Chemistry
Targeting Insulin- and Calcium-related Pathways for Potential Treatments for Alzheimer's Disease and Diabetes
Alzheimer's disease and diabetes are common disorders among the elderly population and have emerged as a major health concern. Both diseases pose considerable risks to one another. Diabetics have a significantly increased probability of getting Alzheimer's disease throughout their lifetime. These diseases are linked because both share common risk factors such as impaired carbohydrate metabolism insulin resistance oxidative stress inflammatory response mitochondrial dysfunction and amyloidosis. Insulin is a vital hormone responsible for bringing extremely high glucose levels back to normal and its receptors available in the hippocampus help in enhancing cognitive function. Insulin resistance consequently serves as a link between both diabetes and AD. Similarly amylin is another hormone secreted by the pancreas along with insulin. During diabetes amylin gets oligomerized and forms a neurotoxic complex with Aβ inside the brain which causes AD to develop. Along with these another main mechanism influencing AD development is Ca2+ dyshomeostasis. Insulin production from the pancreas is generally aided by Ca2+ but in excess it can cause dysregulation of many signaling pathways such as CaMKK2 CAMP CREB MAPK STIM\Orai etc. which can ultimately result in the pathogenesis of AD in diabetic people. In this review we discussed in detail the pathogenesis of AD associated with diabetes and the mechanisms initiating their progression.
Functional Roles of Long Non-coding RNAs on Stem Cell-related Pathways in Glioblastoma
Long non-coding RNAs (lncRNAs) characterized by their length exceeding 200 nucleotides and lack of protein-coding capacity are intricately associated with a wide array of cellular processes encompassing cell invasion differentiation proliferation migration apoptosis and regeneration. Perturbations in lncRNA expression have been observed in numerous diseases and have emerged as pivotal players in the pathogenesis of diverse tumor types. Glioblastoma a highly malignant primary tumor of the central nervous system (CNS) remains a formidable challenge even with the advent of novel therapeutic interventions as primary glioblastomas invariably exhibit therapy resistance and aggressive behavior. Glioblastomas can arise from progenitor cells or neuroglial stem cells revealing profound cellular heterogeneity notably in the form of glioblastoma stem cells (GSCs) possessing stem-like properties. Glioblastomas comprise neural precursors that harbor essential characteristics of neural stem cells (NSCs). Several signaling pathways have been implicated in the regulation of self-renewal in both cancer cells and stem cells. In addition to their involvement in therapy resistance and survival of glioblastoma lncRNAs are implicated in the modulation of GSC behaviors through diverse pathways and the intricate regulation of various genes and proteins. This review aims to comprehensively discuss the interplay between lncRNAs their associated pathways and GSCs shedding light on their potential implications in glioblastoma.
Elucidating the Signaling Pathways Involved in Erectile Dysfunction
Background: Erectile Dysfunction (ED) is a common sexual disorder among men aged 20 years and over. It is predominantly characterized by alterations in the key physiological pathways regulating erectile function such as nitric oxide and Ras homolog gene family member A (RhoA)/Rho-associated protein kinase (ROCK). Beyond these pathways multiple molecular signaling networks are involved in ED pathogenesis. Objective: This review aims to describe the major signal transduction pathways that impact erectile function and contribute to the introduction of the pathogenesis of ED. Methods: A literature review of ED was performed from 2000 to 2023 using PubMed Scopus and Embase. “ED” and “related signaling pathway” “molecular mechanisms” terms were used. Results: Further basic and clinical studies are required to define the underlying molecular mechanisms of ED. The signaling pathways that were not affected by phosphodiesterase type 5 inhibitors (PDE5i) may be the reason for the reduced efficacy of this first-line treatment option in a variety of conditions. Conclusion: There is still a need for a deeper description of the molecular mechanisms in terms of fibrosis angiogenesis apoptosis inflammation oxidative stress autophagy and hypoxia to identify new possible targets underlying the pathogenesis of ED. This comprehensive review expounds on the principal signaling pathways offering valuable insights that may catalyze the development of innovative and enhanced therapies for managing ED.
Synthetic Protocols, Structural Activity Relationship, and Biological Activity of Piperazine and its Derivatives
The versatile basic structure of piperazine allows for the development and production of newer bioactive molecules that can be used to treat a wide range of diseases. Piperazine derivatives are unique and can easily be modified for the desired pharmacological activity. The two opposing nitrogen atoms in a six-membered piperazine ring offer a large polar surface area relative structural rigidity and more acceptors and donors of hydrogen bonds. These properties frequently result in greater water solubility oral bioavailability and ADME characteristics as well as improved target affinity and specificity. Various synthetic protocols have been reported for piperazine and its derivatives. In this review we focused on recently published synthetic protocols for the synthesis of the piperazine and its derivatives. The structure-activity relationship concerning different biological activities of various piperazine-containing drugs was also highlighted to provide a good understanding to researchers for future research on piperazines.
Pyrazole Paradigms: Unveiling Synthetic Pathways and Unraveling Anti-Cancer Potential
This review investigates the synthetic methods and anti-cancer activities of pyrazole compounds. Various synthetic approaches including traditional organic synthesis and microwaveassisted synthesis have been used to change the pyrazole core structure resulting in new compounds with improved pharmacological properties. The paper also covers the mechanisms of action that underpin pyrazole derivatives' anti-cancer characteristics focusing on interactions with major molecular targets implicated in cancer growth and proliferation. SAR insights help to rationally develop novel anti-cancer drugs. In conclusion the review emphasizes the versatility of pyrazole derivatives as scaffolds for the discovery and development of new anti-cancer medicines. By understanding synthesis routes and unravelling anti-cancer potential this study hopes to encourage new research endeavours focused on leveraging the therapeutic advantages of pyrazole paradigms in the fight against cancer.
Synthesis and Antibacterial Evaluation of Novel Small-Molecule Antibacterials of a Reduced Acridine Structure in S. aureus Strains Including MRSA
Background: The increasing antibacterial drug resistance remains a threat to global health with increasing mortality and morbidity. There is an urgent need to find novel antibacterials and develop alternative strategies to combat the increasing antibacterial drug resistance. Objective: We aimed to synthesize novel small-molecule antibacterials to evaluate the structure dependent antibacterial compound activities against S. aureus and MRSA. Methods: Compounds were synthesized by primary N-alkylation to form alkyl acridinium salts that were further functionalized with substituted phenyl residues and finally purified by column chromatography. The antibacterial growth inhibition activity was determined as MIC value. Results: The substituent effects on the determined antibacterial growth inhibitory properties have been discussed. Conclusion: The best activities have been found for compounds with methoxy functions exceeding the activities of reported novel antibacterial peptides. The compounds have also shown antibacterial drug-enhancing effects which have been manifested as a reduction in the MIC values of the used antibiotics.
PPARs (Peroxisome Proliferator-activated Receptors) and Their Agonists in Alzheimer's Disease
Alzheimer's disease (AD) is a neurodegenerative disease leading to dementia because of complex phathomechanisms like amyloid β (Aβ) aggregation tau aggregates and neurofibrillary tangles. Peroxisome proliferator-activated receptor (PPAR) agonists have been reported recently with neuroprotective and anti-inflammatory properties. PPARs belong to the superfamily of nuclear hormone receptors and function as ligand-activated transcription factors. These have emerged as crucial players in the pathogenesis of AD. This review presented the potential of PPARs and their agonists in treating neurodegenerative diseases like AD. PPARs regulate the expression of specific genes vital for synaptic function and neurotransmitter release. PPAR agonists play a critical role in increasing the clearance of Aβ peptides by lowdensity lipoprotein receptor-related protein 1 (LRP1) in the microvascular endothelial cells of the human brain. Studies have shown that PPAR agonists reduce the level of APoE-mRNA contributing to the accumulation of Aβ plaques and up-regulation of PPAR. A knockout of miR-128 has been found to inhibit AD-like cognitive decline amyloid precursor protein (APP) amyloidogenic processing and inflammatory responses in AD. PPARs are involved in the pathomechanism of AD and therefore PPAR agonists could be viable options for controlling the neurodegenerative symptoms and may be useful in treating AD.
Synthesis, Molecular Docking Studies and Biological Evaluation of Thiazolyl Hydrazone Derivatives of Chromone-3-carbaldehyde as Potent Anti-Oxidant and Anti-Inflammatory Agents
Introduction: A series of 15 thiazolyl hydrazone derivatives of chromone-3- carbaldehyde have been designed and synthesized by the cyclization of thiosemicarbazone derivatives of chromone-3-carbaldehydes with 4'-substituted-2-bromo acetophenones. Methods: All these derivatives were evaluated for antioxidant activity by their direct scavenging activity objects to reactive oxygen species such as DPPH and nitric oxide as well as in vitro antiinflammatory activity by a protein denaturation method. Most of these synthesized compounds have shown significant antioxidant activity among which the compounds 5b 5c 5e 5g and 5j showed very good antioxidant activities in comparison with the standard ascorbic acid. The in vitro anti-inflammatory activity revealed that the compounds 5b 5g and 5h possessed significant activity compared to standard diclofenac sodium. Results: Additionally molecular docking studies of these molecules using ovalbumin as the protein showed remarkable interactions with its active site residues and the results indicated that the binding mode of these compounds closely resembled that of the reference compound diclofenac sodium. Conclusion: Thus these compounds represent an attractive template for the evaluation of new antiinflammatory and antioxidant agents and might be useful for exploring new therapeutic tools.
Predicting the Efficacy of Novel Synthetic Compounds in the Treatment of Osteosarcoma via Anti-Receptor Activator of Nuclear Factor-ΚB Ligand (RANKL)/Receptor Activator of Nuclear Factor-ΚB (RANK) Targets
Background: Osteosarcoma (OS) currently demonstrates a rising incidence ranking as the predominant primary malignant tumor in the adolescent demographic. Notwithstanding this trend the pharmaceutical landscape lacks therapeutic agents that deliver satisfactory efficacy against OS. Objective: This study aimed to authenticate the outcomes of prior research employing the HM and GEP algorithms endeavoring to expedite the formulation of efficacious therapeutics for osteosarcoma. Methods: A robust quantitative constitutive relationship model was engineered to prognosticate the IC50 values of innovative synthetic compounds harnessing the power of gene expression programming. A total of 39 natural products underwent optimization via heuristic methodologies within the CODESSA software resulting in the establishment of a linear model. Subsequent to this phase a mere quintet of descriptors was curated for the generation of non-linear models through gene expression programming. Results: The squared correlation coefficients and s2 values derived from the heuristics stood at 0.5516 and 0.0195 respectively. Gene expression programming yielded squared correlation coefficients and mean square errors for the training set at 0.78 and 0.0085 respectively. For the test set these values were determined to be 0.71 and 0.0121 respectively. The s2 of the heuristics for the training set was discerned to be 0.0085. Conclusion: The analytic scrutiny of both algorithms underscores their commendable reliability in forecasting the efficacy of nascent compounds. A juxtaposition based on correlation coefficients elucidates that the GEP algorithm exhibits superior predictive prowess relative to the HM algorithm for novel synthetic compounds.
Trends in the Synthesis of Antimicrobial Derivatives by using the Gewald, Strecker, and Groebke-Blackburn-Bienaymé (GBB) Reactions
Background: Multicomponent reactions are highly useful in synthesizing natural products and bioactive molecules. Out of several MCRs although utilized widely some remain neglected in review articles. The Gewald and Groebke-Blackburn-Bienaymé (GBB) reactions are two such reactions. This comprehensive review assimilates applications of Gewald and Groebke-Blackburn- Bienayme reactions in synthesizing novel antimicrobial agents. It presents the antimicrobial properties of the synthesized molecules providing an overview of their potential druggability. Objective: Developing novel antimicrobial agents is the need of the hour. Toward this objective the scientific community is developing new methods for constructing novel architectures with potential antimicrobial properties. This review will showcase the usefulness of the Gewald Strecker and Groebke-Blackburn-Bienaymé (GBB) reactions in synthesizing antimicrobial molecules. Methods: The articles are searched by using the Sci-finder search tool and summarize the chemistry of their synthesis and antimicrobial evaluation of the molecules. Results: This review focuses on synthesizing antimicrobial molecules using the Gewald Strecker and Groebke-Blackburn-Bienaymé (GBB) reactions. The antimicrobial activities of the synthesized molecules are also summarized in tables. Conclusion: This review will briefly overview the application of the Gewald Strecker and Groebke- Blackburn-Bienaymé (GBB) reactions in synthesizing novel antimicrobial molecules. It contains several molecules with promising activity against resistant and non-resistant microbial strains. These promising molecules could be studied further to develop novel antibiotics.
Pharmacochemical Study of Multitarget Amino Acids’ Hybrids: Design, Synthesis, In vitro, and In silico Studies
Introduction: Neuro-inflammation is a complex phenomenon resulting in several disorders. ALOX-5 COX-2 pro-inflammatory enzymes and amino acid neurotransmitters are tightly correlated to neuro-inflammatory pathologies. Developing drugs that interfere with these targets will offer treatment for various diseases. Objective: Herein we extend our previous research by synthesizing a series of multitarget hybrids of cinnamic acids with amino acids recognized as neurotransmitters. Methods: The synthesis was based on an In silico study of a library of cinnamic amide hybrids with glycine γ- aminobutyric and L - glutamic acids. Drug-likeness and ADMET properties were subjected to In silico analysis. Cinnamic acids were derived from the corresponding aldehydes by Knoevenagel condensation. The synthesis of the amides followed a two-step reaction with 1- hydroxybenzotriazole monohydrate and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride in dry dichloromethane and the corresponding amino acid ester hydrochloride salt in the presence of NN-diisopropyl-Nethylamine. Results: The structure of the synthesized compounds was confirmed spectrophotometrically. The new compounds such as lipoxygenase cyclooxygenase-2 lipid peroxidation inhibitors and antiinflammatories were tested in vitro. The compounds exhibited LOX inhibition with IC50 values in the low μM region). Conclusion: Compounds 18a 23b and 11c are strong lipid peroxidation inhibitors (99% 78% and 92%). Compound 28c inhibits SLOX-1 with IC50 =8.5 μM whereas 11a and 22a highly inhibit COX-2 (IC50 6 and 5 μM Hybrids 14c and 17c inhibit both enzymes. Compound 29c showed the highest anti-inflammatory activity (75%). The In silico ADMET properties of 14c and 11a support their drug-likeness.
A Computational Study of Green Tea Extracts and their Derivatives as Potential Inhibitors for Squalene Monooxygenase
Background: According to the World Health Organisation cardiovascular complications have been recognized as the leading course of death between 2000 and 2019. Cardiovascular complications are caused by excess LDL cholesterol in the body or arteries that can build up to form a plaque. There are drugs currently in clinical use called statins that target HMGCoA reductase. However these drugs result in several side effects. This work investigated using computational approaches to lower cholesterol by investigating green tea extracts as an inhibitors for squalene monooxygenase (the second-rate-controlling step in cholesterol synthesis). Methods: Pharmacophore modeling was done to identify possible pharmacophoric sites based on the pIC50 values. The best hypothesis generated by pharmacophore modeling was further validated by atom-based 3D QSAR where 70% of the data set was treated as the training set. Prior molecular docking ADMET studies were done to investigate the physiochemical properties of these molecules. Glide docking was performed followed by molecular dynamics to evaluate the protein conformational changes. Results: Pharmacophore results suggest that the best molecules to interact with the biological target should have at least one hydrogen acceptor (A5) two hydrogen donors (D9 and D10) and two benzene rings (R14 and R15) for green tea polyphenols and theasinensin A. ADMET result shows that all molecules in this class have low oral adsorption. Molecular docking results showed that some green tea polyphenols have good binding affinities with most of these structures having a docking score of less than -10 kcal/mol. Molecular dynamics further illustrated that the best-docked ligands perfectly stay within the active site over a 100 ns simulation. Conclusion: The results obtained from this study suggest that green tea polyphenols have the potential for inhibition of squalene monooxygenase except for theasinensin A.
New Analogues of the Nicotinamide Phosphoribosyltransferase Inhibitor FK866 as Potential Anti-Pancreatic Cancer Agents
Background: During the past two decades many nicotinamide phosphoribosyltransferase (NAMPT) inhibitors were prepared and tested because this enzyme is overexpressed in pancreatic cancer. Although FK866 is a well-known strong NAMPT inhibitor it suffers severe drawbacks. Objective: Our work aimed to synthesize efficient NAMPT inhibitors featuring better pharmacokinetic properties than the pyridine-containing FK866. To this aim the new anticancer agents were based on benzene pyridazine or benzothiazole moieties as a cap group instead of the pyridine unit found in FK866 and other NAMPT inhibitors. Methods: The new compounds prepared exploiting standard heterocycle chemistry and coupling reactions (e.g. formation of amides ureas and cyanoguanidines copper-mediated azide-alkyne cycloaddition) have been fully characterized using NMR and HRMS analyses. Their activity has been evaluated using cytotoxicity and intracellular NAD depletion assays in the human pancreatic cancer cell line MiaPaCa-2. Results: Among the 14 products obtained compound 28 bearing a pyridazine unit as the cap group and a thiophene moiety as the tail group showed 6.7 nanomolar inhibition activity in the intracellular NAD depletion assay and 43 nanomolar inhibition in the MiaPaCa-2 cells cytotoxicity assay comparable to that observed for FK866. Conclusion: The positive results observed for some newly synthesized molecules particularly those carrying a thiophene unit as a tail group indicate that they could act as in vivo anti-pancreatic cancer agents.
Design and Synthesis of 6-amido-3-carboxypyridazine Derivatives as Potent T3SS Inhibitors of Salmonella enterica Serovar Typhimurium
Background: Salmonella enterica (S. enterica) serovar Typhimurium an anaerobic enteric pathogene could cause human and animal diseases ranging from mild gastroenteritis to whole body serious infections. Objective: The goal of this paper was to synthesize new 6-amido-3-carboxypyridazine derivatives with different lengths of side chains with the aim of getting potent antibacterial agents. Methods: Synthesized compounds were analyzed by analytical techniques such as 1H NMR 13C NMR spectra and mass spectrometry. We designed a series of novel 6-amido-3-carboxypyridazines using FA as the lead compound with the scaffold hopping strategy and their inhibitory activity against the effectors of type III secretion system (T3SS) using SDS-PAGE and western blot analysis for two rounds. Also the preliminary mechanism of action of this series of compounds on T3SS was performed using real-time qPCR. Results: Nine 6-amido-3-carboxypyridazines was synthesized. The inhibitory activities evaluated showed that compound 2i was the most potent T3SS inhibitor which demonstrated potent inhibitory activities on the secretion of the T3SS SPI-1 effectors in a dose-dependent manner. The transcription of SPI-1 may be affected by compound 2i through the SicA/InvF regulatory pathway. Conclusion: The novel synthetic 6-amido-3-carboxypyridazines could act as potent leads for the development of novel antibacterial agents.
Unveiling Therapeutic Avenues for Crohn’s Disease Management: Exploring Inhibitors for Adherent-Invasive Escherichia coli Propanediol Dehydratase
Introduction: Inflammatory Bowel Disease (IBD) encompasses a group of chronic disorders distinguished by inflammation of the gastrointestinal tract. Among these Crohn's Disease (CD) stands out as a complex and impactful condition due to challenges for both diagnosis and management making it a cynosure of research. Methods: In CD there is the predominance of proinflammatory bacteria including the Adherentinvasive Escherichia coli (AIEC) with virulence-associated metabolic enzyme Propanediol Dehydratase (pduC) which has been identified as a therapeutic target for the management of CD. Herein molecular modeling techniques including molecular docking Molecular Mechanics with Generalized Born and Surface Area (MMGBSA) drug-likeness and pharmacokinetics profiling were utilized to probe the potentials of eighty antibacterial compounds to serve as inhibitors of pduC. Results: The results of this study led to the identification of five compounds with promising potentials; the results of the molecular docking simulation revealed the compounds as possessing better binding affinities for the target compared to the standard drug (sulfasalazine) while Lipinski’s rule of five-based assessment of their drug-likeness properties revealed them as potential oral drugs. MMGBSA free energy calculation and Molecular Dynamics (MD) simulation of the complexes formed a sequel to molecular docking revealing the compounds as stable binders in the active site of the protein. Conclusion: Ultimately the results of this study have revealed five compounds to possess the potential to serve as inhibitors of pduC of AIEC. However experimental studies are still needed to validate the findings of this study.
Antibiotic Potentiation Through Phytochemical-Based Efflux Pump Inhibitors to Combat Multidrug Resistance Bacteria
Background: Antimicrobial resistance development poses a significant danger to the efficacy of antibiotics which were once believed to be the most efficient method for treating infections caused by bacteria. Antimicrobial resistance typically involves various mechanisms such as drug inactivation or modification drug target modification drug uptake restriction and drug efflux resulting in decreased antibiotic concentrations within the cell. Antimicrobial resistance has been associated with efflux Pumps known for their capacity to expel different antibiotics from the cell non-specifically. This makes EPs fascinating targets for creating drugs to combat antimicrobial resistance (AMR). The varied structures of secondary metabolites (phytomolecules) found in plants have positioned them as a promising reservoir of efflux pump inhibitors. These inhibitors act as modifiers of bacterial resistance and facilitate the reintroduction of antibiotics that have lost clinical effectiveness. Additionally they may play a role in preventing the emergence of multidrug resistant strains. Objective: The objective of this review article is to discuss the latest studies on plant-based efflux pump inhibitors such as terpenoids alkaloids flavonoids glycosides and tetralones. It highlighted their potential in enhancing the effectiveness of antibiotics and combating the development of multidrug resistance. Results: Efflux pump inhibitors (EPIs) derived from botanical sources including compounds like lysergol chanaoclavine niazrin 4-hydroxy-α-tetralone ursolic acid phytol etc. as well as their partially synthesized forms have shown significant potential as practical therapeutic approaches in addressing antimicrobial resistance caused by efflux pumps. Further several phyto-molecules and their analogs demonstrated superior potential for reversing drug resistance surpassing established agents like reserpine niaziridin etc. Conclusion: This review found that while the phyto-molecules and their derivatives did not possess notable antimicrobial activity their combination with established antibiotics significantly reduced their minimum inhibitory concentration (MIC). Specific molecules such as chanaoclavine and niaziridin exhibited noteworthy potential in reversing the effectiveness of drugs resulting in a reduction of the MIC of tetracycline by up to 16 times against the tested strain of bacteria. These molecules inhibited the efflux pumps responsible for drug resistance and displayed a stronger affinity for membrane proteins. By employing powerful EPIs these molecules can selectively target and obstruct drug efflux pumps. This targeted approach can significantly augment the strength and efficacy of older antibiotics against various drug resistant bacteria given that active drug efflux poses a susceptibility for nearly all antibiotics.
Systematic Review on Major Antiviral Phytocompounds from Common Medicinal Plants against SARS-CoV-2
Background: Viral infections are rising around the globe and with evolving virus types and increasing varieties of viral invasions; the human body is developing antimicrobial resistance continuously. This is making the fight of mankind against viruses weak and unsecured. On the other hand changing lifestyle globalization and human activities adversely affecting the environment are opening up risks for new viral predominance on human race. In this context the world has witnessed the pandemic of the human Coronavirus disease (COVID-19) recently. The disease is caused by the Coronavirus namely Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV- 2). Methods and Materials: Developing potential and effective vaccine is also time consuming and challenging. The huge resource of plants around us has rich source of potent antiviral compounds. Some of these molecules may serve as tremendously potent lead molecules whose slight structural modifications may give us highly bioactive antiviral derivatives of phytocompounds. Every geographical region is rich in unique plant biodiversity and hence every corner of the world with rich plant biodiversity can serve as abode for potential magical phytocompounds most of which have not been extensively explored for development of antiviral drug formulations against various viruses like the HIV HPV etc. and the Coronavirus also known as SARS-CoV-2 which causes the disease COVID-19. Results: Several phytocompounds from various medicinal plants have already been screened using in silico tools and some of them have yielded promising results establishing themselves as potent lead molecules for development of drugs against the highly mutating SARS-CoV-2 virus and thus these phytocompounds may be beneficial in treating COVID-19 and help human to win the life threatening battle against the deadly virus. Conclusion: The best advantage is that these phytocompounds being derived from nature in most of the cases come with minimum or no side effects compared to that of chemically synthesized conventional bioactive compounds and are indigenously available hence are the source of cost effective drug formulations with strong therapeutic potentials.