Targeting the PI3K/AKT signaling pathway in anticancer research: a recent update on inhibitor design and clinical trials (2020-2023).

INTRODUCTION: Recent years have witnessed great achievements in drug design and development targeting the phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT) signaling pathway, a pathway central to cell growth and proliferation. The nearest neighbor protein-protein interaction networks for PI3K and AKT show the interplays between these target proteins which can be harnessed for drug discovery. In this review, we discuss the drug design and clinical development of inhibitors of PI3K/AKT in the past three years. We review in detail the structures, selectivity, efficacy, and combination therapy of 35 inhibitors targeting these proteins, classified based on the target proteins. Approaches to overcoming drug resistance and to minimizing toxicities are discussed. Future research directions for developing combinational therapy and PROTACs of PI3K and AKT inhibitors are also discussed. AREA COVERED: This review covers clinical trial reports and patent literature on inhibitors of PI3K and AKT published between 2020 and 2023. EXPERT OPINION: To address drug resistance and drug toxicity of inhibitors of PI3K and AKT, it is highly desirable to design and develop subtype-selective PI3K inhibitors or subtype-selective AKT1 inhibitors to minimize toxicity or to develop allosteric drugs that can form covalent bonds. The development of PROTACs of PI3Kα or AKT helps to reduce off-target toxicities.

Targeting the EGFR/RAS/RAF signaling pathway in anticancer research: a recent update on inhibitor design and clinical trials (2020-2023).

INTRODUCTION: Recent years have seen significant strides in drug developmenttargeting the EGFR/RAS/RAF signaling pathway which is critical forcell growth and proliferation. Protein-protein interaction networksamong EGFR, RAS, and RAF proteins offer insights for drug discovery. This review discusses the drug design and development efforts ofinhibitors targeting these proteins over the past 3 years, detailingtheir structures, selectivity, efficacy, and combination therapy.Strategies to combat drug resistance and minimize toxicities areexplored, along with future research directions. AREA COVERED: This review encompasses clinical trials and patents on EGFR, KRAS,and BRAF inhibitors from 2020 to 2023, including advancements indesign and synthesis of proteolysis targeting chimeras (PROTACs) forprotein degradation. EXPERT OPINION: To tackle drug resistance, designing allosteric fourth-generationEGFR inhibitors is vital. Covalent, allosteric, or combinationaltherapies, along with PROTAC degraders, are key methods to addressresistance and toxicity in KRAS and BRAF inhibitors.

Chemical Synthesis, Biological Evaluation, and Cheminformatics Analysis of a Group of Chlorinated Diaryl Sulfonamides: Promising Inhibitors of Cholesteryl Ester Transfer Protein.

BACKGROUND: Hyperlipidemia is characterized by an abnormally elevated serum cholesterol, triglycerides, or both. The relationship between an elevated level of LDL and cardiovascular diseases is well-established. Cholesteryl ester transfer protein (CETP) is an enzyme that moves cholesterol esters and triglycerides between LDL, VLDL, and HDL. CETP inhibition leads to a reduction in cardiovascular disease by raising HDL and minimizing LDL. OBJECTIVE: This study synthesized ten meta-chlorinated benzene sulfonamides 6a-6j and explored their structure-activity relationship. METHODS: The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR, and HR-MS. Moreover, cheminformatics analyses included pharmacophore mapping, LibDock studies, and cheminformatics characterization using 2-dimensional (2D) molecular descriptors and principal component analysis. RESULTS: Based on in vitro functional CETP assays, compounds 6e, 6i, and 6j demonstrated the strongest inhibitory activities against CETP, reaching 100% inhibition. The inhibitory activity of compounds 6a-6d and 6f-6h ranged from 47.5% to 96.5% at 10 µM concentration. Pharmacophore mapping results suggested CETP inhibitory action, while the docking scores and calculated binding energies predicted favoring binding at the CETP active site. Best-scoring docking poses predicted critical hydrophobic features corresponding to key interactions with His232 and Cys13. Cheminformatics analysis using 2D molecular descriptors indicated that the synthesized compounds span various physicochemical properties and drug-likeness. CONCLUSION: It was found that a chloro moiety at the ortho-position, or a nitro group at the meta and para-positions, improves the CETP inhibitory activity of synthesized analogs. Computational studies suggest the formation of stable ligand-protein complexes between compounds 6a- 6j and CETP.

A cross-sectional study confirms temporary post-COVID-19 vaccine menstrual irregularity and the associated physiological changes among vaccinated women in Jordan.

Background: COVID-19 vaccines continue to save people's lives around the world; however, some vaccine adverse events have been a major concern which slowed down vaccination campaigns. Anecdotal evidence pointed to the vaccine effect on menstruation but evidence from the adverse event reporting systems and the biomedical literature was lacking. This study aimed to investigate the physiological changes in women during menstruation amid the COVID-19 vaccination. Methods: A cross-sectional online survey was distributed to COVID-19 vaccinated women from Nov 2021 to Jan 2022. The results were analyzed using the SPSS software. Results: Among the 564 vaccinated women, 52% experienced significant menstrual irregularities post-vaccination compared to before regardless of the vaccine type. The kind of menstrual irregularity varied among the vaccinated women, for example, 33% had earlier menstruation, while 35% reported delayed menstruation. About 31% experienced heavier menstruation, whereas 24% had lighter menstrual flow. About 29% had menstruation last longer, but 13% had it shorter than usual. Noteworthy, the menstrual irregularities were more frequent after the second vaccine shot, and they disappeared within 3 months on average. Interestingly, 24% of the vaccinated women reported these irregularities to their gynecologist. Conclusion: The COVID-19 vaccine may cause physiological disturbances during menstruation. Luckily, these irregularities were short-termed and should not be a reason for vaccine hesitancy in women. Further studies are encouraged to unravel the COVID-19 vaccine adverse effect on women's health.

Identifying a causal link between prolactin signaling pathways and COVID-19 vaccine-induced menstrual changes.

COVID-19 vaccines have been instrumental tools in the fight against SARS-CoV-2 helping to reduce disease severity and mortality. At the same time, just like any other therapeutic, COVID-19 vaccines were associated with adverse events. Women have reported menstrual cycle irregularity after receiving COVID-19 vaccines, and this led to renewed fears concerning COVID-19 vaccines and their effects on fertility. Herein we devised an informatics workflow to explore the causal drivers of menstrual cycle irregularity in response to vaccination with mRNA COVID-19 vaccine BNT162b2. Our methods relied on gene expression analysis in response to vaccination, followed by network biology analysis to derive testable hypotheses regarding the causal links between BNT162b2 and menstrual cycle irregularity. Five high-confidence transcription factors were identified as causal drivers of BNT162b2-induced menstrual irregularity, namely: IRF1, STAT1, RelA (p65 NF-kB subunit), STAT2 and IRF3. Furthermore, some biomarkers of menstrual irregularity, including TNF, IL6R, IL6ST, LIF, BIRC3, FGF2, ARHGDIB, RPS3, RHOU, MIF, were identified as topological genes and predicted as causal drivers of menstrual irregularity. Our network-based mechanism reconstruction results indicated that BNT162b2 exerted biological effects similar to those resulting from prolactin signaling. However, these effects were short-lived and didn't raise concerns about long-term infertility issues. This approach can be applied to interrogate the functional links between drugs/vaccines and other side effects.

A Critical Assessment of COVID-19 Genomic Vaccines.

Vaccines are instrumental tools to fight against novel and re-emerging pathogens and curb pandemics. Vaccination has been an integral part of the multifaceted public health response to the COVID-19 pandemic. Diverse vaccine platforms have been designed and are currently at different stages of development. Some vaccines are still in early biological testing, while others have been launched after being approved by regulatory agencies worldwide. Genomic vaccines that deliver parts of the viral DNA or RNA to host cells have gained popularity recently due to their high efficiency and fast manufacture. Furthermore, recent clinical studies encouraged the use of different vaccine platforms within the primary vaccination course to enhance the efficacy of vaccination. Herein, we discuss COVID-19 genomic vaccines, which deliver viral genetic material to host cells through diverse biotechnology platforms, including viral vector vaccines, messenger RNA nucleic acid vaccines, and DNA nucleic acid vaccines. We compare and contrast vaccine characteristics, composition, and pros and cons among different genomic vaccine platforms as well as non-genomic vaccines. This review summarizes all current knowledge about COVID-19 genomic vaccines, which could be highly valuable to researchers interested in public health and vaccine development.

Targeting Human Proteins for Antiviral Drug Discovery and Repurposing Efforts: A Focus on Protein Kinases.

Despite the great technological and medical advances in fighting viral diseases, new therapies for most of them are still lacking, and existing antivirals suffer from major limitations regarding drug resistance and a limited spectrum of activity. In fact, most approved antivirals are directly acting antiviral (DAA) drugs, which interfere with viral proteins and confer great selectivity towards their viral targets but suffer from resistance and limited spectrum. Nowadays, host-targeted antivirals (HTAs) are on the rise, in the drug discovery and development pipelines, in academia and in the pharmaceutical industry. These drugs target host proteins involved in the virus life cycle and are considered promising alternatives to DAAs due to their broader spectrum and lower potential for resistance. Herein, we discuss an important class of HTAs that modulate signal transduction pathways by targeting host kinases. Kinases are considered key enzymes that control virus-host interactions. We also provide a synopsis of the antiviral drug discovery and development pipeline detailing antiviral kinase targets, drug types, therapeutic classes for repurposed drugs, and top developing organizations. Furthermore, we detail the drug design and repurposing considerations, as well as the limitations and challenges, for kinase-targeted antivirals, including the choice of the binding sites, physicochemical properties, and drug combinations.

A Review of the Recent Advances in Alzheimer's Disease Research and the Utilization of Network Biology Approaches for Prioritizing Diagnostics and Therapeutics.

Alzheimer's disease (AD) is a polygenic multifactorial neurodegenerative disease that, after decades of research and development, is still without a cure. There are some symptomatic treatments to manage the psychological symptoms but none of these drugs can halt disease progression. Additionally, over the last few years, many anti-AD drugs failed in late stages of clinical trials and many hypotheses surfaced to explain these failures, including the lack of clear understanding of disease pathways and processes. Recently, different epigenetic factors have been implicated in AD pathogenesis; thus, they could serve as promising AD diagnostic biomarkers. Additionally, network biology approaches have been suggested as effective tools to study AD on the systems level and discover multi-target-directed ligands as novel treatments for AD. Herein, we provide a comprehensive review on Alzheimer's disease pathophysiology to provide a better understanding of disease pathogenesis hypotheses and decipher the role of genetic and epigenetic factors in disease development and progression. We also provide an overview of disease biomarkers and drug targets and suggest network biology approaches as new tools for identifying novel biomarkers and drugs. We also posit that the application of machine learning and artificial intelligence to mining Alzheimer's disease multi-omics data will facilitate drug and biomarker discovery efforts and lead to effective individualized anti-Alzheimer treatments.

Exploring the effect of estrogen on Candida albicans hyphal cell wall glycans and ergosterol synthesis.

Increased levels of 17-ß estradiol (E2) due to pregnancy in young women or to hormonal replacement therapy in postmenopausal women have long been associated with an increased risk of yeast infections. Nevertheless, the effect underlying the role of E2 in Candida albicans infections is not well understood. To address this issue, functional, transcriptomic, and metabolomic analyses were performed on C. albicans cells subjected to temperature and serum induction in the presence or absence of E2. Increased filament formation was observed in E2 treated cells. Surprisingly, cells treated with a combination of E2 and serum showed decreased filament formation. Furthermore, the transcriptomic analysis revealed that serum and E2 treatment is associated with downregulated expression of genes involved in filamentation, including HWP1, ECE1, IHD1, MEP1, SOD5, and ALS3, in comparison with cells treated with serum or estrogen alone. Moreover, glucose transporter genes HGT20 and GCV2 were downregulated in cells receiving both serum and E2. Functional pathway enrichment analysis of the differentially expressed genes (DEGs) suggested major involvement of E2 signaling in several metabolic pathways and the biosynthesis of secondary metabolites. The metabolomic analysis determined differential secretion of 36 metabolites based on the different treatments' conditions, including structural carbohydrates and fatty acids important for hyphal cell wall formation such as arabinonic acid, organicsugar acids, oleic acid, octadecanoic acid, 2-keto-D-gluconic acid, palmitic acid, and steriacstearic acid with an intriguing negative correlation between D-turanose and ergosterol under E2 treatment. In conclusion, these findings suggest that E2 signaling impacts the expression of several genes and the secretion of several metabolites that help regulate C. albicans morphogenesis and virulence.

Analyzing the Systems Biology Effects of COVID-19 mRNA Vaccines to Assess Their Safety and Putative Side Effects.

COVID-19 vaccines have been instrumental tools in reducing the impact of SARS-CoV-2 infections around the world by preventing 80% to 90% of hospitalizations and deaths from reinfection, in addition to preventing 40% to 65% of symptomatic illnesses. However, the simultaneous large-scale vaccination of the global population will indubitably unveil heterogeneity in immune responses as well as in the propensity to developing post-vaccine adverse events, especially in vulnerable individuals. Herein, we applied a systems biology workflow, integrating vaccine transcriptional signatures with chemogenomics, to study the pharmacological effects of mRNA vaccines. First, we derived transcriptional signatures and predicted their biological effects using pathway enrichment and network approaches. Second, we queried the Connectivity Map (CMap) to prioritize adverse events hypotheses. Finally, we accepted higher-confidence hypotheses that have been predicted by independent approaches. Our results reveal that the mRNA-based BNT162b2 vaccine affects immune response pathways related to interferon and cytokine signaling, which should lead to vaccine success, but may also result in some adverse events. Our results emphasize the effects of BNT162b2 on calcium homeostasis, which could be contributing to some frequently encountered adverse events related to mRNA vaccines. Notably, cardiac side effects were signaled in the CMap query results. In summary, our approach has identified mechanisms underlying both the expected protective effects of vaccination as well as possible post-vaccine adverse effects. Our study illustrates the power of systems biology approaches in improving our understanding of the comprehensive biological response to vaccination against COVID-19.

Unlocking the Potential of the Human Microbiome for Identifying Disease Diagnostic Biomarkers.

The human microbiome encodes more than three million genes, outnumbering human genes by more than 100 times, while microbial cells in the human microbiota outnumber human cells by 10 times. Thus, the human microbiota and related microbiome constitute a vast source for identifying disease biomarkers and therapeutic drug targets. Herein, we review the evidence backing the exploitation of the human microbiome for identifying diagnostic biomarkers for human disease. We describe the importance of the human microbiome in health and disease and detail the use of the human microbiome and microbiota metabolites as potential diagnostic biomarkers for multiple diseases, including cancer, as well as inflammatory, neurological, and metabolic diseases. Thus, the human microbiota has enormous potential to pave the road for a new era in biomarker research for diagnostic and therapeutic purposes. The scientific community needs to collaborate to overcome current challenges in microbiome research concerning the lack of standardization of research methods and the lack of understanding of causal relationships between microbiota and human disease.

Shedding the Light on Post-Vaccine Myocarditis and Pericarditis in COVID-19 and Non-COVID-19 Vaccine Recipients.

Myocarditis and pericarditis have been linked recently to COVID-19 vaccines without exploring the underlying mechanisms, or compared to cardiac adverse events post-non-COVID-19 vaccines. We introduce an informatics approach to study post-vaccine adverse events on the systems biology level to aid the prioritization of effective preventive measures and mechanism-based pharmacotherapy by integrating the analysis of adverse event reports from the Vaccine Adverse Event Reporting System (VAERS) with systems biology methods. Our results indicated that post-vaccine myocarditis and pericarditis were associated most frequently with mRNA COVID-19 vaccines followed by live or live-attenuated non-COVID-19 vaccines such as smallpox and anthrax vaccines. The frequencies of cardiac adverse events were affected by vaccine, vaccine type, vaccine dose, sex, and age of the vaccinated individuals. Systems biology results suggested a central role of interferon-gamma (INF-gamma) in the biological processes leading to cardiac adverse events, by impacting MAPK and JAK-STAT signaling pathways. We suggest that increasing the time interval between vaccine doses minimizes the risks of developing inflammatory adverse reactions. We also propose glucocorticoids as preferred treatments based on system biology evidence. Our informatics workflow provides an invaluable tool to study post-vaccine adverse events on the systems biology level to suggest effective mechanism-based pharmacotherapy and/or suitable preventive measures.

Phosphatidylinositol 3-kinase (PI3K) inhibitors: a recent update on inhibitor design and clinical trials (2016-2020).

Introduction: The phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway plays a central role in regulating cell growth and proliferation and thus has been considered as effective anticancer drug targets. Many PI3K inhibitors have been developed and progressed to various stages of clinical trials, and some have been approved as anticancer treatment. In this review, we discuss the drug design and clinical development of PI3K inhibitors over the past 4 years. We review the selectivity and potency of 47 PI3K inhibitors. Structural determinants for increasing selectivity toward PI3K subtype-selectivity or mutant selectivity are discussed. Future research direction and current clinical development in combination therapy of inhibitors involved in PI3Ks are also discussed.Area covered: This review covers clinical trial reports and patent literature on PI3K inhibitors and their selectivity published between 2016 and 2020.Expert opinion: To PI3Kα mutants (E542K, E545K, and H1047R), it is highly desirable to design and develop mutant-specific PI3K inhibitors. It is also necessary to develop subtype-selective PI3Kα inhibitors to minimize toxicity. To reduce drug resistance and to improve efficacy, future studies should include combination therapy of PI3K inhibitors with existing anticancer drugs from different pathways.

Identification of Tumor-Specific MRI Biomarkers Using Machine Learning (ML).

The identification of reliable and non-invasive oncology biomarkers remains a main priority in healthcare. There are only a few biomarkers that have been approved as diagnostic for cancer. The most frequently used cancer biomarkers are derived from either biological materials or imaging data. Most cancer biomarkers suffer from a lack of high specificity. However, the latest advancements in machine learning (ML) and artificial intelligence (AI) have enabled the identification of highly predictive, disease-specific biomarkers. Such biomarkers can be used to diagnose cancer patients, to predict cancer prognosis, or even to predict treatment efficacy. Herein, we provide a summary of the current status of developing and applying Magnetic resonance imaging (MRI) biomarkers in cancer care. We focus on all aspects of MRI biomarkers, starting from MRI data collection, preprocessing and machine learning methods, and ending with summarizing the types of existing biomarkers and their clinical applications in different cancer types.

An Updated Review on Betacoronavirus Viral Entry Inhibitors: Learning from Past Discoveries to Advance COVID-19 Drug Discovery.

Even after one year of its first outbreak reported in China, the coronavirus disease 2019 (COVID-19) pandemic is still sweeping the World, causing serious infections and claiming more fatalities. COVID-19 is caused by the novel coronavirus SARS-CoV-2, which belongs to the genus Betacoronavirus (ß-CoVs), which is of greatest clinical importance since it contains many other viruses that cause respiratory disease in humans, including OC43, HKU1, SARS-CoV, and MERS. The spike (S) glycoprotein of ß-CoVs is a key virulence factor in determining disease pathogenesis and host tropism, and it also mediates virus binding to the host's receptors to allow viral entry into host cells, i.e., the first step in virus lifecycle. Viral entry inhibitors are considered promising putative drugs for COVID-19. Herein, we mined the biomedical literature for viral entry inhibitors of other coronaviruses, with special emphasis on ß-CoVs entry inhibitors. We also outlined the structural features of SARS-CoV-2 S protein and how it differs from other ß-CoVs to better understand the structural determinants of S protein binding to its human receptor (ACE2). This review highlighted several promising viral entry inhibitors as potential treatments for COVID-19.

New derivatives of sulfonylhydrazone as potential antitumor agents: Design, synthesis and cheminformatics evaluation.

Phosphoinositide 3-kinase α (PI3Kα) is a propitious target for designing anticancer drugs. A series of new N'-(diphenylmethylene)benzenesulfonohydrazide was synthesized and characterized using FT-IR, NMR (1H and 13C), HRMS, and elemental analysis. Target compounds exhibited an antiproliferative effect against the human colon carcinoma (HCT-116) cell line. Our cheminformatics analysis indicated that the para-tailored derivatives [p-NO2 (3) and p-CF3 (7)] have better ionization potentials based on calculated Moran autocorrelations and ionization potentials. Subsequent in vitro cell proliferation assays validated our cheminformatics results by providing experimental evidence that both derivatives 3 and 7 exhibited improved antiproliferative activities against HCT-116. Hence, our results emphasized the importance of electron-withdrawing groups and hydrogen bond-acceptors in the rational design of small-molecule chemical ligands targeting PI3Kα. These results agreed with the induced-fit docking against PI3Kα, highlighting the role of p-substituted aromatic rings in guiding the ligand-PI3Kα complex formation, by targeting a hydrophobic pocket in the ligand-binding site and forming π-stacking interactions with a nearby tryptophan residue.

An Updated Review on SARS-CoV-2 Main Proteinase (MPro): Protein Structure and Small-Molecule Inhibitors.

[Coronaviruses (CoVs) are enveloped positive-stranded RNA viruses with spike (S) protein projections that allow the virus to enter and infect host cells. The S protein is a key virulence factor determining viral pathogenesis, host tropism, and disease pathogenesis. There are currently diverse corona viruses that are known to cause disease in humans. The occurrence of Middle East respiratory syndrome coronavirus (MERS-CoV) and Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), as fatal human CoV diseases, has induced significant interest in the medical field. The novel coronavirus disease (COVID-19) is an infectious disease caused by a novel strain of coronavirus (SAR-CoV-2). The SARS-CoV2 outbreak has been evolved in Wuhan, China, in December 2019, and identified as a pandemic in March 2020, resulting in 53.24 M cases and 1.20M deaths worldwide. SARS-CoV-2 main proteinase (MPro), a key protease of CoV-2, mediates viral replication and transcription. SARS-CoV-2 MPro has been emerged as an attractive target for SARS-CoV-2 drug design and development. Diverse scaffolds have been released targeting SARS-CoV-2 MPro. In this review, we culminate the latest published information about SARS-CoV-2 main proteinase (MPro) and reported inhibitors.

Sitagliptin: a potential drug for the treatment of COVID-19?

Recently, an outbreak of a fatal coronavirus, SARS-CoV-2, has emerged from China and is rapidly spreading worldwide. Possible interaction of SARS-CoV-2 with DPP4 peptidase may partly contribute to the viral pathogenesis. An integrative bioinformatics approach starting with mining the biomedical literature for high confidence DPP4-protein/gene associations followed by functional analysis using network analysis and pathway enrichment was adopted. The results indicate that the identified DPP4 networks are highly enriched in viral processes required for viral entry and infection, and as a result, we propose DPP4 as an important putative target for the treatment of COVID-19. Additionally, our protein-chemical interaction networks identified important interactions between DPP4 and sitagliptin. We conclude that sitagliptin may be beneficial for the treatment of COVID-19 disease, either as monotherapy or in combination with other therapies, especially for diabetic patients and patients with pre-existing cardiovascular conditions who are already at higher risk of COVID-19 mortality.

An Integrative Informatics Approach to Explain the Mechanism of Action of N1-(Anthraquinon-2-yl) Amidrazones as BCR/ABL Inhibitors.

BACKGROUND: Drugs incorporating heterocyclic chemical skeletons possess a plethora of therapeutic activities such as anticancer, antimicrobial, antihypertensive, and antipsychiatric effects. It is becoming routine, nowadays, to use cheminformatics and bioinformatics methods to elucidate the mechanism(s) of action of such drugs. OBJECTIVE: This study aimed to probe the activity of a recently published series of N1- (anthraquinon-2-yl) amidrazone piperazine derivatives employing computational strategies[1], identify their structural basis of binding to BCR/ABL kinase domain, and explain their anticancer activities in human breast adenocarcinoma (MCF-7) and chronic myelogenous leukemia (K562) cell lines. METHODS: We applied an in silico integrative informatics approach integrating molecular descriptors, docking studies, cheminformatics, and network analysis. RESULTS: Our results highlighted the possible involvement of the BCR/ABL and DRD2 pathways in the anticancer activity of the studied compounds, and induced fit docking (IFD) indicated that the BCR/ABL kinase domain is a putative drug target. Additionally, high-scoring docking poses identified a unique network of hydrogen bonding with amino acids Y253, K271, E286, V299, L301, T315, M318, I360, R362, V379, and D3810. CONCLUSION: Using an integrative informatics approach to characterize our anticancer compounds, we were able to explain the biological differences between synthesized and biologically validated amidrazone piperazine anticancer agents. We were also able to postulate a mechanism of action of this novel group of anticancer agents.

N-Phenyl-6-Chloro-4-Hydroxy-2-Quinolone-3-CarboxAmides: Molecular Docking, Synthesis, and Biological Investigation as Anticancer Agents.

Cancer is a multifactorial disease and the second leading cause of death worldwide. Diverse factors induce carcinogenesis, such as diet, smoking, radiation, and genetic defects. The phosphatidylinositol 3-kinase (PI3Kα) has emerged as an attractive target for anticancer drug design. Eighteen derivatives of N-phenyl-6-chloro-4-hydroxy-2-quinolone-3-carboxamide were synthesized and characterized using FT-IR, NMR (1H and 13C), and high-resolution mass spectra (HRMS). The series exhibited distinct antiproliferative activity (IC50 µM) against human epithelial colorectal adenocarcinoma (Caco-2) and colon carcinoma (HCT-116) cell lines, respectively: compounds 16 (37.4, 8.9 µM), 18 (50.9, 3.3 µM), 19 (17.0, 5.3 µM), and 21 (18.9, 4.9 µM). The induced-fit docking (IFD) studies against PI3Kαs showed that the derivatives occupy the PI3Kα binding site and engage with key binding residues.