Exploring diverse frontiers: Advancements of bioactive 4-aminoquinoline-based molecular hybrids in targeted therapeutics and beyond.

Amongst heterocyclic compounds, quinoline and its derivatives are advantaged scaffolds that appear as a significant assembly motif for developing new drug entities. Aminoquinoline moiety has gained significant attention among researchers in the 21stcentury. Considering the biological and pharmaceutical importance of aminoquinoline derivatives, herein, we review the recent developments (since 2019) in various biological activities of the 4-aminoquinoline scaffold hybridized with diverse heterocyclic moieties such as quinoline, pyridine, pyrimidine, triazine, dioxine, piperazine, pyrazoline, piperidine, imidazole, indole, oxadiazole, carbazole, dioxole, thiazole, benzothiazole, pyrazole, phthalimide, adamantane, benzochromene, and pyridinone. Moreover, by gaining knowledge about SARs, structural insights, and molecular targets, this review may help medicinal chemists design cost-effective, selective, safe, and more potent 4-aminoquinoline hybrids for diverse biological activities.

Chalcone Mannich base derivatives: synthesis, antimalarial activities against Plasmodium knowlesi, and molecular docking analysis.

Development and discovery of new antimalarial drugs are needed to overcome the multi-resistance of Plasmodium parasites to commercially available drugs. Modifying the substitutions on the amine groups has been shown to increase antimalarial activities and decrease cross-resistance with chloroquine. In this study, we have synthesized several chalcone derivatives via the substitution of aminoalkyl groups into the aromatic chalcone ring using the Mannich-type reaction. The chalcone derivatives were evaluated for their antimalarial properties against Plasmodium knowlesi A1H1 and P. falciparum 3D7, as well as their molecular docking on Plasmodium falciparum dihydrofolate reductases-thymidylate synthase (PfDHFR-TS). Data from in vitro evaluation showed that chalcone Mannich-type base derivatives 2a, 2e, and 2h displayed potential antimalarial activities against P. knowlesi with EC50 of 2.64, 2.98, and 0.10 µM, respectively, and P. falciparum 3D7 with EC50 of 0.08, 2.69, and 0.15 µM, respectively. The synthesized compounds 2a, 2e, and 2h exerted high selectivity index (SI > 10) values on the A1H1 and 3D7 strains. The molecular docking analysis on PfDHFR-TS supported the in vitro assay of 2a, 2e, and 2h by displaying CDOCKER energy of -48.224, -43.292, and -45.851 kcal mol-1. Therefore, the evidence obtained here supports that PfDHFR-TS is a putative molecular target for the synthesized compound.

Bioactivity and Pharmacological Potential of Date Palm (Phoenix dactylifera L.) Against Pandemic COVID-19: a Comprehensive Review.

A novel coronavirus disease (COVID-19) or severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), transmitted from person to person, has quickly emerged as the pandemic responsible for the current global health crisis. This infection has been declared a global pandemic, resulting in a concerning number of deaths as well as complications post-infection, primarily among vulnerable groups particularly older people and those with multiple comorbidities. In this article, we review the most recent research on the role of date palm (Phoenix dactylifera L.) fruits (DPFs) to prevent or treat COVID-19 infection. The mechanisms underlying this preventive or therapeutic effect are also discussed in terms of bioactivity potentials in date palm, e.g., antimicrobial, antioxidant, anticancer, anti-diabetic, anti-inflammatory, neuroprotective, and hemolytic potential, as well as prospect against COVID-19 disease and the potential product development. Therefore, it can be concluded that regular consumption of DPFs may be associated with a lower risk of some chronic diseases. Indeed, DPFs have been widely used in folk medicine since ancient times to treat a variety of health conditions, demonstrating the importance of DPFs as a nutraceutical and source of functional nourishment. This comprehensive review aims to summarize the majority of the research on DPFs in terms of nutrient content and biologically active components such as phenolic compounds, with an emphasis on their roles in improving overall health as well as the potential product development to ensure consumers' satisfaction in a current pandemic situation. In conclusion, DPFs can be given to COVID-19 patients as a safe and effective add-on medication or supplement in addition to routine treatments.

Normalisation of human chorionic gonadotrophin (hCG) levels in a patient with partial molar pregnancy with a uterine mass without chemotherapy: impact of using herbal remedies.

OBJECTIVES: Level of ßhCG and the presence of any uterine mass of hydatidiform mole need a careful review or monitoring in order to prevent metastasis, provide an early treatment and avoid unnecessary chemotherapy. CASE PRESENTATION: A 36-year old fifth gravida patient who had a missed abortion was diagnosed as having a molar pregnancy with beta human chorionic gonadotrophin (ßhCG) level of 509,921 IU/L. Her lung field was clear and she underwent suction and curettage (S & C) procedure. However, after six weeks, AA presented to the emergency department with a massive bleeding, although her ßhCG level had decreased to 65,770 IU/L. A trans-abdominal ultrasound indicated the presence of an intra-uterine mass (3.0 × 4.4 cm). Nevertheless, her ßhCG continued to show a declining trend (8,426 IU/L). AA was advised to undergo a chemotherapy but she refused, citing preference for alternative medicine like herbs instead. She opted for an "at own risk" (AOR) discharge with scheduled follow up. Subsequently, her condition improved with her ßhCG showing a downward trend. Surprisingly, at six months post S & C, her ßhCG ameliorated to 0 IU/L with no mass detected by ultrasound. CONCLUSIONS: Brucea javanica fruits, Pereskia bleo and Annona muricata leaves can potentially be useful alternatives to chemotherapy and need further studies.

Gold nanoparticles conjugated with anti-CD133 monoclonal antibody and 5-fluorouracil chemotherapeutic agent as nanocarriers for cancer cell targeting.

The enhanced permeability and retention effect allows for passive targeting of solid tumours by nanoparticles carrying anticancer drugs. However, active targeting by incorporation of various ligands onto nanoparticles can provide for a more selective and enhanced chemotherapeutic effect and complement the deficiencies of the passive targeting approach. Here we report on the design of the carboxyl-terminated PEGylated gold nanoparticles (AuNPs), their functionalization with anti-CD133 monoclonal antibody (mAb) via a crosslinking reaction, and subsequent 5-fluorouracil (5-FU) drug loading. The synthesized products in the form of stable colloids were characterised using a range of physicochemical techniques, including X-ray diffraction (XRD), UV-Vis spectroscopy, transmission electron microscopy (TEM), and dynamic light scattering (DLS). Conjugation of anti-CD133 mAb onto PEGylated AuNPs was confirmed with the use of UV-Vis, BCA protein assay and fluorescence microscopy. HCT116 colorectal cancer cells abundantly expressed CD133: 92.4 ± 1.3%, as measured by flow cytometry. Whereas PEGylated AuNPs not conjugated with anti-CD133 mAb accumulated mainly at the cellular membrane, nanoparticles conjugated with anti-CD133 mAb were contained within the nuclear region of the cells. Anti-CD133 mAb conjugation facilitated the specific intracellular uptake due to specific antigen-antibody binding interaction. In vitro cytotoxicity studies on HCT116 cells showed that PEGylated AuNPs and PEGylated AuNPs-CD133 did not elicit any toxicity at any of the tested concentrations. Meanwhile, 5-FU-PEGylated AuNPs-CD133 significantly reduced the cell viability relative to the treatment with 5-FU-PEGylated AuNPs without anti-CD133 mAb conjugates (p < 0.0001). This study shows that the conjugation of nanocarriers with the anti-CD133 antibody improves the specific targeting of 5-FU against colorectal cancer cells. These results demonstrate that simultaneous functionalisation of PEGylated AuNPs with antibodies and chemotherapeutic drugs is a viable strategy to combat cancer through targeted drug delivery.

Pereskia bleo Leaves Extract Induces Cell Death via Cell Cycle Arrest and Apoptosis in Cervical Cancer Cells HeLa.

Introduction: Pereskia bleo is a leafy and edible plant, locally known as "Pokok Jarum Tujuh Bilah" which has anticancer properties. This study purposed to determine the cytotoxic effects of P. bleo leaves extracts on several well-known cancer cells and elucidate its underlying mechanism in inducing cell death.Methods: Cytotoxic activity on selected cell lines was determined using MTT assay. Mechanism of cell death was investigated through cell cycle and Annexin V assay. Expression of apoptotic proteins was measured by flow cytometry method.Results: Ethyl acetate extract of P. bleo leaves (PBEA) appeared to have the strongest IC50 value (14.37 ± 8.40 µg/ml) and most active against HeLa cells was further studied for apoptosis. The cell cycle investigation by flow cytometry evidenced the increment of PBEA treated HeLa cells in G0/G1 phase and apoptotic event was detected in Annexin V assay. Analysis of apoptotic protein showed pro-apoptotic proteins (Bax, p53 and caspase 3) were triggered where as anti-apoptotic protein Bcl-2 was suppressed in treated HeLa cells.Conclusions: Our findings demonstrated that PBEA treatment induced cell death in HeLa cells by p53-mediated mechanism through arresting cell cycle at G0/G1 phase and mitochondrial-mediated pathway with involvement of pro-apoptotic proteins, anti-apoptotic protein, and caspase 3.

Methanolic extract of Abrus precatorius promotes breast cancer MDA-MB-231 cell death by inducing cell cycle arrest at G0/G1 and upregulating Bax

Objective: To determine the anti-proliferative activity of Abrus precatorius (A. precatorius) leaf extracts and their effect on cell death. Methods: A. precatorius leaves were extracted successively with hexane, ethyl acetate and methanol by Soxhlet extraction. Aqueous extract was prepared by decoction at 50 ℃. Extracts of A. precatorius leaves were used to treat selected cancer and normal cell lines for 72 h. Furthermore, 3-(4,5-dimethyl thiazol-2-yl) 2,5-diphenyl tetrazolium bromide assay was performed to determine cell viability. Analysis of cell cycle arrest, apoptosis assay and apoptosis protein expressions were determined by flow cytometry. Results: Methanolic extract of A. precatorius leaves showed the lowest IC50 on MDA-MB-231 cells at (26.40±5.40) μg/mL. Flow cytometry analysis revealed that cell arrest occurred at G0/G1 phase and the apoptosis assay showed the occurrence of early apoptosis at 48 h in MDA-MB-231 cells treated with methanolic extract of A. precatorius leaves. Methanolic extract of A. precatorius leaves induced apoptosis by upregulation of Bax, p53 and caspase-3 and downregulation of Bcl-2. Conclusions: Methanolic extract of A. precatorius leaves promotes MDA-MB-231 cell death by inducing cell cycle arrest and apoptosis possibly via the mitochondrial-related pathway.

Xanthorrhizol induces apoptosis via the up-regulation of bax and p53 in HeLa cells.

Xanthorrhizol is a sesquiterpenoid compound extracted from Curcuma xanthorrhiza, which is known locally as Temulawak. Traditionally, C. xanthorrhiza was found to have antibacterial, anticancer and anti-inflammatory activity. The rhizome has also been used to treat inflammation in postpartum uterine bleeding. An antiproliferative assay using methylene blue staining revealed that xanthorrhizol inhibited the proliferation of the cervical cancer cell line HeLa with an EC50 value of 6.16 microg/ml. Xanthorrhizol significantly increased apoptosis in HeLa cells, as evaluated by the Tdt-mediated dUTP nick end-labelling (TUNEL) assay and nuclear morphology by Hoechst 33258 staining. Western blot analysis, which was further confirmed by the immunostaining results, implied an up-regulation of tumor suppressor protein p53 and the pro-apoptotic protein Bax, following the treatment with xanthorrhizol. Xanthorrhizol, however, did not affect the expression of the anti-apoptotic protein, Bcl-2 and the viral oncoprotein, E6. Hence, xanthorrhizol is a promising antiproliferative and anticancer agent which induces p53 and Bax-dependent apoptosis in HeLa cervical cancer cells.