Indoloquinoline Alkaloids as Antimalarials: Advances, Challenges, and Opportunities.

Malaria infections affect almost half of the world's population, with over 200 million cases reported annually. Cryptolepis sanguinolenta, a plant native to West Africa, has long been used across various regions of Africa for malaria treatment. Chemical analysis has revealed that the plant is abundant in indoloquinolines, which have been shown to possess antimalarial properties. Cryptolepine, neocryptolepine, and isocryptolepine are well-studied indoloquinoline alkaloids known for their potent antimalarial activity. However, their structural rigidity and associated cellular toxicity are major drawbacks for preclinical development. This review focuses on the potential of indoloquinoline alkaloids (cryptolepine, neocryptolepine, and isocryptolepine) as scaffolds in drug discovery. The article delves into their antimalarial effects in vitro and in vivo, as well as their proposed mechanisms of action and structure-activity relationship studies. Several studies aim to improve these leads by reducing cytotoxicity while preserving or enhancing antimalarial activity and gaining insights into their mechanisms of action. These investigations highlight the potential of indoloquinolines as a scaffold for developing new antimalarial drugs.

Porous Organic Polymers for Efficient and Selective SO2 Capture from CO2-rich Flue Gas.

The quest for effective technologies to reduce SO2 pollution is crucial due to its adverse effects on the environment and human health. Markedly, removing a ppm level of SO2 from CO2-containing waste gas is a persistent challenge, and current technologies suffer from low SO2/CO2 selectivity and energy-intensive regeneration processes. Here using the molecular building blocks approach and theoretical calculation, we constructed two porous organic polymers (POPs) encompassing pocket-like structures with exposed imidazole groups, promoting preferential interactions with SO2 from CO2-containing streams. Markedly, the evaluated POPs offer outstanding SO2/CO2 selectivity, high SO2 capacity, and an easy regeneration process, making it one of the best materials for SO2 capture. To gain better structural insights into the notable SO2 selectivity of the POPs, we used dynamic nuclear polarization NMR spectroscopy (DNP) and molecular modelling to probe the interactions between SO2 and POP adsorbents. The newly developed materials are poised to offer an energy-efficient and environment-friendly SO2 separation process while we are obliged to use fossil fuels for our energy needs.

Rare Earth alb-MOFs: From Synthesis to Their Deployment for Amine-Sensing Application in Aqueous Media.

The pursuit of developing sensors, characterized by their fluorescence-intensity enhancement or "turn-on" behavior, for accurately detecting noxious small molecules, such as amines, at minimal levels remains a significant challenge. Metal-organic frameworks (MOFs) have emerged as promising candidates as sensors as a result of their diverse structural features and tunable properties. This study introduces the rational synthesis of a new highly coordinated (6,12)-connected rare earth (RE) alb-MOF-3, by combining the nonanuclear 12-connected hexagonal prismatic building units, [RE9(µ3-O)2(µ3-X)12(OH)2(H2O)7(O2C-)12], with the 6-connected rigid trigonal prismatic extended triptycene ligand. The resulting Y-alb-MOF-3 material is distinguished by its high microporosity and Brunauer-Emmett-Teller surface area of approximately 1282 m2/g, which offers notable hydrolytic stability. Remarkably, it demonstrates selective detection capabilities for primary aliphatic amines in aqueous media, as evidenced by fluorescence turn-on behavior and photoluminescence (PL) titration measurements. This work emphasizes the potential of MOFs as sensors in advancing their selectivity and sensitivity toward various analytes.

In Vitro Antimalarial Activity of Trichothecenes against Liver and Blood Stages of Plasmodium Species.

Trichothecenes (TCNs) are a large group of tricyclic sesquiterpenoid mycotoxins that have intriguing structural features and remarkable biological activities. Herein, we focused on three TCNs (anguidine, verrucarin A, and verrucarol) and their ability to target both the blood and liver stages of Plasmodium species, the parasite responsible for malaria. Anguidine and verrucarin A were found to be highly effective against the blood and liver stages of malaria, while verrucarol had no effect at the highest concentration tested. However, these compounds were also found to be cytotoxic and, thus, not selective, making them unsuitable for drug development. Nonetheless, they could be useful as chemical probes for protein synthesis inhibitors due to their direct impact on parasite synthesis processes.

Shotgun Kinetic Target-Guided Synthesis Approach Enables the Discovery of Small-Molecule Inhibitors against Pathogenic Free-Living Amoeba Glucokinases.

Pathogenic free-living amoebae (pFLA) can cause life-threatening central nervous system (CNS) infections and warrant the investigation of new chemical agents to combat the rise of infection from these pathogens. Naegleria fowleri glucokinase (NfGlck), a key metabolic enzyme involved in generating glucose-6-phosphate, was previously identified as a potential target due to its limited sequence similarity with human Glck (HsGlck). Herein, we used our previously demonstrated multifragment kinetic target-guided synthesis (KTGS) screening strategy to identify inhibitors against pFLA glucokinases. Unlike the majority of previous KTGS reports, our current study implements a "shotgun" approach, where fragments were not biased by predetermined binding potentials. The study resulted in the identification of 12 inhibitors against 3 pFLA glucokinase enzymes─NfGlck, Balamuthia mandrillaris Glck (BmGlck), and Acanthamoeba castellanii Glck (AcGlck). This work demonstrates the utility of KTGS to identify small-molecule binders for biological targets where resolved X-ray crystal structures are not readily accessible.

Going beyond Binary: Rapid Identification of Protein-Protein Interaction Modulators Using a Multifragment Kinetic Target-Guided Synthesis Approach.

Kinetic target-guided synthesis (KTGS) is a powerful screening approach that enables identification of small molecule modulators for biomolecules. While many KTGS variants have emerged, a majority of the examples suffer from limited throughput and a poor signal/noise ratio, hampering reliable hit detection. Herein, we present our optimized multifragment KTGS screening strategy that tackles these limitations. This approach utilizes selected reaction monitoring liquid chromatography tandem mass spectrometry for hit detection, enabling the incubation of 190 fragment combinations per screening well. Consequentially, our fragment library was expanded from 81 possible combinations to 1710, representing the largest KTGS screening library assembled to date. The expanded library was screened against Mcl-1, leading to the discovery of 24 inhibitors. This work unveils the true potential of KTGS with respect to the rapid and reliable identification of hits, further highlighting its utility as a complement to the existing repertoire of screening methods used in drug discovery.

A Tailored COF for Visible-Light Photosynthesis of 2,3-Dihydrobenzofurans.

Heterogeneous photocatalysis is considered as an ecofriendly and sustainable approach for addressing energy and environmental persisting issues. Recently, heterogeneous photocatalysts based on covalent organic frameworks (COFs) have gained considerable attention due to their remarkable performance and recyclability in photocatalytic organic transformations, offering a prospective alternative to homogeneous photocatalysts based on precious metal/organic dyes. Herein, we report Hex-Aza-COF-3 as a metal-free, visible-light-activated, and reusable heterogeneous photocatalyst for the synthesis of 2,3-dihydrobenzofurans, as a pharmaceutically relevant structural motif, via the selective oxidative [3+2] cycloaddition of phenols with olefins. Moreover, we demonstrate the synthesis of natural products (±)-conocarpan and (±)-pterocarpin via the [3+2] cycloaddition reaction as an important step using Hex-Aza-COF-3 as a heterogeneous photocatalyst. Interestingly, the presence of phenazine and hexaazatriphenylene as rigid heterocyclic units in Hex-Aza-COF-3 strengthens the covalent linkages, enhances the absorption in the visible region, and narrows the energy band, leading to excellent activity, charge transport, stability, and recyclability in photocatalytic reactions, as evident from theoretical calculations and real-time information on ultrafast spectroscopic measurements.

Structure-activity and structure-property relationship studies of spirocyclic chromanes with antimalarial activity.

Malaria is a prevalent and lethal disease. The fast emergence and spread of resistance to current therapies is a major concern and the development of a novel line of therapy that could overcome, the problem of drug resistance, is imperative. Screening of a set of compounds with drug/natural product-based sub-structural motifs led to the identification of spirocyclic chroman-4-one 1 with promising antimalarial activity against the chloroquine-resistant Dd2 and chloroquine-sensitive 3D7 strains of the parasite. Extensive structure-activity and structure-property relationship studies were conducted to identify the essential features necessary for its activity and properties.

Total synthesis of (±)-decursivine via BINOL-phosphoric acid catalyzed tandem oxidative cyclization.

The synthesis of tetracyclic indole alkaloid (±)-decursivine was accomplished using BINOL-phosphoric acid catalyzed tandem oxidative cyclization as a key step with (bis(trifluoroacetoxy)iodo)benzene (PIFA) as an oxidizing agent. This represents one of the shortest and highest yielding routes for the synthesis of (±)-decursivine from readily available starting materials.

Design, synthesis, and functional evaluation of triazine-based bivalent agents that simultaneously target the active site and hot spot of phosphatase Cdc25B.

Cdc25B phosphatase catalyzes the dephosphorylation and activation of cyclin-dependent kinases 2 (CDK2/CycA) and their overexpression has been reported in cancers. Although Cdc25B has received much attention as a drug target, its flat and featureless surface makes it challenging to develop new agents targeting this protein. In this study, we investigated the rational design of a series of bivalent triazine-based derivatives with the aim of simultaneously targeting the active site and the remote hotspot critical for the interaction with CDK2/CycA. Compounds 1e and 10, containing aromatic residues, were shown to inhibit Cdc25B activity selectively over Cdc25A at low micromolar concentration.

Aminoalkoxycarbonyloxymethyl Ether Prodrugs with a pH-Triggered Release Mechanism: A Case Study Improving the Solubility, Bioavailability, and Efficacy of Antimalarial 4(1H)-Quinolones with Single Dose Cures.

Preclinical and clinical development of numerous small molecules is prevented by their poor aqueous solubility, limited absorption, and oral bioavailability. Herein, we disclose a general prodrug approach that converts promising lead compounds into aminoalkoxycarbonyloxymethyl (amino AOCOM) ether-substituted analogues that display significantly improved aqueous solubility and enhanced oral bioavailability, restoring key requirements typical for drug candidate profiles. The prodrug is completely independent of biotransformations and animal-independent because it becomes an active compound via a pH-triggered intramolecular cyclization-elimination reaction. As a proof-of-concept, the utility of this novel amino AOCOM ether prodrug approach was demonstrated on an antimalarial compound series representing a variety of antimalarial 4(1H)-quinolones, which entered and failed preclinical development over the last decade. With the amino AOCOM ether prodrug moiety, the 3-aryl-4(1H)-quinolone preclinical candidate was shown to provide single-dose cures in a rodent malaria model at an oral dose of 3 mg/kg, without the use of an advanced formulation technique.

Introducing a Cantellation Strategy for the Design of Mesoporous Zeolite-like Metal-Organic Frameworks: Zr-sod-ZMOFs as a Case Study.

Herein we report novel mesoporous zirconium-based metal-organic frameworks (MOFs) with zeolitic sodalite (sod) topology. Zr-sod-ZMOF-1 and -2 are constructed based on a novel cantellation design strategy. Distinctly, organic linkers are judiciously designed in order to promote the deployment of the 12-coordinated Zr hexanuclear molecular building block (MBB) as a tetrahedral secondary building unit, a prerequisite for zeolite-like nets. The resultant Zr-sod-ZMOFs exhibit mesopores with a diameter up to ≈43 Å, while the pore volume of 1.98 cm3·g-1 measured for Zr-sod-ZMOF-1 is the highest reported experimental value for zeolite-like MOFs based on MBBs as tetrahedral nodes.

A Guanidyl-Based Bivalent Peptidomimetic Inhibits K-Ras Prenylation and Association with c-Raf.

Unusual lipid modification of K-Ras makes Ras-directed cancer therapy a challenging task. Aiming to disrupt electrostatic-driven protein-protein interactions (PPIs) of K-Ras with FTase and GGTase I, a series of bivalent dual inhibitors that recognize the active pocket and the common acidic surface of FTase and GGTase I were designed. The structure-activity-relationship study resulted in 8 b, in which a biphenyl-based peptidomimetic FTI-277 was attached to a guanidyl-containing gallate moiety through an alkyl linker. Cell-based evaluation demonstrated that 8 b exhibited substantial inhibition of K-Ras processing without apparent interference with Rap-1A processing. Fluorescent imaging showed that 8 b disrupts localization of K-Ras to the plasma membrane and impairs interaction with c-Raf, whereas only FTI-277 was found to be inactive. These results suggest that targeting the PPI interface of K-Ras may provide an alternative method of inhibiting K-Ras.

A Whole-Cell Screen for Adjunctive and Direct Antimicrobials Active against Carbapenem-Resistant Enterobacteriaceae.

Carbapenem-resistant Enterobacteriaceae (CRE) are an emerging antimicrobial resistance threat for which few if any therapeutic options remain. Identification of new agents that either inhibit CRE or restore activity of existing antimicrobials is highly desirable. Therefore, a high-throughput screen of 182,427 commercially available compounds was used to identify small molecules which either enhanced activity of meropenem against a carbapenem-resistant Klebsiella pneumoniae ST258 screening strain and/or directly inhibited its growth. The primary screening methodology was a whole-cell screen/counterscreen combination assay that tested for reduction of microbial growth in the presence or absence of meropenem, respectively. Screening hits demonstrating eukaryotic cell toxicity based on an orthogonal screening effort or identified as pan-assay interference compounds (PAINS) by computational methods were triaged. Primary screening hits were then clustered and ranked according to favorable physicochemical properties. Among remaining hits, we found 10 compounds that enhanced activity of carbapenems against a subset of CRE. Direct antimicrobials that passed toxicity and PAINS filters were not, however, identified in this relatively large screening effort. It was previously shown that the same screening strategy was productive for identifying candidates for further development when screening known bioactive libraries inclusive of natural products. Our findings therefore further highlight liabilities of commercially available small-molecule screening libraries in the Gram-negative antimicrobial space. In particular, there was especially low yield in identifying compelling activity against a representative, highly multidrug-resistant, carbapenemase-producing K. pneumoniae strain.

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.

Structural Effects of Fusicoccin upon Upregulation of 14-3-3-Phospholigand Interaction and Cytotoxic Activity.

Fusicoccins (FCs) exhibit various cellular activities in mammalian cells, but details of the mechanism of action are not fully understood. In this study, we synthesized two pairs of model derivatives of FCs differing only in the presence and absence of a 12-hydroxyl group and evaluated their binding to a 14-3-3 protein together with various mode 1 and mode 3 phosphopeptide ligands. Our results demonstrate that the 12-hydroxyl group hampers binding to 14-3-3 with mode 1 phospholigands, presumably due to steric repulsion with the i+2 residue. Furthermore, cell-based evaluations showed that only non-substituted FCs exhibit significant cytotoxicity and all 12-hydroxyl derivatives were inactive, demonstrating a clear correlation with their ability to form ternary complexes with 14-3-3 and a mode 1 ligand. These results suggest that binding to 14-3-3 and a partner protein(s) possessing a mode 1 sequence plays a role in the mechanism of action of 12-non-substituted FCs.

Intracellular Generation of a Diterpene-Peptide Conjugate that Inhibits 14-3-3-Mediated Interactions.

Synthetic agents that disrupt intracellular protein-protein interactions (PPIs) are highly desirable for elucidating signaling networks and developing new therapeutics. However, designing cell-penetrating large molecules equipped with the many functional groups necessary for binding to large interfaces remains challenging. Here, we describe a rational strategy for the intracellular oxime ligation-mediated generation of an amphipathic bivalent inhibitor composed of a peptide and diterpene natural product, fusicoccin, which binds 14-3-3 protein with submicromolar affinity. Our results demonstrate that co-treatment of cells with small module molecules, the aldehyde-containing fusicoccin 1 and the aminooxy-containing peptide 2, generates the corresponding conjugate 3 in cells, resulting in significant cytotoxicity. In contrast, chemically synthesized 3 is not cytotoxic, likely due to its inability to penetrate cells. Compound 3, but not 1 or 2, disrupts endogenous 14-3-3/cRaf interactions, suggesting that cell death is caused by inhibition of 14-3-3 activity. These results suggest that intracellular generation of large-sized molecules may serve as a new approach for modulating PPIs.

Next generation biofilm inhibitors for Pseudomonas aeruginosa: Synthesis and rational design approaches.

The bacterial biofilms and the emergence of multiple drug resistance have become a major threat for current medical treatment of nosocomial infections. It has been estimated that about 65-80% of microbial infections in the developed countries are associated with biofilms. Given the prominence of biofilms in infectious diseases, increasing efforts toward the development of small molecules that will modulate bacterial biofilm development and maintenance is on the rise. Till date, marine natural products have shown a tremendous potential as pharma leads and also given new skeletons which would be used as biofilm/QS inhibitors. Medically relevant biofilm forming bacteria such as Pseudomonas aeruginosa which is most frequently isolated bacteria in nosocomial infection is believed to be a model organism for biofilm studies. Hence, in this review, we have highlighted the development of small molecules that inhibit and/or disperse bacterial biofilms of P. aeruginosa in particular. Additionally, the rational design approaches as well as synthetic methodologies along with biological studies has been accounted in this article.

Recent developments in the synthesis of five- and six-membered heterocycles using molecular iodine.

Heterocyclic scaffolds represent the key structural subunits of many biologically active compounds. Over the last few years iodine-mediated reactions have been extensively studied due to their low cost and eco-friendliness. This Review covers advances in the field of iodine-mediated synthesis of heterocyclic compounds since 2006, especially with an emphasis on mechanisms of ring formation. In this article, syntheses of different heterocycles are classified based on the manipulation of functional groups.

An expeditious I2-catalyzed entry into 6H-indolo[2,3-b]quinoline system of cryptotackieine.

A synthesis of a series of novel 6H-indolo[2,3-b]quinolines with different substituents on the quinoline ring is described. The method involves reaction of indole-3-carboxyaldehyde with aryl amines in the presence of a catalytic amount of iodine in refluxing diphenyl ether to yield indolo[2,3-b]quinolines in one-pot. The present approach provides a new route for the synthesis of polycyclic structures related to an alkaloid cryptotackieine (neocryptolepine).