Benzofuran-indole heterobiaryls are important structural motifs with widespread applications. However, their synthesis is limited to methods requiring Pd catalysts and prefunctionalized substrates. Herein, we report the first general oxidative cross-coupling of benzofurans with indoles under aerobic, Fe(III)-catalyzed conditions with NaI as a catalytic promoter. The reaction displays wide substrate scope and high chemo- and regioselectivity. Preliminary mechanistic experiments indicate a single-electron-transfer (SET)-based mechanism with radical cation-nucleophile coupling as the crucial bond-forming step.

Herein, we report an elusive oxidative cross-coupling of pyrroles with furans and other heteroaryls under Earth-abundant, metal-catalyzed, partially aqueous aerial conditions while circumventing the polymerization of pyrroles.

Di(hetero)arylmethane represents a valuable chemical motif in natural products and pharmaceuticals. Bis(indolyl)methane is a valuable member of this class of compounds with diverse bioactivity profiles. Many other indolyl(heteroaryl)methane have also shown promising bioactivity, which necessitates development of expedient methods for the synthesis and biological evaluation of previously underexplored scaffolds. Herein, we report the development of a step-economical and highly practical synthesis of furyl(indolyl)methane using feedstock chemical DMSO as a C1 synthon under metal-free conditions. This methodology represents a significant advantage over the known methods, which use Au catalysts and highly functionalized substrates. The reaction conditions enabled excellent cross-selectivity through chemoselective activation of indole in the presence of highly nucleophilic furan. The reaction displayed excellent scope with the rare possibility to use completely unsubstituted indole as well as furan as viable substrates. Additionally, we also demonstrate two vital applications of the methodology─first, through direct functionalization of biomass-derived platform chemicals such as 2-methylfuran (2-MF) and furan and second, through the biological evaluation and disclosure of furyl(indolyl)methane as novel antiproliferative agents in a breast cancer cell line with comparable activity as compared to corresponding bis(indolyl)methanes.

Antimicrobial resistance is perceived as a silent pandemic with dire predictions for humanity. S. aureus and its methicillin- and vancomycin-resistant variants have been identified as some of the leading pathogens for deaths associated with resistance. The quest to discover novel agents against these pathogens has proven difficult. Compounds with novel chemotype and/or novel mechanism of action have been put forth as one of the innovation criteria. In search for novel chemotypes with potential bioactivity, Pseudo-Natural product hypothesis relies on designing hitherto unknown scaffolds by combining natural product fragments in a biologically pre-validated and synthetically tractable ways. Herein, we report the discovery of a novel antibacterial chemotype, derived from indotropane pseudo natural products, with potent activity against both susceptible and resistant strains of S. aureus. The hit compound, 7af possesses potent bactericidal nature, shows synergy with FDA-approved Gentamicin and doesn't induce resistance up to the 28th passage. It eradicates pre-formed biofilm by up to 5% and displays good in vivo efficacy in murine skin infection model. Despite the presence of nitro-group, 7af does not act as substrate of nitro-reductase enzyme in both S.aureus and M. smegmatis, thereby, hinting towards a different mechanism of action. Excellent structural features (sp3-rich, presence of H-bond donors and acceptors, polarity etc.) combined with a compelling antibacterial activity profile make 7af a validated lead compound for further development against resistant strains.

The Nazarov reaction and its variants such as aza-Nazarov and iso-Nazarov cyclizations are versatile methods for the synthesis of five-membered ring systems including pyrroles and indenes. The 1,2-Wagner Meerwein shift has been combined in a domino sequence with both Nazarov and aza-Nazarov-like reactions for the synthesis of cyclopentenone and indole derivatives, respectively. However, the same sequence has not been applied for the synthesis of pyrroles, possibly due to the high reactivity of 1-azapentadienyl cation intermediates. In this report, we present the first example of an aza-Nazarov/1,2-Wagner Meerwein shift domino sequence for the synthesis of highly substituted pyrroles. The use of Bi(iii) as a mild main group metal catalyst was found to be crucial to control the high reactivity of the intermediate. The substrate demonstrated substituent-dependent divergence in product formation to selectively give indenes through iso-Nazarov cyclization. Detailed mechanistic investigations reveal the electrocyclization nature of the reaction involving a cationic intermediate generated under Lewis acid and/or 'hidden Bronsted acid' catalysis conditions.

Catalytic oxidative cross-coupling has emerged as a vital tool for C-C bond formation. Herein, we disclose a hitherto unknown highly efficient catalytic oxidative cross-coupling of furans with 2-naphthols and 2,6-dihydroxynaphthalene using an earth-abundant Fe(III) catalyst. The methodology is characterized by exquisite chemoselectivity in oxidation, high cross-selectivity in coupling, excellent functional group tolerance, and a broad substrate scope. Mechanistic studies indicate chemoselective oxidation of naphthol in the presence of furan, despite their comparable oxidation potentials (ΔEox of 0.15 V).

An expeditious synthesis of indolyl-furans achieved through oxidative coupling of indoles with furans is reported. A few representative products show interesting photophysical properties with blue fluorescence and large Stokes shift.

Sustainability in chemical processes is a crucial aspect in contemporary chemistry with sustainable catalysis as a vital parameter of the same. There has been a renewed focus on utilizing earth-abundant metal catalysts to expand the repertoire of organic reactions. Furan is a versatile heterocycle of natural origin used for multiple applications. However, it has scarcely been used in cross-dehydrogenative coupling. In this work, we have explored the cross-dehydrogentive coupling of furans with indoles using commonly available, inexpensive FeCl3 & sdot; 6H(2)O (<0.25 $/g) as catalyst in the presence of so called 'ultimate oxidant' - oxygen, without the need for any external ligand or additive. The reactions were found to be scalable and to work even under partially aqueous conditions. This makes the reaction highly economical, practical, operationally simple and sustainable. The methodology provides direct access to pi-conjugated short oligomers consisting of furan, thiophene and indole. These compounds were found to show interesting fluorescence properties with remarkably large Stokes shift (up to 205 nm). Mechanistic investigations reveal that the reaction proceeds through chemoselective oxidation of indole by the metal catalyst followed by nucleophilic trapping by furan.

Deciphering the functional relevance of every protein is crucial to developing a better (patho)physiological understanding of human biology. The discovery and use of quality chemical probes propel exciting developments for developing drugs in therapeutic areas with unmet clinical needs. Myosin light-chain kinase (MLCK) serves as a possible therapeutic target in a plethora of diseases, including inflammatory diseases, cancer, etc. Recent years have seen a substantial increase in interest in exploring MLCK biology. However, there is only one widely used MLCK modulator, namely, ML-7, that too with a narrow working concentration window and high toxicity profile leading to limited insights. Herein, we report the identification of a potent and highly selective chemical probe, Myokinasib-II, from the synthesis and structure-activity relationship studies of a focused indotropane-based compound collection. Notably, it is structurally distinct from ML-7 and hence meets the need for an alternative inhibitor to study MLCK biology as per the recommended best practices. Moreover, our extensive benchmarking studies demonstrate that Myokinasib-II displays better potency, better selectivity profile, and no nonspecific interference in relevant assays as compared to other known MLCK inhibitors.

Highly arylated heteroarenes constitute an intriguing class of molecular scaffolds for material science applications. Among these, tetraarylated furans have demonstrated differentiated properties as compared to other similar heterocyclic cores. Among tetraarylated furans, the synthetic complexity increases drastically with increasing number of different peripheral aryl groups. There are only a very limited number of methodologies developed to access furans with four different (hetero)aryl substituents, none of which involve oxidative coupling on furan core. Herein, we report the first methodology based on a sequential two-fold oxidative C-C coupling of furans with indoles to access bis(indolyl)furans - a new class of tetra-(hetero)arylated furans with up to four different substituents. Moreover, the reaction is mediated by inexpensive, earth-abundant FeCl3.6H2O and displays wide substrate scope and aqueous compatibility. Through the characterization of the photophysical and electrochemical properties of this novel class of furans, we present the first validation of the extensively studied aggregation-caused quenching (ACQ) property of tetraarylated furans beyond phenyls as peripheral groups.

The COVID-19 pandemic ignited research centered around the identification of robust biomarkers and therapeutic targets. SARS-CoV-2, the virus responsible, hijacks the metabolic machinery of the host cells. It relies on lipids and lipoproteins of host cells for entry, trafficking, immune evasion, viral replication, and exocytosis. The infection causes host cell lipid metabolic remodelling. Targeting lipid-based processes is thus a promising strategy for countering COVID-19. Here, we review the role of lipids in the different steps of the SARS-CoV-2 pathogenesis and identify lipid-centric targetable avenues. We discuss lipidome changes in infected patients and their relevance as potential clinical diagnostic or prognostic biomarkers. We summarize the emerging direct and indirect therapeutic approaches for targeting COVID-19 using lipid-inspired approaches. Given that viral protein-targeted therapies may become less effective due to mutations in emerging SARS-CoV-2 variants, lipid-inspired interventions may provide additional and perhaps better means of combating this and future pandemics.

For the discovery of novel chemical matter generally endowed with bioactivity, strategies may be particularly efficient that combine previous insight about biological relevance, e.g., natural product (NP) structure, with methods that enable efficient coverage of chemical space, such as fragment-based design. We describe the de novo combination of different 5-membered NP-derived N-heteroatom fragments to structurally unprecedented "pseudo-natural products" in an efficient complexity-generating and enantioselective one-pot synthesis sequence. The pseudo-NPs inherit characteristic elements of NP structure but occupy areas of chemical space not covered by NP-derived chemotypes, and may have novel biological targets. Investigation of the pseudo-NPs in unbiased phenotypic assays and target identification led to the discovery of the first small-molecule ligand of the RHO GDP-dissociation inhibitor 1 (RHOGDI1), termed Rhonin. Rhonin inhibits the binding of the RHOGDI1 chaperone to GDP-bound RHO GTPases and alters the subcellular localization of RHO GTPases.

Infectious diseases remain significant health concerns worldwide, and resistance is particularly common in patients with tuberculosis caused by Mycobacterium tuberculosis. The development of anti-infectives with novel modes of action may help overcome resistance. In this regard, membrane-active agents, which modulate membrane components essential for the survival of pathogens, present attractive antimicrobial agents. Key advantages of membrane-active compounds include their ability to target slow-growing or dormant bacteria and their favorable pharmacokinetics. Here, we comprehensively review recent advances in the development of membrane-active chemotypes that target mycobacterial membranes and discuss clinically relevant membrane-active antibacterial agents that have shown promise in counteracting bacterial infections. We discuss the relationship between the membrane properties and the synthetic requirements within the chemical scaffold, as well as the limitations of current membrane-active chemotypes. This review will lay the chemical groundwork for the development of membrane-active antituberculosis agents and will foster the discovery of more effective antitubercular agents.

Heterobiaryls serve as relevant structural motifs in many fields of high applicative importance such as drugs, agrochemicals, organic functional materials etc. Cross-dehydrogenative coupling involving direct oxidation of two C-H bonds to construct a C-C bond is actively being pursued as a more benign and 'greener' alternative for synthesizing heterobiaryls. Herein, we report a Cu(I)-catalyzed cross-dehydrogenative coupling of indoles and furans, two of the most important aromatic heterocycles using air as the terminal oxidant. The reaction proceeds with regio- and chemoselectivity to give the cross-coupled products in good to excellent yields generally. A broad substrate scope with respect to both the coupling partners has been demonstrated to prove the generality of this reaction. This represents the hitherto unexplored cross-dehydrogenative coupling methodology to obtain an indole-furan biaryl motif.

The centrosome in animal cells is instrumental in spindle pole formation, nucleation, proper alignment of microtubules during cell division, and distribution of chromosomes in each daughter cell. Centrosome amplification involving structural and numerical abnormalities in the centrosome can cause chromosomal instability and dysregulation of the cell cycle, leading to cancer development and metastasis. However, disturbances caused by centrosome amplification can also limit cancer cell survival by activating mitotic checkpoints and promoting mitotic catastrophe. As a smart escape, cancer cells cluster their surplus of centrosomes into pseudo-bipolar spindles and progress through the cell cycle. This phenomenon, known as centrosome clustering (CC), involves many proteins and has garnered considerable attention as a specific cancer cell-targeting weapon. The kinesin-14 motor protein KIFC1 is a minus end-directed motor protein that is involved in CC. Because KIFC1 is upregulated in various cancers and modulates oncogenic signaling cascades, it has emerged as a potential chemotherapeutic target. Many molecules have been identified as KIFC1 inhibitors because of their centrosome declustering activity in cancer cells. Despite the ever-increasing literature in this field, there have been few efforts to review the progress. The current review aims to collate and present an in-depth analysis of known KIFC1 inhibitors and their biological activities. Additionally, we present computational docking data of putative KIFC1 inhibitors with their binding sites and binding affinities. This first-of-kind comparative analysis involving experimental biology, chemistry, and computational docking of different KIFC1 inhibitors may help guide decision-making in the selection and design of potent inhibitors.

Owing to its importance in various realms of chemistry, furan occupies a position of eminence among heterocycles. Despite the availability of many methodologies for the synthesis of variably substituted furans, a modular convenient synthesis of 2,4-disubstituted furans remains challenging. The present work attempts to bridge that gap through a novel annulation-based approach using feedstock chemicals such as methyl ketones and their easily available derivatives, β-bromoenol phosphates. We have demonstrated a hitherto unknown reactivity of β-bromoenol phosphates which is responsible for the observed regioselectivity. The reaction requires only sodium hydride as the base under mild conditions. The scope of the reaction was found to be broad with the possibility of obtaining even tri-substituted furans besides a variety of 2,4-disubstituted furans. The methodology was applied to obtain synthetically challenging 3-acylfuran derivatives as well. The newly developed methodology is characterized by the modularity, regioselectivity as well as its practicality owing to easily available starting materials and fast reaction times.

Mycobacterium species, including Mycobacterium tuberculosis, employs atypical long (C60-90) and branched lipids to produce a complex cell wall and localizes these toward distinct spatial locations, inner membrane (IM) and outer membrane (OM), thus forming a robust permeability barrier. The properties and functional roles of these spatially orchestrated membrane platforms remain unknown. Herein, we report the distinctive lateral organization, fluidity, and lipid domain architecture of protein-free membranes reconstituted from IM and OM lipids in vitro from M. smegmatis (Msm) underscored by their lipid packing and lipid dynamics. We show that Msm OM, against common notion, is more dynamic and fluid compared with IM and reveal the role of cell wall-associated peptidoglycans and lipoarabinomannan on the Msm OM organization. Overall, these studies indicate that mycobacterial species may regulate their overall membrane functionality by regulating the synthesis of these complex arrays of lipids. Based on the structure-function relationship drawn here, documented alteration in the mycobacterial lipidome during cellular infection and/or drug treatment could reflect a mechanism to fine-tune M. tuberculosis membrane properties to its advantage. These findings are expected to inspire development of lipid-centric therapeutic approaches targeted toward its membrane.

Tuberculosis (TB) remains one of the deadliest infectious diseases and begs the scientific community to up the ante for research and exploration of completely novel therapeutic avenues. Chemical biology-inspired design of tunable chemical tools has aided in clinical diagnosis, facilitated discovery of therapeutics, and begun to enable investigation of virulence mechanisms at the host-pathogen interface of Mycobacterium tuberculosis. This Perspective highlights chemical tools specific to mycobacterial proteins and the cell lipid envelope that have furnished rapid and selective diagnostic strategies and provided unprecedented insights into the function of the mycobacterial proteome and lipidome. We discuss chemical tools that have enabled elucidating otherwise intractable biological processes by leveraging the unique lipid and metabolite repertoire of mycobacterial species. Some of these probes represent exciting starting points with the potential to illuminate poorly understood aspects of mycobacterial pathogenesis, particularly the host membrane-pathogen interactions.

This chapter details the uses of copper(I)–phosphine complexes in enantioselective catalysis of selected important organic reactions. The reactions have been chosen based on the generality of application of this metal-ligand combination as well as the importance of the reactions. The first section covers the enantioselective conjugate addition reactions along with 1,2-addition as well as 1,6-addition reactions which utilize similar catalyst systems. This is followed by a description of relevant asymmetric allylic alkylation reactions. In the next section, important transformations catalyzed by chiral copper–hydride complexes, such as conjugate reduction, hydroamination, etc. are described. The following section encompasses developments in the area of enantioselective 1,3-dipolar cycloaddition and nitroso Diels–Alder reactions. In the final section, enantioselective addition of copper acetylides to iminium ions as well as preparation of chiral propargyl amines through enantioselective nucleophilic substitution are documented. In each section, the focus is on detailing the recent developments with a limited account of the historical perspective.

Small-molecule chemotypes with unexpected bioactivity may be identified by combining strategies built on the biological relevance of, e.g., natural products (NPs), such as biology-oriented synthesis, with principles that enable efficient coverage of chemical space, such as fragment-based compound design. Evaluation in target-agnostic phenotypic assays and target identification may link biologically relevant chemotypes to unexpected and unknown targets. We describe the phenotypic identification of an unprecedented kinase inhibitor chemotype obtained by synthetic combination of two biosynthetically unrelated NP fragment types. Target identification and biological characterization revealed that the inhibitor, termed Myokinasib, impairs cytokinesis, induces formation of multinucleated cells, and reduces phosphorylated myosin II light chain abundance on stress fibers by selective inhibition of myosin light chain kinase 1.