxicity than ciprofloxacin against two mammalian cell lines, suggesting the utility for the future investigation of these compounds for in vivo efficacy and pharmacokinetic studies.

Formic Acid-Driven Rapid and Green Anti-Markovnikov Hydrothiolation of Styrenes.

A novel formic acid-assisted rapid and efficient route for C-S bond construction via the thiol-ene reaction has been reported. Exclusively, the anti-Markovnikov product was obtained in good to excellent yield using the developed protocol. Various styrenes and thiols bearing different functionalities were well tolerated. The reaction also provided a good yield of sulfones in a one-pot two-step protocol. The developed method is operationally simple, green, metal-free, solvent-free, and having a high atom economy with high regioselectivity.

2-Aminoquinazolin-4(3H)-one as an Organocatalyst for the Synthesis of Tertiary Amines.

The potential of 2-aminoquinazolin-4(3H)-one as an organocatalyst for the activation of aldehydes via noncovalent interaction for the synthesis of tertiary amines using formic acid as a reducing agent is reported for the first time. The developed protocol demonstrated a dilated substrate scope for aromatic and aliphatic amines with aromatic and aliphatic aldehydes. Furthermore, the current method was also fruitful for the derivatization of ciprofloxacin and its derivative in good to excellent yields.

A screening pipeline for antiparasitic agents targeting cryptosporidium inosine monophosphate dehydrogenase.

BACKGROUND: The protozoan parasite Cryptosporidium parvum is responsible for significant disease burden among children in developing countries. In addition Cryptosporidiosis can result in chronic and life-threatening enteritis in AIDS patients, and the currently available drugs lack efficacy in treating these severe conditions. The discovery and development of novel anti-cryptosporidial therapeutics has been hampered by the poor experimental tractability of this pathogen. While the genome sequencing effort has identified several intriguing new targets including a unique inosine monophosphate dehydrogenase (IMPDH), pursuing these targets and testing inhibitors has been frustratingly difficult. METHODOLOGY AND PRINCIPAL FINDINGS: Here we have developed a pipeline of tools to accelerate the in vivo screening of inhibitors of C. parvum IMPDH. We have genetically engineered the related parasite Toxoplasma gondii to serve as a model of C. parvum infection as the first screen. This assay provides crucial target validation and a large signal window that is currently not possible in assays involving C. parvum. To further develop compounds that pass this first filter, we established a fluorescence-based assay of host cell proliferation, and a C. parvum growth assay that utilizes automated high-content imaging analysis for enhanced throughput. CONCLUSIONS AND SIGNIFICANCE: We have used these assays to evaluate C. parvum IMPDH inhibitors emerging from our ongoing medicinal chemistry effort and have identified a subset of 1,2,3-triazole ethers that exhibit excellent in vivo selectivity in the T. gondii model and improved anti-cryptosporidial activity.

Triazole inhibitors of Cryptosporidium parvum inosine 5'-monophosphate dehydrogenase.

Cryptosporidium parvum is an important human pathogen and potential bioterrorism agent. This protozoan parasite cannot salvage guanine or guanosine and therefore relies on inosine 5'-monophosphate dehydrogenase (IMPDH) for biosynthesis of guanine nucleotides and hence for survival. Because C. parvum IMPDH is highly divergent from the host counterpart, selective inhibitors could potentially be used to treat cryptosporidiosis with minimal effects on its mammalian host. A series of 1,2,3-triazole containing ether CpIMPDH inhibitors are described. A structure-activity relationship study revealed that a small alkyl group on the alpha-position of the ether was required, with the (R)-enantiomer significantly more active than the (S)-enantiomer. Electron-withdrawing groups in the 3- and/or 4-positions of the pendent phenyl ring were best, and conversion of the quinoline containing inhibitors to quinoline-N-oxides retained inhibitory activity both in the presence and absence of bovine serum albumin. The 1,2,3-triazole CpIMPDH inhibitors provide new tools for elucidating the role of IMPDH in C. parvum and may serve as potential therapeutics for treating cryptosporidiosis.