A comprehensive overview of selective and novel fibroblast growth factor receptor inhibitors as a potential anticancer modality.

The arrival of comprehensive genome sequencing has accelerated the understanding of genetically aberrant advanced cancers and target identification for possible cancer treatment. Fibroblast growth factor receptor (FGFR) gene alterations are frequent findings in various rare and advanced cancers refractive to mainstay chemo-therapy or surgical interventions. Several FGFR inhibitors have been developed for addressing these genetically altered FGFR-harboring malignancies, and some have performed well in clinical trials. In contrast, others are still being investigated in different phases of clinical trials. FDA has approved four anticancer agents such as erdafitinib, pemigatinib, infigratinib, and futibatinib, for clinical use in oncogenic FGFR-driven malignancies. These include cholangiocarcinoma, urothelial carcinoma, and myeloid/lymphoid malignancies. Pemigatinib is the only FGFR inhibitor globally approved (USA, EU, and Japan) and available as a targeted therapy for two types of cancer, including FGFR2 fusion or other rearrangements harboring cholangiocarcinoma and relapsed/refractory myeloid/lymphoid neoplasms with FGFR1 rearrangements. Myeloid/lymphoid neoplasm is the latest area of application added to the therapeutic armamentarium of FGFR inhibitors. Furthermore, futibatinib is the first-in-class covalent or irreversible pan-FGFR inhibitor that has received FDA approval for locally advanced or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 gene aberrations. This review highlights the current clinical progress concerning the safety and efficacy of all the approved FGFR-TKIs (tyrosine kinase inhibitors) and their ongoing investigations in clinical trials for other oncogenic FGFR-driven malignancies.

Pesticides: An alarming detrimental to health and environment.

Pesticides are chemical substances of natural or synthetic origin that are used to eradicate pests and insects. These are indispensable in the agricultural processes for better crop production. Pesticide use aims to promote crop yield and protect the crops from diseases and damage. Pesticides must be handled carefully and disposed of appropriately because they are dangerous to people and other species by default. Environmental pollution occurs when pesticide contamination spreads away from the intended plants. Older pesticides such as lindane and dichlorodiphenyltrichloroethane (DDT) may remain in water and soil for a longer time. These accumulate in various parts of the food chain and cause damage to the ecosystem. Biological techniques in the management of pest control such as importation, augmentation, and conservation, and the accompanying procedures are more efficient, less expensive, and ecologically sound than other ways. This review mainly focuses on the consequences on the targeted and non-targeted organisms including the health and well-being of humans by the use of pesticides and their toxicity. The side effects that occur when a pesticide's LD50 exceeds the accepted limit through oral or skin penetration due to their binding to various receptors such as estrogen receptors, GABA, EGFR, and others. These pesticide classes include carbamates, pyrethroids, organochlorides, organophosphorus, and others. The current study seeks to highlight the urgent requirement for a novel agricultural concept that includes a major reduction in the use of chemical pesticides.

Target protein degradation by protacs: A budding cancer treatment strategy.

Cancer is one of the most common causes of death. So, its lethal effect increases with time. Near about hundreds of cancers are known in humans. Cancer treatment is done to cure or prolonged remission, and shrinkage of the tumor. Cytotoxic agents, biological agents/targeted drugs, hormonal drugs, surgery, radiotherapy/proton therapy, chemotherapy, immunotherapy, and gene therapy are currently used in the treatment of cancer but their cost is high and cause various side effects. Seeing this, some new targeted strategies such as PROTACs are the need of the time. Proteolysis targeting chimera (PROTAC) has become one of the most discussed topics regarding cancer treatment. Few of the PROTAC molecules are in the trial phases. PROTACs have many advantages over other strategies such as modularity, compatibility, sub-stoichiometric activity, acting on undruggable targets, molecular design, and acts on intracellular targets, selectivity and specificity can be recruited for any cancer, versatility, and others. PROTACs are having some unclear questions on their pharmacokinetics, heavy-molecular weight, etc. PROTACs are anticipated to bring about a conversion in current healthcare and will emerge as booming treatments. In this review article we summarize PROTACs, their mechanism of action, uses, advantages, disadvantages, challenges, and future aspects for the successful development of potent PROTACs as a drug strategy.

Neurological Consequences of SARS-CoV-2 Infection and Concurrence of Treatment-Induced Neuropsychiatric Adverse Events in COVID-19 Patients: Navigating the Uncharted.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the angiotensin-converting enzyme 2 (ACE2) receptor and invade the human cells to cause COVID-19-related pneumonia. Despite an emphasis on respiratory complications, the evidence of neurological manifestations of SARS-CoV-2 infection is rapidly growing, which is substantially contributing to morbidity and mortality. The neurological disorders associated with COVID-19 may have several pathophysiological underpinnings, which are yet to be explored. Hypothetically, SARS-CoV-2 may affect the central nervous system (CNS) either by direct mechanisms like neuronal retrograde dissemination and hematogenous dissemination, or via indirect pathways. CNS complications associated with COVID-19 include encephalitis, acute necrotizing encephalopathy, diffuse leukoencephalopathy, stroke (both ischemic and hemorrhagic), venous sinus thrombosis, meningitis, and neuroleptic malignant syndrome. These may result from different mechanisms, including direct virus infection of the CNS, virus-induced hyper-inflammatory states, and post-infection immune responses. On the other hand, the Guillain-Barre syndrome, hyposmia, hypogeusia, and myopathy are the outcomes of peripheral nervous system injury. Although the therapeutic potential of certain repurposed drugs has led to their off-label use against COVID-19, such as anti-retroviral drugs (remdesivir, favipiravir, and lopinavir-ritonavir combination), biologics (tocilizumab), antibiotics (azithromycin), antiparasitics (chloroquine and hydroxychloroquine), and corticosteroids (dexamethasone), unfortunately, the associated clinical neuropsychiatric adverse events remains a critical issue. Therefore, COVID-19 represents a major threat to the field of neuropsychiatry, as both the virus and the potential therapies may induce neurologic as well as psychiatric disorders. Notably, potential COVID-19 medications may also interact with the medications of pre-existing neuropsychiatric diseases, thereby further complicating the condition. From this perspective, this review will discuss the possible neurological manifestations and sequelae of SARS-CoV-2 infection with emphasis on the probable underlying neurotropic mechanisms. Additionally, we will highlight the concurrence of COVID-19 treatment-associated neuropsychiatric events and possible clinically relevant drug interactions, to provide a useful framework and help researchers, especially the neurologists in understanding the neurologic facets of the ongoing pandemic to control the morbidity and mortality.

Therapeutic Potentials of A2B Adenosine Receptor Ligands: Current Status and Perspectives.

BACKGROUND: Adenosine receptors (ARs) are classified as A1, A2A, A2B, and A3 subtypes belong to the superfamily of G-protein coupled receptors (GPCRs). More than 40% of modern medicines act through either activation or inhibition of signaling processes associated with GPCRs. In particular, A2B AR signaling pathways are implicated in asthma, inflammation, cancer, ischemic hyperfusion, diabetes mellitus, cardiovascular diseases, gastrointestinal disorders, and kidney disease. METHODS: This article reviews different disease segments wherein A2B AR is implicated and discusses the potential role of subtype-selective A2B AR ligands in the management of such diseases or disorders. All the relevant publications on this topic are reviewed and presented scientifically. RESULTS: This review provides an up-to-date highlight of the recent advances in the development of novel and selective A2B AR ligands and their therapeutic role in treating various disease conditions. A special focus has been given to the therapeutic potentials of selective A2B AR ligands in the management of airway inflammatory conditions and cancer. CONCLUSIONS: This systematic review demonstrates the current status and perspectives of A2B AR ligands as therapeutically useful agents that would assist medicinal chemists and pharmacologists in discovering novel and subtype-selective A2B AR ligands as potential drug candidates.

Molecular modeling approaches for the discovery of adenosine A2B receptor antagonists: current status and future perspectives.

Adenosine receptors (ARs) are classified as A1, A2A, A2B, and A3 subtypes belonging to the superfamily of G-protein-coupled receptors (GPCRs). Several molecular modeling approaches have been developed for A2BAR and its antagonists, from the construction of a homology model, molecular docking, molecular dynamics (MD) simulations, and 3D quantitative structure-activity relationship (QSAR) modeling to pharmacophore modeling, each of which has different objectives and outcomes. In this review, we provide a systematic outline of advances in molecular modeling approaches towards A2BAR for deducing its structure and interactions with various types of antagonist. The information, methods and perspectives presented here provides impetus for medicinal chemists to discover potential ligands that can bind selectively with higher affinity to A2BAR.

7-Amino-2-aryl/hetero-aryl-5-oxo-5,8-dihydro[1,2,4]triazolo[1,5-a]pyridine-6-carbonitriles: Synthesis and adenosine receptor binding studies.

A series of novel 7-amino-5-oxo-2-substituted-aryl/hetero-aryl-5,8-dihydro[1,2,4]triazolo[1,5-a]pyridine-6-carbonitriles (4a-4t) was synthesized, characterized and evaluated for their binding affinity and selectivity towards hA1 , hA2A , hA2B and hA3 adenosine receptors (ARs). Compound 4a with a phenyl ring at 2-position of the triazolo moiety of the scaffold showed high affinity and selectivity for hA1 AR (Ki hA1  = 0.076 µM, hA2A  = 25.6 µM and hA3  > 100 µM). Introduction of various electron donating and withdrawing groups at different positions of the phenyl ring resulted in drastic reduction in affinity and selectivity towards all the ARs, except compound 4b with a 4-hydroxyphenyl group at 2-position. Interestingly, the replacement of the phenyl ring with a smaller heterocyclic thiophene ring (π excessive system) resulted in further improvement of affinity for hA1 AR of compound 4t (Ki hA1  = 0.051 µM, hA2A  = 9.01 µM and hA3  > 13.9 µM) while retaining the significant selectivity against all other AR subtypes similar to compound 4a. The encouraging results for compounds 4a and 4t indicate that substitution at 2-position of the scaffold with π-excessive systems other than thiophene may lead to even more potent and selective hA1 AR antagonists.

Recent Advances in the In-silico Structure-based and Ligand-based Approaches for the Design and Discovery of Agonists and Antagonists of A2A Adenosine Receptor.

A2A receptor belongs to the family of GPCRs, which are the most abundant membrane protein family. Studies in the last few decades have shown the therapeutic applications of A2A receptor in various diseases. In the present mini-review, we have discussed the recent progress in the in-silico studies of the A2A receptor. Herein, we described the different structures of A2A receptor, the discovery of new agonists and antagonists using virtualscreening/ docking, pharmacophore modeling, and QSAR based pharmacophore modeling. We have also discussed various molecular dynamics (MD) simulations studies of A2A receptor in complex with ligands.

Design and synthesis of novel thiadiazole-thiazolone hybrids as potential inhibitors of the human mitotic kinesin Eg5.

A novel series of 1,3,4-thiadiazole-thiazolone hybrids 5a-v were designed, synthesized, characterized, and evaluated against the basal and the microtubule (MT)-stimulated ATPase activity of Eg5. From the evaluated derivatives, 5h displayed the highest inhibition with an IC50 value of 13.2 µM against the MT-stimulated Eg5 ATPase activity. Similarly, compounds 5f and 5i also presented encouraging inhibition with IC50 of 17.2 µM and 20.2 µM, respectively. A brief structure-activity relationship (SAR) analysis indicated that 2-chloro and 4-nitro substituents on the phenyl ring of the thiazolone motif contributed significantly to enzyme inhibition. An in silico molecular docking study using the crystal structure of Eg5 further supported the SAR and reasoned the importance of crucial molecular protein-ligand interactions in influencing the inhibition of the ATPase activity of Eg5. The magnitude of the electron-withdrawing functionalities over the hybrids and the critical molecular interactions contributed towards higher in vitro potency of the compounds. The drug-like properties of the synthesized compounds 5a-v were also calculated based on the Lipinski's rule of five and in silico computation of key pharmacokinetic parameters (ADME). Thus, the present work unveils these hybrid molecules as novel Eg5 inhibitors with promising drug-like properties for future development.

Crystal structure of the Eg5 - K858 complex and implications for structure-based design of thiadiazole-containing inhibitors.

The thiadiazole scaffold is an important core moiety in a variety of clinical drug candidates targeting a range of diseases. For example, the 2,4,5-substituted 1,3,4-thiadiazole scaffold is present in a lead compound and at least two clinical candidates targeting the human motor protein Eg5, against neoplastic diseases. An inhibitor named K858 has in vivo activity in various mouse xenografts whereas the clinical candidates (S)-ARRY-520 and (R)-Litronesib have entered clinical trials with the former one in phase III clinical trials either alone or in combination with a proteasome inhibitor against relapsed/refractory multiple myeloma. Astonishingly, structural data are lacking for all thiadiazole-containing Eg5 inhibitors. Here we report the structure determination of two crystal forms of the ternary Eg5-ADP-K858 complex, locking the motor in the so-called final inhibitor bound state, thus blocking ADP release, a crucial stage for Eg5 activity. K858 acts at the established allosteric inhibitor-binding pocket formed of helix α2, loop L5 and helix α3. The structure of the complex has far reaching consequences for thiadiazole containing Eg5 inhibitors. For example, we could rationalise the structure-activity relationship in the crucial 5-position of the thiadiazole scaffold and the complex will serve in the future as a basis for strucutre-based drug design.

Synthesis, anticancer evaluation, and molecular docking studies of some novel 4,6-disubstituted pyrazolo[3,4-d]pyrimidines as cyclin-dependent kinase 2 (CDK2) inhibitors.

A novel series of 4,6-disubstituted pyrazolo[3,4-d]pyrimidines (7-43) bearing various anilines at C-4 position and thiophenethyl or thiopentane moieties at C-6 position have been designed and synthesized by molecular hybridization approach. All the synthesized compounds were evaluated for in vitro CDK2/cyclin E and Abl kinase inhibitory activity as well as anti-proliferative activity against K-562 (chronic myelogeneous leukemia), and MCF-7 (breast adenocarcinoma) cell lines. The structure-activity relationship (SAR) studies revealed that compounds with thiophenethyl group at C-6 with mono-substituted anilines at C-4 exhibited better CDK2 inhibitory activity compared to alkyl group (thiopentane) at C-6 and di-substituted anilines at C-4 of the scaffold. In particular, compounds having 2-chloro, 3-nitro and 4-methylthio aniline groups at C-4 displayed significant enzymatic inhibitory activity against CDK2 with single digit micromolar IC50 values. The in silico molecular docking studies suggested possible binding orientation and the binding energies were in agreement with the observed SAR as well as experimental results. In addition, some of the synthesized compounds showed anti-proliferative effects against K-562 and MCF-7 cancer cell lines with IC50 values in a micromolar range. Thus, the synthesized compounds could be considered as new anticancer hits for further lead optimization.

Synthesis, adenosine receptor binding and molecular modelling studies of novel thieno[2,3-d]pyrimidine derivatives.

A series of new molecules containing a thieno[2,3-d]pyrimidine scaffold was synthesized and characterized by adopting an efficient synthetic scheme. The effect of a free or substituted amino group at 2-position as well as an oxo-group, imidazole or 1,2,4-triazole ring at 4-position of the scaffold on the affinity and selectivity towards adenosine receptors (ARs) was evaluated. Compounds 17-19 with a free amino group at 2-position along with the presence of an imidazole/1,2,4-triazole ring at 4-position of the scaffold showed selective binding affinities for hA2A AR, whereas carbamoylation of the amino group at 2-position (in the presence of an oxo-group at 4-position of the scaffold) increased the affinity and selectivity of certain compounds (7-10) for hA3 AR. Molecular dynamic simulation study of one of the most active compound 8 (Ki hA1  > 30 µm, hA2A  = 0.65 µm, and hA3  = 0.124 µm) revealed the role of important amino acid residues for imparting good affinity towards hA3 and hA2A ARs. Molecular docking studies were carried out for other compounds using the crystal structure of hA2A AR and a homology model of hA3 AR to rationalize their structure-activity relationships. The molecular docking results were in agreement with the experimental binding affinity data of ARs.

An appraisal on synthetic and pharmaceutical perspectives of pyrazolo[4,3-d]pyrimidine scaffold.

Pyrazolo[4,3-d]pyrimidine, a fused heterocycle bearing pyrazole and pyrimidine portions has gained a significant attention in the field of bioorganic and medicinal chemistry. Pyrazolo[4,3-d]pyrimidine derivatives have demonstrated numerous pharmacological activities particularly, anti-cancer, anti-infectious, phosphodiesterase inhibitors, adenosine antagonists and cytokinin antagonists etc. This review extensively unveils the synthetic and pharmacological diversity with special emphasis on structural variations around pyrazolo[4,3-d]pyrimidine scaffold. This endeavour has thus uncovered the medicinal worthiness of pyrazolo[4,3-d]pyrimidine framework. To the best of our knowledge this review is the first compilation on synthetic, medicinal and structure activity relationship (SAR) aspects of pyrazolo[4,3-d]pyrimidines since 1956.

An insight on synthetic and medicinal aspects of pyrazolo[1,5-a]pyrimidine scaffold.

Pyrazolo[1,5-a]pyrimidine scaffold is one of the privileged hetrocycles in drug discovery. Its application as a buliding block for developing drug-like candidates has displayed broad range of medicinal properties such as anticancer, CNS agents, anti-infectious, anti-inflammatory, CRF1 antagonists and radio diagnostics. The structure-activity relationship (SAR) studies have acquired greater attention amid medicinal chemists, and many of the lead compounds were derived for various disease targets. However, there is plenty of room for the medicinal chemists to further exploit this privileged scaffold in developing potential drug candidates. The present review briefly outlines relevant synthetic strategies employed for pyrazolo[1,5-a]pyrimidine derivatives. It also extensively reveals significant biological properties along with SAR studies. To the best of our understanding current review is the first attempt made towards the compilation of significant advances made on pyrazolo[1,5-a]pyrimidines reported since 1980s.

Synthesis of novel pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives: potent and selective adenosine A3 receptor antagonists.

A series of novel pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives 5 was prepared from 2-amino-3-cyano-4-trifluoromethyl-6-phenylpyridine 1 in two steps via formation of iminoether 3 followed by reaction with different aroylhydrazides 4. Representative products 5 were evaluated for their affinity towards all four subtypes of human adenosine receptors. Compounds 2-(3-fluorophenyl)-8-phenyl-10-(trifluoromethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (5b), 2-(furan-2-yl)-8-phenyl-10-(trifluoromethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (5d), and 2-(furan-2-yl)-5-methyl-8-phenyl-10-(trifluoromethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (5j) showed high affinity for the A3 receptors, with Ki values of 8.1, 10.4, and 12.1 nM, respectively, and were >1000-fold selective versus all other adenosine receptor subtypes.