Imidazopyrimidine: from a relatively exotic scaffold to an evolving structural motif in drug discovery.

Nitrogen-fused heterocycles are of immense importance in modern drug discovery and development. Among them, imidazopyrimidine is a highly versatile scaffold with vast pharmacological utility. These compounds demonstrate a broad spectrum of pharmacological actions, including antiviral, antifungal, anti-inflammatory, and anticancer. Their adaptable structure allows for extensive structural modifications, which can be utilized for optimizing pharmacological effects via structure-activity relationship (SAR) studies. Additionally, imidazopyrimidine derivatives are particularly noteworthy for their ability to target specific molecular entities, such as protein kinases, which are crucial components of various cellular signaling pathways associated with multiple diseases. Despite the evident importance of imidazopyrimidines in drug discovery, there is a notable lack of a comprehensive review that outlines their role in this field. This review highlights the ongoing interest and investment in exploring the therapeutic potential of imidazopyrimidine compounds, underscoring their pivotal role in shaping the future of drug discovery and clinical medicine.

New Perspectives on Crosstalks Between Bacterial Regulatory RNAs from Outer Membrane Vesicles and Eukaryotic Cells.

Regulatory small RNAs (sRNAs) help the bacteria to survive harsh environmental conditions by posttranscriptional regulation of genes involved in various biological pathways including stress responses, homeostasis, and virulence. These sRNAs can be found carried by different membrane-bound vesicles like extracellular vesicles (EVs), membrane vesicles (MVs), or outer membrane vesicles (OMVs). OMVs provide myriad functions in bacterial cells including carrying a cargo of proteins, lipids, and nucleic acids including sRNAs. A few interesting studies have shown that these sRNAs can be transported to the host cell by membrane vesicles and can regulate the host immune system. Although there is evidence that sRNAs can be exported to host cells and sometimes can even cross the blood-brain barrier, the exact mechanism is still unknown. In this review, we investigated the new techniques implemented in various studies, to elucidate the crosstalks between bacterial cells and human immune systems by membrane vesicles carrying bacterial regulatory sRNAs.

Glucose regulation by newly synthesized boronic acid functionalized molecules as dipeptidyl peptidase IV inhibitor: a potential compound for therapeutic intervention in hyperglycaemia.

Management of type 2 diabetes mellitus (T2DM) using dipeptidyl peptidase IV (DPP IV) inhibitors is gaining precedence as this enzyme plays an indispensable role in cleaving and inactivating peptides, such as glucagon-like peptide-1 (GLP-1), incretin hormones, and glucose-dependent insulinotropic polypeptide (GIP). There are several DPP IV inhibitors used to treat T2DM, but limited by side effects such as disturbed GIT, flu-like symptoms, etc. Thus, there is an urgent need for the development of novel and better DPP IV inhibitors for the management of the same. In the present study, we investigated the effect of new boronic acid-based thiazole compounds as DPP IV inhibitors. We used substituted anilines that were progressively modified through a multi-step synthesis and then chemically characterised. These molecules have good binding affinity and molecular interactions at the active site of the DPP IV enzyme. Two boronic acid-based molecules, i.e. PC06R58 and PC06R108, were used for the assessment of their in-vitro enzymatic activities. Both molecules (PC06108 and PC06R58) exhibited potent uncompetitive DPP IV enzyme inhibition at two different concentrations of 90.9 and 15.6 nM, respectively, compared to sitagliptin having an IC50 of 17.3 nM. Furthermore, the oral glucose tolerance test suggested significantly reduced blood glucose levels at 20 mg/kg of the body weight upon administration of PC06R58 and PC06R108 molecules in rats after glucose ingestion (2 g/kg of the body weight). The compounds showed satisfactory DPP IV inhibition. Furthermore, DPP IV inhibitory activity and acceptable pre-ADME/Tox profile indicate it is a lead compound in this novel class of DPP IV inhibitors.Communicated by Ramaswamy H. Sarma.

Optimizing Fecal Occult Blood Test (FOBT) Colorectal Cancer Screening Using Gut Bacteriome as a Biomarker.

BACKGROUND: Colorectal cancer (CRC) is a major cause of cancer mortality in the world. One of the most widely used screening tests for CRC is the immunochemical fecal occult blood test (iFOBT), which detects human hemoglobin from patient's stool sample. Although it is highly efficient in detecting blood from patients with gastro-intestinal lesions, such as polyps and cancers, the iFOBT has a high rate of false positive discovery. Recent studies suggested gut bacteria as a promising noninvasive biomarker for improving the diagnosis of CRC. In this study, we examined the composition of gut bacteria using iFOBT leftover from patients undergoing screening test along with a colonoscopy. METHODS: After collecting data from more than 800 patients, we considered 4 groups for this study. The first and second groups were respectively "healthy" in which the patients had either no blood in their stool or had blood but no lesions. The third and fourth groups of patients had both blood in their stools with precancerous and cancerous lesions and considered either as low-grade and high-grade lesion groups, respectively. An amplification of 16S rRNA (V4 region) gene was performed, followed by sequencing along with various statistical and bioinformatic analysis. RESULTS: We analyzed the composition of the gut bacteriome at phylum, class, genus, and species levels. Although members of the Firmicute phylum increased in the 3 groups compared to healthy patients, the phylum Actinobacteriota was found to decrease. Moreover, Blautia obeum and Anaerostipes hadrus from the phylum Firmicutes were increased and Collinsella aerofaciens from phylum Actinobacteriota was found decreased when healthy group is compared to the patients with high-grade lesions. Finally, among the 5 machine learning algorithms used to perform our analysis, both elastic net (AUC > 0.7) and random forest (AUC > 0.8) performs well in differentiating healthy patients from 3 other patient groups having blood in their stool. CONCLUSION: Our study integrates the iFOBT screening tool with gut bacterial composition to improve the prediction of CRC lesions.

[3+2] Cascade Ring-Closing/Ring-Opening Strategy: Access to N-Indene-Tethered Amino Alcohols.

An unprecedented atom-economic redox neutral regioselective Rh(III)-catalyzed cascade [3+2] annulation of 2-aryl oxazoline with α,ß-unsaturated nitro olefins has been accomplished, furnishing a novel set of nitro-functionalized indene-tethered amino alcohols through a synergistic ring-closing/ring-opening strategy via the formation of two new C-C bonds and the regioselective cleavage of the C2-O bond of oxazoline under silver free mild reaction conditions with a broad substrate scope.

Roadmap to Pyruvate Kinase M2 Modulation - A Computational Chronicle.

Pyruvate kinase M2 (PKM2) has surfaced as a potential target for anti-cancer therapy. PKM2 is known to be overexpressed in the tumor cells and is a critical metabolic conduit in supplying the augmented bioenergetic demands of the recalcitrant cancer cells. The presence of PKM2 in structurally diverse tetrameric as well as dimeric forms has opened new avenues to design novel modulators. It is also a truism to state that drug discovery has advanced significantly from various computational techniques like molecular docking, virtual screening, molecular dynamics, and pharmacophore mapping. The present review focuses on the role of computational tools in exploring novel modulators of PKM2. The structural features of various isoforms of PKM2 have been discussed along with reported modulators. An extensive analysis of the structure-based and ligand- based in silico methods aimed at PKM2 modulation has been conducted with an in-depth review of the literature. The role of advanced tools like QSAR and quantum mechanics has been established with a brief discussion of future perspectives.

PROTACting the kinome with covalent warheads.

The dawn of targeted degradation using proteolysis-targeting chimeras (PROTACs) against recalcitrant proteins has prompted numerous efforts to develop complementary drugs. Although many of these are specifically directed against undruggable proteins, there is increasing interest in small molecule-based PROTACs that target intracellular pathways, and some have recently entered clinical trials. Concurrently, small molecule-based PROTACs that target protumorigenic pathways in cancer cells, the tumor microenvironment (TME), and angiogenesis have been found to have potent effects that synergize with the action of antibodies. This has led to the augmentation of PROTACs with variable substitution patterns. Several combinations with small molecules targeting undruggable proteins are now under clinical investigation. In this review, we discuss the recent milestones achieved as well as challenges encountered in this area of drug development, as well as our opinion on the best path forward.

Objective assessment of adrenocortical carcinoma driver genes and their correlation with tumor pyruvate kinase M2.

Glandular cancers have a significant share of the total cancer patients all over the world. In the case of adrenocortical carcinomas (ACCs), although the benign form is more frequent and common, the malignant form provides a very less percentage of patients with five or more than five years of survival rate. There are gene alterations that are involved as a crucial factor behind the occurrence of ACCs. Out of these, the most prominent genetic alterations (PRKAR-1A, CTNNB1, ZNRF3, TP53, CCNE1 and TERF2 genes) are linked with a glycolytic enzyme pyruvate kinase M2 (PKM2), which converts phosphoenolpyruvate (PEP) to pyruvate in the glycolytic pathway. The involvementof PKM2 renders a cumulative effect through different pathways that may result in the onset of ACCs. Thus, this review aims to establish a link between ACCs, alterations of specific genes and PKM2.

Genome-wide prediction of cauliflower miRNAs and lncRNAs and their roles in post-transcriptional gene regulation.

MAIN CONCLUSION: We have predicted miRNAs, their targets and lncRNAs from the genome of Brassica oleracea along with their functional annotation. Selected miRNAs and their targets are experimentally validated. Roles of these non-coding RNAs in post-transcriptional gene regulation are also deciphered. Cauliflower (Brassica oleracea var. Botrytis) is an important vegetable crop for its dietary and medicinal values with rich source of vitamins, dietary fibers, flavonoids and antioxidants. MicroRNAs (miRNAs) are small non-coding RNAs (ncRNAs), which regulate gene expression by inhibiting translation or by degrading messenger RNAs (mRNAs). On the other hand, long non-coding RNAs (lncRNAs) are responsible for the up regulation and the down regulation of transcription. Although the genome of cauliflower is reported, yet the roles of these ncRNAs in post-transcriptional gene regulation (PTGR) remain elusive. In this study, we have computationally predicted 355 miRNAs, of which 280 miRNAs are novel compared to miRBase 22.1. All the predicted miRNAs belong to 121 different families. We have also identified 934 targets of 125 miRNAs along with their functional annotation. These targets are further classified into biological processes, molecular functions and cellular components. Moreover, we have predicted 634 lncRNAs, of which 61 are targeted by 30 novel miRNAs. Randomly chosen 10 miRNAs and 10 lncRNAs are experimentally validated. Five miRNA targets including squamosa promoter-binding-like protein 9, homeobox-leucine zipper protein HDG12-like, NAC domain-containing protein 100, CUP-SHAPED COTYLEDON 1 and kinesin-like protein NACK2 of four miRNAs including bol-miR156a, bol-miR162a, bol-miR164d and bol-miR2673 are also experimentally validated. We have built network models of interactions between miRNAs and their target mRNAs, as well as between miRNAs and lncRNAs. Our findings enhance the knowledge of non-coding genome of cauliflower and their roles in PTGR, and might play important roles in improving agronomic traits of this economically important crop.

Tiny Yet Indispensable Plant MicroRNAs Are Worth to Explore as Key Components for Combating Genotoxic Stresses.

Plants being sessile are always exposed to various stresses including biotic and abiotic stresses. Some of these stresses are genotoxic to cells causing DNA damage by forming lesions which include altered bases, cross-links, and breaking of DNA strands, which in turn hamper the genomic integrity. In order to survive through all these adverse conditions, plants have evolved different DNA repair mechanisms. As seen from the mammalian system and different human diseases, various microRNAs (miRNAs) can target the 3'-untranslated region of mRNAs that code for the proteins involved in DNA repair pathways. Since miRNAs play an important role in plant cells by regulating various metabolic pathways, it can also be possible that miRNAs play an important role in DNA repair pathways too. However, till date, only a handful of plant miRNAs have been identified to play important role in combating genotoxic stresses in plants. Limitation of information regarding involvement of miRNAs in DNA repair as well as in ROS scavenging prompted us to gather information about plant miRNAs specific for these tasks. This mini-review aims to present pertinent literature dealing with different genotoxic stresses that cause genome instability as well as plant specific responses to survive the damage. This is intertwined with the involvement of miRNAs in genotoxic stress in plants, challenges of applying miRNAs as a tool to combat DNA damage along with ways to overcome these challenges, and finally, the future prospective of these understudied aspects.

Porous microspheres: Synthesis, characterisation and applications in pharmaceutical & medical fields.

Porous microspheres have interconnective external and internal pores leading to very low mass density and enormous specific surface area, enabling them to have excellent adsorption capabilities. Due to this uniqueness over traditional microsphere, they find extensive pharmaceutical applications. Porous microspheres are very promising for gastro retentive drug delivery, alveoli targeted drug delivery, high-speed chromatography, development of tissue regeneration scaffolds and as carrier of biopharmaceuticals. Pore structure and porosity are the main factors that govern their applications. There are different well-established methods for their synthesis, like seed swelling, solvent evaporation, polymerization, spray drying and phase separation. But most of the methods are time consuming and consists of numbers of complicated steps. The size, shape and pore structure of the particles depend on many experimental variables like temperature, pH, stirring speed, type and concentration of porogen, polymer and its concentration. Thus, synthesis of porous microparticle with predefined porosity is really challenging.

Corrigendum: What Is the Link between Stringent Response, Endoribonuclease Encoding Type II Toxin-Antitoxin Systems and Persistence?

[This corrects the article on p. 1882 in vol. 7, PMID: 27933045.].

Cancer nanotheranostics: Strategies, promises and impediments.

Cancer has remained one of the most indomitable conundrums for scientists over centuries due to its multifarious etiology. While improved therapeutic and diagnostic approaches have commendably augmented the rate of survival of cancer patients, a holistic riddance from the ailment is still implausible. Hence, further explorations to scout for novel strategies of cancer therapy and diagnosis are necessary. Theranostics (amalgamation of therapy and diagnostics) has emerged as one of the avant-garde strategies, which provides a two-pronged advantage in cancer management. This integrative approach has found immense relevance in light of nanotechnology. Nanoparticles can be customized (loaded with a mélange of therapeutic drugs and diagnostic probes) to develop theranostic properties, thereby constructing nanotheranostic agents. These nano-composites are lucrative tools for cancer cell obliteration and simultaneous monitoring of the drug action, and can also be tailored for targeted drug delivery. Nanotheranostic agents have emerged as a prudent ploy for synchronized cancer intervention and detection of the 'route and reach' of the drugs. In this review, we discuss the diversified state-of-the-art facets of theranostic nanoparticles, including various nanoparticle-based platforms as well as the plethora of reported therapeutic drugs, aptamers, markers and diagnostic molecules that have found use in the precincts of nanotheranostics.

Gellan co-polysaccharide micellar solution of budesonide for allergic anti-rhinitis: an in vitro appraisal.

The aim of this study was to design a novel amphiphilic co-polysaccharide for the development of anti-rhinitis micellar solution of budesonide. Herein, a long alkyl chain (C18) was successfully grafted onto gellan polysaccharide by etherification reaction. The dispersion of co-polysaccharide in water led to formation of spherical, nanomicellar structures. Depending upon the co-polysaccharide:drug weight ratio (1:1, 1:2 and 1:3), a maximum drug loading (>95%) was noted at the lowest level. The nanomicelles were in the range of 371-750nm and showed negative zeta potential (-48.3 to -67.2mV) values indicating their stability in aqueous system. They exhibited a longer dissolution profile in simulated nasal fluid (pH 5.5). The dissolution efficiency (39.79±0.93%) was maximal at the lowest polymer: drug ratio in 6h. The drug release was found to follow first order kinetic model. Korsmeyer-peppas modeling of in vitro drug release data indicated that besides simple diffusion, no other physical phenomenon was involved in the event of drug release from the nanostructures. Differential scanning calorimetry analysis suggested some degree of physical incompatibility; however Infrared spectroscopy revealed chemical compatibility between drug and co-polysaccharide. Thus, the co-polysaccharide micellar system offers a splendid outlook in controlled intranasal delivery of budesonide for the symptomatic relief of anti-rhinitis.

Novel gastroulcer protective micro(hydro)gels of sulfated locust bean gum-aluminium complex for immediate release of diclofenac sodium.

In this study, carboxymethyl sulfate derivative (CLBS) of locust bean gum (LBG) was synthesized by varying the strength of sulfating reagent. CLBS was characterized by Fourier transform infrared (FTIR) spectroscopy, elemental analysis, and viscosity measurements. Furthermore, the degree of sulfation and carboxymethylation in CLBS was determined. Novel micro(hydro)gel particles of CLBS were fabricated in basic aluminum chloride solution and different concentration of diclofenac sodium was incorporated into these particles. Differential scanning calorimetry and FTIR analyses did not suggest any drug-polymer interaction. Spherical morphological structures of the particles were evident under scanning electron microscope. Regardless of the formulation variables, a maximum of ~60% drug entrapment efficiency was achieved. For a higher degree of substitution, CLBS particles disintegrated rapidly (~20 min) and released >80% drug in acidic medium (pH1.2 and pH4.0) in 60 min. However, the particles liberated only ~60% drug in phosphate buffer medium (pH6.8) during this period. Following disintegration of the particles, the pH of gastric environment elevated. In stomach histopathology, the ulcers were scored and it was estimated that CLBS afforded ~86% protection to the gastric mucosa from ulceration. Thus, the micro(hydro)gel particles of CLBS-aluminium complex could be useful for immediate analgesic effect of the drug without any significant gastric distress.