Therapeutic potential of anticancer activity of nitrogen-containing heterocyclic scaffolds as Janus kinase (JAK) inhibitor: Biological activity, selectivity, and structure-activity relationship.

The JAK-STAT signalling pathway is primarily involved in cytokine signalling and induces various factors namely, erythropoietin, thrombopoietin, interferons, interleukins, and granulocyte colony-stimulating factors. These factors tremendously influenced understanding human health and illness, specifically cancer. Inhibiting the JAK/STAT pathway offers enormous therapeutic promises against cancer. Many JAK inhibitors are now being studied due to their efficacy in various cancer treatments. Further, the Nitrogen-heterocyclic (N-heterocyclic) scaffold has always shown to be a powerful tool for designing and discovering synthetic compounds with diverse pharmacological characteristics. The review focuses on several FDA-approved JAK inhibitors and their systematic categorization. The medicinal chemistry perspective is highlighted and classified review on the basis of N-heterocyclic molecules. Several examples of designing strategies of N-heterocyclic rings including pyrrolo-azepine, purine, 1H-pyrazolo[3,4-d]pyrimidine, 1H-pyrrolo[2,3-b]pyridine, pyrazole, thieno[3,2-d] pyrimidine, and, pyrimidine-based derivatives and their structure-activity relationships (SAR) are discussed. Among the various N-heterocyclic-based JAK inhibitors pyrimidine-containing compound 1 exhibited excellent inhibition activity against JAK2WT and mutated-JAK2V617F with IC50 of 2.01 and 18.84 nM respectively. Amino pyrimidine-containing compound 6 and thiopheno[3,2-d]pyrimidine-containing compound 13 expressed admirable JAK3 inhibition activity with IC50 of 1.7 nM and 1.38 nM respectively. Our review will support the medicinal chemists in refining and directing the development of novel N-heterocyclic-based JAK inhibitors.

Advancements of anticancer agents by targeting the Hippo signalling pathway: biological activity, selectivity, docking analysis, and structure-activity relationship.

The Hippo signalling pathway is prominent and governs cell proliferation and stem cell activity, acting as a growth regulator and tumour suppressor. Defects in Hippo signalling and hyperactivation of its downstream effector's Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) play roles in cancer development, implying that pharmacological inhibition of YAP and TAZ activity could be an effective cancer treatment strategy. Conversely, YAP and TAZ can also have beneficial effects in promoting tissue repair and regeneration following damage, therefore their activation may be therapeutically effective in certain instances. Recently, a complex network of intracellular and extracellular signalling mechanisms that affect YAP and TAZ activity has been uncovered. The YAP/TAZ-TEAD interaction leads to tumour development and the protein structure of YAP/TAZ-TEAD includes three interfaces and one hydrophobic pocket. There are clinical and preclinical trial drugs available to inhibit the hippo signalling pathway, but these drugs have moderate to severe side effects, so researchers are in search of novel, potent, and selective hippo signalling pathway inhibitors. In this review, we have discussed the hippo pathway in detail, including its structure, activation, and role in cancer. We have also provided the various inhibitors under clinical and preclinical trials, and advancement of small molecules their detailed docking analysis, structure-activity relationship, and biological activity. We anticipate that the current study will be a helpful resource for researchers.

Pyrazole, Pyrazoline, and Fused Pyrazole Derivatives: New Horizons in EGFR-Targeted Anticancer Agents.

Pyrazole and its derivatives remain popular heterocycles in drug design, and development. Pyrazole derivatives been extensively studied by the scientific community and as they possess a wide range of biological activity, especially anti-EGFR properies. Overexpression of EGFR signaling promotes tumor growth by inhibiting apoptosis. EGFR dysfunction has been described in several cancer. Therefore, EGFR represents a prospective target for cancer treatment. Several anti-EGFR drugs are thriving the market, notably dacomitinib, afatinib, erlotinib etc. However, almost all drugs have limited therapeutic effectiveness due to a lack of selectivity as well as substantial side effects.  To address this, innovative therapeutic anti-EGFR drugs with high effectiveness and low toxicity are needed. To combat therapeutic resistance to EGFR inhibitors, pyrazole, and pyrazole-based derivatives have been explored as a promising pharmacophore for developing novel compounds with higher potency, lower toxicity, and desirable pharmacokinetic profiles. The current review outlines the investigation of advancements towards anti- EGFR via pyrazole, pyrazoline, and fused pyrazole-based compounds and represents inclusive data on pyrazole-based marketed drugs as well as therapeutic candidates undergoing preclinical and clinical development. We have also summarised structure-activity relationship (SAR), mechanistic studies to afford ideas for the design and development of new anti-EGFR derivatives.

An updated literature on BRAF inhibitors (2018-2023).

BRAF is the most common serine-threonine protein kinase and regulates signal transduction from RAS to MEK inside the cell. The BRAF is a highly active isoform of RAF kinase. BRAF has two domains such as regulatory and kinase domains. The BRAF inhibitors bind in the c-terminus of the kinase domain and inhibit the downstream pathways. The mutation occurs mainly in the A-loop of the kinase domain. The mutation occurs due to a conversion of valine to glutamate/lysine/arginine/aspartic acid at 600th position. Among the diverse mutations, BRAFV600E is the most common and responsible for numerous cancer such as melanoma, colorectal, ovarian, and thyroid cancer. Due to mutations in RAC1, loss of PTEN, NF1, CCND1, USP28-FBW7 complex, COT overexpression, and CCND1 amplification, the BRAF kinase enzyme developed resistance over the commercially available BRAF inhibitors. There is still unmute urgence for the development of BRAF inhibitors to overcome the persistent limitation such as resistance, mutation, and adverse effects of drugs. In the current study, we described the structure, activation, downstream signaling pathway, and mutation of BRAF. Our group also provided a detailed review of BRAF inhibitors from the last five years (2018-2023) highlighting the structure-activity relationship, mechanistic study, and molecular docking studies. We hope that the current analysis will be a useful resource for researchers and provide chemists a glimpse into the future as design and development of more effective and secure BRAF kinase inhibitors. The development of BRAF inhibitors to overcome the persistent limitation such as resistance, mutation, and adverse effects of drugs. In depth description about different heterocyclic scaffolds (quinoline, imidazole, pyridine, triazole, pyrrole etc.) as BRAF inhibitors from the last five years (2018-2023) highlighting the structure-activity relationship, mechanistic study, and molecular docking studies.

Medicinal Chemistry Perspectives on Recent Advances in Src Kinase Inhibitors as a Potential Target for the Development of Anticancer Agents: Biological Profile, Selectivity, Structure-Activity Relationship.

The physiological Src proto-oncogene is a protein tyrosine kinase receptor that served as the essential signaling pathway in different types of cancer. Src kinase receptor is divided into different domains: a unique domain, an SH3 domain, an SH2 domain, a protein tyrosine kinase domain, and a regulatory tail, which runs from the N-terminus to the C-terminus. Src kinase inhibitors bind in the kinase domain and are activated by phosphorylation. The etiology of cancer involved various signaling pathways and Src signaling pathways are also involved in those clusters. Although the dysregulation of Src kinase resulted in cancer being discovered in the late 19th century it is still considered a cult pathway because it is not much explored by different medicinal chemists and oncologists. The Src kinase regulated through different kinase pathways (MAPK, PI3K/Akt/mTOR, JAK/STAT3, Hippo kinase, PEAK1, and Rho/ROCK pathways) and proceeded downstream signaling to conduct cell proliferation, angiogenesis, migration, invasion, and metastasis of cancer cells. There are numerous FDA-approved drugs flooded the market but still, there is a huge demand for the creation of novel anticancer drugs. As the existing drugs are accompanied by several adverse effects and drug resistance due to rapid mutation in proteins. In this review, we have elaborated about the structure and activation of Src kinase, as well as the development of Src kinase inhibitors. Our group also provided a comprehensive overview of Src inhibitors throughout the last two decades, including their biological activity, structure-activity relationship, and Src kinase selectivity. The Src binding pocket has been investigated in detail to better comprehend the interaction of Src inhibitors with amino acid residues. We have strengthened the literature with our contribution in terms of molecular docking and ADMET studies of top compounds. We hope that the current analysis will be a useful resource for researchers and provide glimpse of direction toward the design and development of more specific, selective, and potent Src kinase inhibitors.

Management of COVID-19-induced cytokine storm by Keap1-Nrf2 system: a review.

The natural pathway of antioxidant production is mediated through Kelch-like erythroid cell-derived protein with Cap and collar homology [ECH]-associated protein 1 (Keap1)-Nuclear factor erythroid 2-related factor 2 (Nrf2) system. Keap1 maintains a low level of Nrf2 by holding it in its protein complex. Also, Keap1 facilitates the degradation of Nrf2 by ubiquitination. In other words, Keap1 is a down-regulator of Nrf2. To boost the production of biological antioxidants, Keap1 has to be inhibited and Nrf2 has to be released. Liberated Nrf2 is in an unbound state, so it travels to the nucleus to stimulate the antioxidant response element (ARE) present on the antioxidant genes. AREs activate biosynthesis of biological antioxidants through genes responsible for the production of antioxidants. In some cases of coronavirus disease 2019 (COVID-19), there is an enormous release of cytokines. The antioxidant defense mechanism in the body helps in counteracting symptoms induced by the cytokine storm in COVID-19. So, boosting the production of antioxidants is highly desirable in such a condition. In this review article, we have compiled the role of Keap1-Nrf2 system in antioxidant production. We further propose its potential therapeutic use in managing cytokine storm in COVID-19.

Poly (ADP-ribose) polymerase (PARP) inhibitors as anticancer agents: An outlook on clinical progress, synthetic strategies, biological activity, and structure-activity relationship.

Poly (ADP-ribose) polymerase (PARP) is considered an essential component in case of DNA (Deoxyribonucleic acid) damage, response by sensing DNA damage and engaging DNA repair proteins. Those proteins repair the damaged DNA via an aspect of posttranslational modification, known as poly (ADP-Ribosyl)ation (PARylation). Specifically, PARP inhibitors (PARPi) have shown better results when administered alone in a variety of cancer types with BRCA (Breast Cancer gene) mutation. The clinical therapeutic benefits of PARP inhibitors have been diminished by their cytotoxicity, progression of drug resistance, and limitation of indication, regardless of their tremendous clinical effectiveness. A growing number of PARP-1 inhibitors, particularly those associated with BRCA-1/2 mutations, have been identified as potential cancer treatments. Recently, several researchers have identified various promising scaffolds, which have resulted in the resuscitation of the faith in PARP inhibitors as cancer therapies. This review provided a comprehensive update on the anatomy and physiology of the PARP enzyme, the profile of FDA (Food and Drug Administration) and CFDA (China Food and Drug Administration)-approved drugs, and small-molecule inhibitors of PARP, including their synthetic routes, biological evaluation, selectivity, and structure-activity relationship.

An insight into sustainable and green chemistry approaches for the synthesis of quinoline derivatives as anticancer agents.

Quinolones, a key class of heterocyclics, are gaining popularity among organic and medicinal chemists due to their promising properties. Quinoline, with its broad spectrum of action, plays a primordial role in chemotherapy for cancer. Drugs include lenvatinib and its structural derivatives carbozantinib and bosutinib, and tipifarnib are the popular anticancer agents. Owing to the importance of quinoline, there are several classical methods for the synthesis such as, such as Gould-Jacobs, Conrad-Limpach, Camps cyclization, Skraup, Doebnervon Miller, Combes, Friedlander, Pfitzinger, and Niementowski synthesis. These methods are well-commended for developing an infinite variety of quinoline analogues. However, these procedures are associated with several drawbacks such as long reaction times, use of hazardous chemicals or stoichiometric proportions, difficulty of working up conditions, high temperatures, organic solvents, and the presence of numerous steps, all of which have an impact on the environment and the economy. As a result, researchers are working hard to develop green quinoline compounds in the hopes of making groundbreaking discoveries in the realm of cancer. In this review, we have highlighted significant research on quinoline-based compounds and their structure-activity relationship (SAR). Furthermore, because of the significant economic and environmental health and safety (EHS) concerns, more research is being dedicated to the green synthesis of quinolone derivatives. The current review offers recent advances in quinoline derivatives as anticancer agents for green synthesis using microwave, ultrasound, and one-pot synthesis. We believe that our findings will provide useful insight and inspire more green research on this framework to produce powerful and selective quinoline derivatives.

The role of natural anti-parasitic guided development of synthetic drugs for leishmaniasis.

Leishmaniasis is a parasitic disease and categorised as a neglected tropical disease (NTD). Each year, between 70,0000 and 1 million new cases are believed to occur. There are approximately 90 sandfly species which can spread the Leishmania parasites (over 20 species) causing 20,000 to 30,000 death per year. Currently, leishmaniasis has no specific therapeutic treatment available. The prescribed drugs with several drawbacks including high cost, challenging administration, toxicity, and drug resistance led to search for the alternative treatment with less toxicity and selectivity. Introducing the molecular features like that of phytoconstituents for the search of compounds with less toxicity is another promising approach. The current review classifies the synthetic compounds according to the core rings present in the natural phytochemicals for the development of antileishmanial agents (2020-2022). Considering the toxicity and limitations of synthetic analogues, natural compounds are at the higher notch in terms of effectiveness and safety. Synthesized compounds of chalcones (Compound 8; IC50: 0.03 µM, 4.7 folds more potent than Amphotericin B; IC50: 0.14 µM), pyrimidine (compound 56; against L. tropica; 0.04 µM and L. infantum; 0.042 µM as compared to glucantime: L. tropica; 8.17 µM and L. infantum; 8.42 µM), quinazoline and (compound 72; 0.021 µM, 150 times more potent than miltefosine). The targeted delivery against DHFR have been demonstrated by one of the pyrimidine compounds 62 with an IC50 value of 0.10 µM against L. major as compared to the standard trimethoprim (IC50: 20 µM). The review covers the medicinal importance of antileishmanial agents from synthetic and natural sources such as chalcone, pyrazole, coumarins, steroids, and alkaloidal-containing drugs (indole, quinolines, pyridine, pyrimidine, carbolines, pyrrole, aurones, and quinazolines). The efforts of introducing the core rings present in the natural phytoconstituents as antileishmanial in the synthetic compounds are discussed with their structural activity relationship. The perspective will support the medicinal chemists in refining and directing the development of novel molecules phytochemicals-based antileishmanial agents.