Natural products as IL-6 inhibitors for inflammatory diseases: Synthetic and SAR perspective.

Interleukin-6 (IL-6), a pleiotropic cytokine, plays a pivotal role in the pathophysiology of various diseases including diabetes, atherosclerosis, Alzheimer's disease, multiple myeloma, rheumatoid arthritis, and prostate cancer. The signaling pathways associated with IL-6 offer promising targets for therapeutic interventions in inflammatory diseases and IL-6-dependent tumors. Although certain anti-IL-6 monoclonal antibodies are currently employed clinically, their usage is hampered by drawbacks such as high cost and potential immunogenicity, limiting their application. Thus, the imperative arises to develop novel small non-peptide molecules acting as IL-6 inhibitors. Various natural products derived from diverse sources have been investigated for their potential to inhibit IL-6 activity. Nevertheless, these natural products remain inadequately explored in terms of their structure-activity relationships. In response, our review aims to provide syntheses and structure activity perspective of natural IL-6 inhibitors. The comprehensive amalgamation of information presented in this review holds the potential to serve as a foundation for forthcoming research endeavors by medicinal chemists, facilitating the design of innovative IL-6 inhibitors to address the complexities of inflammatory diseases.

Chalcone-based benzenesulfonamides as potent and selective inhibitors for human carbonic anhydrase II: Design, synthesis, in vitro, and in silico studies.

Sulfonamides are promising classical carbonic anhydrase (CA; EC 4.2.1.1) inhibitors, being used for several medical purposes such as diuretics, anticonvulsants, topically acting antiglaucoma agents, for antiobesity and anticancer therapies. Herein, a series of chalcone-based benzenesulfonamides (3a‒m) was synthesized and assessed for its inhibitory activity against a panel of four human carbonic anhydrases (hCA isoforms I, II, IX, and XII). Most compounds displayed single- to double-digit nanomolar inhibition constants (Kis), with some derivatives being more potent and/or selective than the standard drug acetazolamide (AAZ). Among the synthesized compounds, 3g compound demonstrated the highest inhibitory activity against the hCA II isoform (Ki = 2.5 nM) with 30-, 9-, and 11-fold selectivity for hCA II over the I, IX, and XII isoforms, respectively. Structure-activity relationships for different substitution patterns were analyzed. Additionally, a molecular docking study showed that compound 3g bound to hCA II by coordinating with the zinc ion through the deprotonated benzenesulfonamide moiety, in addition to a hydrogen bond formed between an oxygen of the sulfonamide moiety and Thr199. Moreover, the chalcone core participated in van der Waals interactions with some active site residues, such as Ile91, Val121, and Leu198. Consequently, this report introduces a successful approach toward identifying compound 3g as a highly potent and selective chalcone-based benzenesulfonamide inhibitor of hCA II worthy of further investigation.

A novel indole derivative, 2-{3-[1-(benzylsulfonyl)piperidin-4-yl]-2-methyl-1H-indol-1-yl}-1-(pyrrolidin-1-yl)ethenone, suppresses hedgehog signaling and drug-resistant tumor growth.

The Hedgehog (Hh) signaling pathway plays important roles in various physiological functions. Several malignancies, such as basal cell carcinoma (BCC) and medulloblastoma (MB), have been linked to the aberrant activation of Hh signaling. Although therapeutic drugs have been developed to inhibit Hh pathway-dependent cancer growth, drug resistance remains a major obstacle in cancer treatment. Here, we show that the newly identified, 2-{3-[1-(benzylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]-2-methyl-1H-indol-1-yl}-1-(pyrrolidin-1-yl)ethenone analog (LKD1214) exhibits comparable potency to vismodegib in suppressing the Hh pathway activation. LKD1214 represses Smoothened (SMO) activity by blocking its ciliary translocation. Interestingly, we also identified that it has a distinctive binding interface with SMO compared with other SMO-regulating chemicals. Notably, it maintains an inhibitory activity against the SmoD477H mutant, as observed in a patient with vismodegib-resistant BCC. Furthermore, LKD1214 inhibits tumor growth in the mouse model of MB. Collectively, these findings suggest that LKD1214 has the therapeutic potential to overcome drug-resistance in Hh-dependent cancers.

Small Molecule c-KIT Inhibitors for the Treatment of Gastrointestinal Stromal Tumors: A Review on Synthesis, Design Strategies, and Structure-Activity Relationship (SAR).

The proto-oncogenic protein, c-KIT, plays a crucial role in regulating cellular transformation and differentiation processes, such as proliferation, survival, adhesion, and chemotaxis. The overexpression of, and mutations, in c-KIT can lead to its dysregulation and promote various human cancers, particularly gastrointestinal stromal tumors (GISTs); approximately 80-85% of cases are associated with oncogenic mutations in the KIT gene. Inhibition of c-KIT has emerged as a promising therapeutic target for GISTs. However, the currently approved drugs are associated with resistance and significant side effects, highlighting the urgent need to develop highly selective c-KIT inhibitors that are not affected by these mutations for GISTs. Herein, the recent research efforts in medicinal chemistry aimed at developing potent small-molecule c-KIT inhibitors with high kinase selectivity for GISTs are discussed from a structure-activity relationship perspective. Moreover, the synthetic pathways, pharmacokinetic properties, and binding patterns of the inhibitors are also discussed to facilitate future development of more potent and pharmacokinetically stable small-molecule c-KIT inhibitors.

Integration of Hybridization Strategies in Pyridine-Urea Scaffolds for Novel Anticancer Agents: Design, Synthesis, and Mechanistic Insights.

Annually, millions of new cancer cases are reported, leading to millions of deaths worldwide. Among the newly reported cases, breast and colon cancers prevail as the most frequently detected variations. To effectively counteract this rapid increase, the development of innovative therapies is crucial. Small molecules possessing pyridine and urea moieties have been reported in many of the currently available anticancer agents, especially VEGFR2 inhibitors. With this in mind, a rational design approach was employed to create hybrid small molecules combining urea and pyridine. These synthesized compounds underwent in vitro testing against breast and colon cancer cell lines, revealing potent submicromolar anticancer activity. Compound 8a, specifically, exhibited an impressive GI50 value of 0.06 µM against the MCF7 cancer cell line, while compound 8h displayed the highest cytotoxic activity against the HCT116 cell line, with a GI50 of 0.33 ± 0.042 µM. Notably, compounds 8a, 8h, and 8i demonstrated excellent safety profiles when tested on normal cells. Molecular docking, dynamic studies, and free energy calculations were employed to validate the affinity of these compounds as VEGFR2 inhibitors.

4-Anilinoquinazoline-based benzenesulfonamides as nanomolar inhibitors of carbonic anhydrase isoforms I, II, IX, and XII: design, synthesis, in-vitro, and in-silico biological studies.

Human carbonic anhydrase inhibitors (hCAIs) are a key therapeutic class with a multitude of novel applications such as anticonvulsants, topically acting antiglaucoma, and anticancer drugs. Herein, a new series of 4-anilinoquinazoline-based benzenesulfonamides were designed, synthesised, and biologically assessed as potential hCAIs. The target compounds are based on the well-tolerated kinase scaffold (4-anilinoquinazoline). Compounds 3a (89.4 nM), 4e (91.2 nM), and 4f (60.9 nM) exhibited 2.8, 2.7, and 4 folds higher potency against hCA I when compared to the standard (AAZ, V), respectively. A single digit nanomolar activity was elicited by compounds 3a (8.7 nM), 4a (2.4 nM), and 4e (4.6 nM) with 1.4, 5, and 2.6 folds of potency compared to AAZ (12.1 nM) against isoform hCA II, respectively. Structure-activity relationship (SAR) and molecular docking studies validated our design approach that revealed highly potent hCAIs.

Identification of Novel and Potent Indole-Based Benzenesulfonamides as Selective Human Carbonic Anhydrase II Inhibitors: Design, Synthesis, In Vitro, and In Silico Studies.

In recent decades, human carbonic anhydrase inhibitors (hCAIs) have emerged as an important therapeutic class with various applications including antiglaucoma, anticonvulsants, and anticancer agents. Herein, a novel series of indole-based benzenesulfonamides were designed, synthesized, and biologically evaluated as potential hCAIs. A regioisomerism of the sulfonamide moiety was carried out to afford a total of fifteen indole-based benzenesulfonamides possessing different amide linkers that enable the ligands to be flexible and develop potential H-bond interaction(s) with the target protein. The activity of the synthesized compounds was evaluated against four hCA isoforms (I, II, IX and, XII). Compounds 2b, 2c, 2d, 2f, 2h and 2o exhibited potent and selective profiles over the hCA II isoform with Ki values of 7.3, 9.0, 7.1, 16.0, 8.6 and 7.5 nM, respectively. Among all, compound 2a demonstrated the most potent inhibition against the hCA II isoform with an inhibitory constant (Ki) of 5.9 nM, with 13-, 34-, and 9-fold selectivity for hCA II over I, IX and XII isoforms, respectively. Structure-activity relationship data attained for various substitutions were rationalized. Furthermore, a molecular docking study gave insights into both inhibitory activity and selectivity of the target compounds. Accordingly, this report presents a successful scaffold hoping approach that reveals compound 2a as a highly potent and selective indole-based hCA II inhibitor worthy of further investigation.

The Journey of DDR1 and DDR2 Kinase Inhibitors as Rising Stars in the Fight Against Cancer.

Discoidin domain receptor (DDR) is a collagen-activated receptor tyrosine kinase that plays critical roles in regulating essential cellular processes such as morphogenesis, differentiation, proliferation, adhesion, migration, invasion, and matrix remodeling. As a result, DDR dysregulation has been attributed to a variety of human cancer disorders, for instance, non-small-cell lung carcinoma (NSCLC), ovarian cancer, glioblastoma, and breast cancer, in addition to some inflammatory and neurodegenerative disorders. Since the target identification in the early 1990s to date, a lot of efforts have been devoted to the development of DDR inhibitors. From a medicinal chemistry perspective, we attempted to reveal the progress in the development of the most promising DDR1 and DDR2 small molecule inhibitors covering their design approaches, structure-activity relationship (SAR), biological activity, and selectivity.

Structure Activity Relationship of Key Heterocyclic Anti-Angiogenic Leads of Promising Potential in the Fight against Cancer.

Pathological angiogenesis is a hallmark of cancer; accordingly, a number of anticancer FDA-approved drugs act by inhibiting angiogenesis via different mechanisms. However, the development process of the most potent anti-angiogenics has met various hurdles including redundancy, multiplicity, and development of compensatory mechanisms by which blood vessels are remodeled. Moreover, identification of broad-spectrum anti-angiogenesis targets is proved to be required to enhance the efficacy of the anti-angiogenesis drugs. In this perspective, a proper understanding of the structure activity relationship (SAR) of the recent anti-angiogenics is required. Various anti-angiogenic classes have been developed over the years; among them, the heterocyclic organic compounds come to the fore as the most promising, with several drugs approved by the FDA. In this review, we discuss the structure-activity relationship of some promising potent heterocyclic anti-angiogenic leads. For each lead, a molecular modelling was also carried out in order to correlate its SAR and specificity to the active site. Furthermore, an in silico pharmacokinetics study for some representative leads was presented. Summarizing, new insights for further improvement for each lead have been reviewed.

Inhibition studies on a panel of human carbonic anhydrases with N1-substituted secondary sulfonamides incorporating thiazolinone or imidazolone-indole tails.

Being the primary sulfonamide among the most efficient zinc binding group (ZBG) to design inhibitors for the metallo-enzymes carbonic anhydrases (CA, EC 4.2.1.1), herein, we propose an investigation on four physiologically important human (h) CAs (hCA I, II, IV, and IX) with N1-substituted secondary sulfonamides incorporating thiazolinone or imidazolone-indole tails. The effect of the functionalisation of the sulfonamide group with five different substitution patterns, namely acetyl, pyridine, thiazole, pyrimidine, and carbamimidoyl, was evaluated in relation to the inhibition profile of the corresponding primary sulfonamide analogues. With most of these latter being nanomolar inhibitors of all four considered isoforms, a totally counterproductive effect on the inhibition potency can be ascribed to N1-functionalisations of the ZBG primary sulfonamide structure with pyridine, thiazole, and pyrimidine moieties. On the other hand, incorporation of less hindered groups, such as sulfonylacetamides and sulfonylguanidines, maintained a certain degree of activity dependent on the tailing moiety, with KIs spanning in the low micromolar range.

PT-Finder: A multi-modal neural network approach to target identification.

Efficient target identification for bioactive compounds, including novel synthetic analogs, is crucial for accelerating the drug discovery pipeline. However, the process of target identification presents significant challenges and is often expensive, which in turn can hinder the drug discovery efforts. To address these challenges machine learning applications have arisen as a promising approach for predicting the targets for novel chemical compounds. These methods allow the exploration of ligand-target interactions, uncovering of biochemical mechanisms, and the investigation of drug repurposing. Typically, the current target identification tools rely on assessing ligand structural similarities. Herein, a multi-modal neural network model was built using a library of proteins, their respective sequences, and active inhibitors. Subsequent validations showed the model to possess accuracy of 82 % and MPRAUC of 0.80. Leveraging the trained model, we developed PT-Finder (Protein Target Finder), a user-friendly offline application that is capable of predicting the target proteins for hundreds of compounds within a few seconds. This combination of offline operation, speed, and accuracy positions PT-Finder as a powerful tool to accelerate drug discovery workflows. PT-Finder and its source codes have been made freely accessible for download at https://github.com/PT-Finder/PT-Finder.

From pixels to druggable leads: A CADD strategy for the design and synthesis of potent DDR1 inhibitors.

BACKGROUND AND OBJECTIVE: While numerous in silico tools exist for target-based drug discovery, the inconsistent integration of in vitro data with predictive models hinders research and development productivity. This is particularly apparent during the Hit-to-Lead stage, where unreliable in-silico tools often lead to suboptimal lead selection. Herein, we address this challenge by presenting a CADD-guided pipeline that successfully integrates rational drug design with in-silico hits to identify a promising DDR1 lead. METHODS: 2 × 1000 ns MD simulations along with their respective FEL and MMPBSA analyses were employed to guide the rational design and synthesis of 12 novel compounds which were evaluated for their DDR inhibition. RESULTS: The molecular dynamics investigation of the initial hit led to the identification of key structural features within the DDR1 binding pocket. The identified key features were used to guide the rational design and synthesis of twelve novel derivatives. SAR analysis, biological evaluation, molecular dynamics, and free energy calculations were carried out for the synthesized derivatives to understand their mechanism of action. Compound 4c exhibited the strongest inhibition and selectivity for DDR1, with an IC50 of 0.11 µM. CONCLUSIONS: The MD simulations led to the identification of a key hydrophobic groove in the DDR1 binding pocket. The integrated approach of SAR analysis with molecular dynamics led to the identification of compound 4c as a promising lead for further development of potent and selective DDR1 inhibitors. Moreover, this work establishes a protocol for translating in silico hits to real world bioactive druggable leads.

Chemical induction of the interaction between AIMP2-DX2 and Siah1 to enhance ubiquitination.

AIMP2-DX2 (hereafter DX2) is an oncogenic variant of aminoacyl-tRNA synthetase-interacting multifunctional protein 2 (AIMP2) that mediates tumorigenic interactions with various factors involved in cancer. Reducing the levels of DX2 can effectively inhibit tumorigenesis. We previously reported that DX2 can be degraded through Siah1-mediated ubiquitination. In this study, we identified a compound, SDL01, which enhanced the interaction between DX2 and Siah1, thereby facilitating the ubiquitin-dependent degradation of DX2. SDL01 was found to bind to the pocket surrounding the N-terminal flexible region and GST domain of DX2, causing a conformational change that stabilized its interaction with Siah1. Our findings demonstrate that protein-protein interactions (PPIs) can be modulated through chemically induced conformational changes.

Identification of Potent hDHODH Inhibitors for Lung Cancer via Virtual Screening of a Rationally Designed Small Combinatorial Library.

Cancer is characterized by altered cellular metabolism, and metabolic enzymes are considered as a promising target for anticancer therapy. Pyrimidine metabolism dysregulation is associated with various types of cancer, particularly lung cancer, which is one of the leading causes of cancer-related mortality worldwide. Recent studies have shown that small-cell lung cancer cells are particularly reliant on the pyrimidine biosynthesis pathway and are sensitive to its disruption. DHODH, the rate-limiting enzyme of the de novo pyrimidine production pathway, is essential in the production of RNA and DNA and is overexpressed in malignancies such as AML, skin cancer, breast cancer, and lung cancer, thereby highlighting DHODH as a viable target for developing drugs to combat lung cancer. Herein, rational drug design and computational techniques were used to discover novel DHODH inhibitors. A small combinatorial library was generated, and the top hits were synthesized and tested for anticancer activity against three lung cancer cell lines. Among the tested compounds, compound 5c possessed a stronger cytotoxicity (TC50 of 11 µM) compared to the standard FDA-approved drug (Regorafenib, TC50 of 13 µM) on the A549 cell line. Furthermore, compound 5c demonstrated potent inhibitory activity against hDHODH at a nanomolar level of 421 nM. DFT, molecular docking, molecular dynamic simulations, and free energy calculations were also carried out to understand the inhibitory mechanisms of the synthesized scaffolds. These in silico studies identified key mechanisms and structural features that will be crucial for future studies.

Discovery and optimization of natural-based nanomolar c-Kit inhibitors via in silico and in vitro studies.

c-Kit is a receptor tyrosine kinase which is involved in intracellular signaling and mutations of c-Kit have been associated with various types of cancers. Investigations have shown that inhibition of c-Kit, using tyrosine kinase inhibitors, yielded promising results in cancer treatment marking it as a promising target for cancer therapy. However, the emerging resistance for the current therapy necessitates the development of more potent inhibitors which are not affected by these mutations. Herein, virtual screening of a library of natural-based compounds yielded three hits (2, 5 and 6) which possessed nanomolar inhibitory (2.02, 4.33 and 2.80 nM, respectively) activity when tested in vitro against c-Kit. Single point mutation docking studies showed the hits to be unaffected by the most common resistance mutation in imatinib-resistant cells, mutation of Val654. Although, the top hits exhibited around 3000 higher inhibitory potency toward c-Kit when compared to imatinib (5.4 µM), previous studies have shown that they are metabolically unstable. Fragment-based drug design approaches were then employed to enhance binding affinity of the top hit and make it more metabolically stable. Screening of the generated fragments yielded a new derivative, F1, which demonstrated stronger binding affinity, stability and binding free energy when compared to the hit compound 2.Communicated by Ramaswamy H. Sarma.

Cantharidin-Based Verbenone Derivatives as a Novel Insecticide against Plutella xylostella: Design, Synthesis, Insecticidal Activity Evaluation, and 3D QSAR Study.

The diamondback moth is a detrimental insect pest of brassicaceous crops which was among the first crop insects to be reported as DDT resistant. It has since proven to be significantly resistant to nearly every synthetic insecticide used in the field in many crucifer-producing regions. Due to insecticide control failures in some parts of the world, economically viable crucifer production is now all but impossible. As a result, there has been an increasing effort to identify new compounds with strong pesticidal activity. Cantharidin is one such compound that has been shown to be highly effective against a variety of insect pests. However, its chemical synthesis and potential toxicity to non-target organisms have been a major source of concern. Herein, using rational design approaches, a new series of cantharidin-based verbenone derivatives were synthesized and evaluated for their insecticidal activities against the diamondback moth. Among different compounds screened, compounds 6a, 6h, 6i, and 6q emerged as the most potent compounds exhibiting 100% mortality at a concentration of 100 mg/L after four days. These compounds demonstrated a good anti-feeding effect against the diamondback moth on cabbage leaves. Subsequently, a 3D QSAR study was carried out to identify the key structural features of the synthesized compounds and their correlation with insecticidal activity.

Perspective for Discovery of Small Molecule IL-6 Inhibitors through Study of Structure-Activity Relationships and Molecular Docking.

Interleukin-6 (IL-6) is a proinflammatory cytokine that plays a key role in the pathogenesis and physiology of inflammatory and autoimmune diseases, such as coronary heart disease, cancer, Alzheimer's disease, asthma, rheumatoid arthritis, and most recently COVID-19. IL-6 and its signaling pathway are promising targets in the treatment of inflammatory and autoimmune diseases. Although, anti-IL-6 monoclonal antibodies are currently being used in clinics, huge unmet medical needs remain because of the high cost, administration-related toxicity, lack of opportunity for oral dosing, and potential immunogenicity of monoclonal antibody therapy. Furthermore, nonresponse or loss of response to monoclonal antibody therapy has been reported, which increases the importance of optimizing drug therapy with small molecule drugs. This work aims to provide a perspective for the discovery of novel small molecule IL-6 inhibitors by the analysis of the structure-activity relationships and computational studies for protein-protein inhibitors targeting the IL-6/IL-6 receptor/gp130 complex.

Machine Learning-Based Approach to Developing Potent EGFR Inhibitors for Breast Cancer-Design, Synthesis, and In Vitro Evaluation.

The epidermal growth factor receptor (EGFR) is vital for regulating cellular functions, including cell division, migration, survival, apoptosis, angiogenesis, and cancer. EGFR overexpression is an ideal target for anticancer drug development as it is absent from normal tissues, marking it as tumor-specific. Unfortunately, the development of medication resistance limits the therapeutic efficacy of the currently approved EGFR inhibitors, indicating the need for further development. Herein, a machine learning-based application that predicts the bioactivity of novel EGFR inhibitors is presented. Clustering of the EGFR small-molecule inhibitor (∼9000 compounds) library showed that N-substituted quinazolin-4-amine-based compounds made up the largest cluster of EGFR inhibitors (∼2500 compounds). Taking advantage of this finding, rational drug design was used to design a novel series of 4-anilinoquinazoline-based EGFR inhibitors, which were first tested by the developed artificial intelligence application, and only the compounds which were predicted to be active were then chosen to be synthesized. This led to the synthesis of 18 novel compounds, which were subsequently evaluated for cytotoxicity and EGFR inhibitory activity. Among the tested compounds, compound 9 demonstrated the most potent antiproliferative activity, with 2.50 and 1.96 µM activity over MCF-7 and MDA-MB-231 cancer cell lines, respectively. Moreover, compound 9 displayed an EGFR inhibitory activity of 2.53 nM and promising apoptotic results, marking it a potential candidate for breast cancer therapy.

Design, Synthesis and Biological Evaluation of Novel MDH Inhibitors Targeting Tumor Microenvironment.

MDH1 and MDH2 enzymes play an important role in the survival of lung cancer. In this study, a novel series of dual MDH1/2 inhibitors for lung cancer was rationally designed and synthesized, and their SAR was carefully investigated. Among the tested compounds, compound 50 containing a piperidine ring displayed an improved growth inhibition of A549 and H460 lung cancer cell lines compared with LW1497. Compound 50 reduced the total ATP content in A549 cells in a dose-dependent manner; it also significantly suppressed the accumulation of hypoxia-inducible factor 1-alpha (HIF-1α) and the expression of HIF-1α target genes such as GLUT1 and pyruvate dehydrogenase kinase 1 (PDK1) in a dose-dependent manner. Furthermore, compound 50 inhibited HIF-1α-regulated CD73 expression under hypoxia in A549 lung cancer cells. Collectively, these results indicate that compound 50 may pave the way for the development of next-generation dual MDH1/2 inhibitors to target lung cancer.

Identification of 1H-purine-2,6-dione derivative as a potential SARS-CoV-2 main protease inhibitor: molecular docking, dynamic simulations, and energy calculations.

The rapid spread of the coronavirus since its first appearance in 2019 has taken the world by surprise, challenging the global economy, and putting pressure on healthcare systems across the world. The introduction of preventive vaccines only managed to slow the rising death rates worldwide, illuminating the pressing need for developing effective antiviral therapeutics. The traditional route of drug discovery has been known to require years which the world does not currently have. In silico approaches in drug design have shown promising results over the last decade, helping to decrease the required time for drug development. One of the vital non-structural proteins that are essential to viral replication and transcription is the SARS-CoV-2 main protease (Mpro). Herein, using a test set of recently identified COVID-19 inhibitors, a pharmacophore was developed to screen 20 million drug-like compounds obtained from a freely accessible Zinc database. The generated hits were ranked using a structure based virtual screening technique (SBVS), and the top hits were subjected to in-depth molecular docking studies and MM-GBSA calculations over SARS-COV-2 Mpro. Finally, the most promising hit, compound (1), and the potent standard (III) were subjected to 100 ns molecular dynamics (MD) simulations and in silico ADME study. The result of the MD analysis as well as the in silico pharmacokinetic study reveal compound 1 to be a promising SARS-Cov-2 MPro inhibitor suitable for further development.