VEGF plays a crucial role in cancer development, angiogenesis and progression, principally liver and breast cancer. It is vital to uncover novel chemical candidates of VEGFR inhibitors to develop more potent anti-breast and anti-liver cancer agents than the currently available candidates, sorafenib and regorafenib, that face resistance obstacles and severe side effects. Herein, nine pyrazolopyrimidine derivatives were designed, synthesized as sorafenib and regorafenib analogues and screened for their in vitro cytotoxic and growth inhibition activities against four human cancer cell lines, namely breast cancer (Michigan Cancer Foundation-7 (MCF-7), hepatocellular carcinoma (HCC) type (HepG2), lung carcinoma (A-549) and human colorectal carcinoma-116 (HCT-116)). Among the tested compounds, compounds 1, 2a, 4b and 7 showed the uppermost cytotoxic activities against all aforementioned cell lines with IC₅₀ estimates varying from 6 to 50 µM, among which compound 7 showed the best inhibitory activity on all tested compounds. Stunningly, compound 7 showed the best significant inhibition of the VEGFR-2 protein expression level (72.3%) as compared to the control and even higher than that produced with sorafenib and regorafenib (70.4% and 55.6%, respectively). Modeling studies provided evidence for the possible interactions of the synthesized compounds with the key residues of the ATP binding sites on the hinge region and the “DFG out” motif of VEGFR-2 kinase. Collectively, our present study suggests that pyrazolopyrimidine derivatives are a novel class of anti-cancer drug candidates to inhibit VEGF-VEGFR function. Aspiring to promote constrained aqueous solubility, hence poor oral bioavailability of the developed lead molecule, 7 and 2a-charged D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) surface-coated niosomes were successfully constructed, adopting a thin film hydration technique striving to overcome these pitfalls. A 2³ full factorial design was involved in order to investigate the influence of formulation variables: type of surfactant, either Span 60 or Span 40; surfactant:cholesterol ratio (8:2 or 5:5) along with the amount of TPGS (25 mg or 50 mg) on the characteristics of the nanosystem. F2 and S2 were picked as the optimum formula for compounds 2a and 7 with desirability values of 0.907 and 0.903, respectively. In addition, a distinguished improvement was observed in the compound’s oral bioavailability and cytotoxic activity after being included in the nano-TPGS-coated niosomal system relative to the unformulated compound. The nano-TPGS-coated niosomal system increased the hepatocellular inhibitory activity four times fold of compound 7a (1.6 µM) and two-fold of 2a (3 µM) relative to the unformulated compounds (6 µM and 6.2 µM, respectively).

Morin hydrate (MH) is a widely-used Asian phytomedicinal flavonoid with a wide range of reported therapeutic activities. However, MH has limited oral bioavailability due to its low aqueous solubility and intestinal permeability, which in turn hinders its potential antiviral activity. The study reported herein was designed to encapsulate MH in polyethyleneglycolated (PEGylated) chylomicrons (PCMs) and to boost its antiviral activity and biological availability for oral administration using a rat experimental model. The PEGylated edge activator combined with the conventional components of chylomicrons (CMs) amplify the transport of the drug across the intestine and its circulation period, hence its therapeutic impact. The implementation of variables in the in vitro characterization of the vesicles was investigated. Using Design Expert^® software, a 2⁴ factorial design was conducted, and the resulting PCM formulations were fabricated utilizing a thin-film hydration technique. The efficacy of the formulations was assessed according to their zeta potential (ZP), entrapment efficiency percentage (EE%), amount of drug released after 8 h (Q8h), and particle size (PS) data. Formulation F9, which was deemed to be the optimal formula, used compritol as the lipidic core together in defined amounts with phosphatidylcholine (PC) and Brij52. Computer-aided studies revealed that MH alone in a suspension had both diminished intestinal permeability and absorption, but was enhanced when loaded in PCMs. This was affirmed by the superiority of formulation F9 results in ex vivo permeation and pharmacokinetic studies. Furthermore, formulation F9 had a superior safety profile and antiviral activity over a pure MH suspension. Molecular-docking studies revealed the capability of MH to inhibit MERS-CoV 3CL^pro, the enzyme shown to exhibit a crucial role in viral replication. Additionally, F9 suppressed both MERS-CoV-induced histopathological alteration in lung tissue and resulting oxidative and inflammatory biomarkers. Collectively, the results reported herein affirmed the potential of PCMs as nanocarriers for the effective oral administration of MH as an antiviral.

Persistent inflammation contributes to various inflammatory conditions. Inflammation-related diseases may be treated by inhibiting pro-inflammatory mediators and cytokines. Curcumin and coumarin derivatives can target signalling pathways and cellular factors to address immune-related and inflammatory ailments. This study involved designing and synthesising three series of coumarin-based analogs that incorporated curcumin and other heterocycles. These analogs were evaluated for their potential as anti-inflammatory agents in LPS-induced macrophages. Among the fourteen synthesised coumarin derivatives, compound 14b, which contained 3,4-dimethoxybenzylidene hydrazinyl, demonstrated the highest anti-inflammatory activity with an EC₅₀ value of 5.32 μM. The anti-inflammatory effects of 14b were achieved by modulating signalling pathways like AKT/mTOR and Nrf2/HO-1, and downregulating NF-kβ, resulting in reduced production of pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α. The modelling studies revealed that 14b and dexamethasone bind to the same TNF-α pocket, suggesting that 14b has potential as a therapeutic agent superior to dexamethasone for TNF-α.

Dual inhibition of VEGFR-2 and Aurora A is a promising strategy for treating complex malignancies like hepatocellular carcinoma (HCC) and breast cancer. In this study, a series of new pyrazolopyrimidine derivatives were designed and synthesized via a one-pot multicomponent reaction using both conventional and microwave-assisted techniques. Structural characterization was confirmed by spectroscopic data. The compounds were evaluated as dual inhibitors of Aurora A and VEGFR-2 kinases through molecular docking, in vitro cytotoxicity assays, and expression analysis. Docking simulations revealed compound 5b had the strongest binding affinity for both kinases. Consistently, MTT assays showed that compounds 5b, 5c, and 6b exhibited potent cytotoxicity, with compound 5b displaying the highest activity against HepG2 and MCF-7 cells (IC₅₀ = 3.0 μM and 3.5 μM, respectively). In particular, in HepG2 cells, compound 5b inhibited VEGFR-2 by 86.3 % and Aurora A by 66.7 %, demonstrating stronger dual-target inhibition compared to the reference compound, sunitinib. Furthermore, compound 5b significantly downregulated VEGFR-2 and Aurora A protein and gene expression. Toxicity evaluation in vivo indicated no lethal effects at doses up to 1000 mg/kg, with an LD₅₀ exceeding 1500 mg/kg, suggesting a favorable safety profile. These findings identify compound 5b as a promising dual-target inhibitor and potential lead candidate for the treatment of HCC and breast cancer.

Triple-negative breast cancer (TNBC) lacks targeted therapies due to the absence of hormone receptors. The oncogenic crosstalk between STAT3 and NF-κB pathways drives tumor proliferation, epithelial-mesenchymal transition (EMT), metastasis, and therapeutic resistance, underscoring a critical need for novel dual inhibitors. Here, we report the rational design and synthesis of new 1-phenyl-2-thioaryl-4-benzyl-5-methylimidazole derivatives targeting this dual pathway axis. Optimized, metal-free S-alkylation reactions of imidazole-2-thione afforded twelve new analogs (5a,b, 6, 7a-g, 8a,b) in excellent yields. Their antiproliferative activity was evaluated in 4 T1 and MDA-MB-231 cells, while the mechanistic leads (5a,b and 8a,b) were assessed for specific STAT3/NF-κB inhibition using luciferase reporter assays together with migration and invasion assays. Structure-activity relationship (SAR) analysis identified the difluorobenzylthio derivative 5b as the optimal lead candidate. At a sub-cytotoxic concentration (10 μM), 5b exhibited potent and specific targeted blockade, suppressing NF-κB and STAT3 transcriptional activities by ∼80% and ∼ 60%, respectively. In contrast, structurally related analogs (5a, 8a, 8b) only exhibited inhibitory effects that were inextricably linked to severe cytotoxicity. Furthermore, 5b demonstrated robust antimetastatic efficacy at non-toxic doses, maintaining >91% wound persistence in 4 T1 cells at 24 h and markedly blocking Matrigel invasion. Molecular docking studies at the STAT3-SH2 domain corroborated the biological data, confirming that the flexibility of the thioether linkage in the 5a and 5b provided optimal binding energies compared to the more rigid or bulkier inactive analogs. This newly accessible imidazole class successfully establishes dual STAT3/NF-κB inhibition with direct antimetastatic efficacy, positioning 5b as a highly promising TNBC lead warranting further in vivo validation and clinical translation.