Biological Evaluation Research Articles

Discovery of baloxavir sodium as a novel anti-CCHFV inhibitor: biological evaluation of in vitro and in vivo

Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic bunyavirus with a fatality rate of up to 40%. Currently, there are no licensed antiviral drugs for the treatment of CCHF; thus, the World Health Organization (WHO) listed the disease as a priority. A unique viral transcription initiation mechanism called “cap-snatching” is shared by influenza viruses and bunyaviruses. Thus, we tested whether baloxavir (an FDA-approved anti-influenza drug that targets the “cap-snatching” mechanism) could inhibit CCHFV infection. In cell culture, baloxavir acid effectively inhibited CCHFV infection and targeted CCHFV RNA transcription/replication. However, it has weak oral bioavailability. Baloxavir marboxil (the oral prodrug of baloxavir) failed to protect mice against a lethal dose challenge of CCHFV. To solve this problem, baloxavir sodium was synthesized owing to its enhanced aqueous solubility and pharmacokinetic properties. It consistently and significantly improved survival rates and decreased tissue viral loads. This study identified baloxavir sodium as a novel scaffold structure and mechanism of anti-CCHF compound, providing a promising new strategy for clinical treatment of CCHF after further optimization.

Synthesis and biological evaluation of echinomycin analogues as potential colon cancer agent

Colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer-related death, thus a novel chemotherapeutic agent for colon cancer therapy is needed. In this study, analogues of echinomycin, a cyclic peptide natural product with potent toxicity to several human cancer cell lines, were synthesized, and their biological activities against human colon cancer cells were investigated. Analogue 3 as well as 1 inhibit HIF-1α-mediated transcription. Notably, transcriptome analysis indicated that the cell cycle and its regulation were involved in the effects on cells treated with 3. Analogue 3 exhibited superior in vivo efficacy to echinomycin without significant toxicity in mouse xenograft model. The low dose of 3 needed to be efficacious in vivo is also noteworthy and our data suggest that 3 is an attractive and potentially novel agent for the treatment of colon cancer.

Synthetic Approaches for Pyranoquinolines: A Concise Review

Abstract: The pyranoquinoline frameworks have a wide distribution in natural products and have displayed a great amplitude of biological activities, attracting the attention of synthetic and medicinal chemists due to their usefulness in agrochemical and pharmaceutical industries. Among the twenty possible isomeric pyranoquinoline frameworks, research reports for only six of them that were found during the period of time covered in this review article (i.e. 2000 to 2023). According to the literature reports during this frame of time, the synthesis of pyranoquinoline derivatives was achieved by following three general synthetic approaches [i.e. (i) via multicomponent cyclizations (MCC), (ii) via bimolecular cyclizations (BMC) and via intramolecular cyclizations (IMC)], mediated by catalyst-free conditions or by diverse environmentally friendly catalysts, in which mechanistic proposal was discussed for several of such processes. Additionally, various obtained pyranoquinoline derivatives reported in this review were subjected to diverse biological evaluations, such as Parkinson´s and Alzheimer´s diseases, as antibacterials, antifungals, and anticancer drugs, among others, indicating the promising biological potential of this class of heterocyclic structure.

Design, Synthesis, and Biological Evaluation of a New Series of 2,4-Position Modified Pyrimidine Derivatives

Design, Synthesis, and Biological Evaluation of a New Series of 2,4-Position Modified Pyrimidine Derivatives

Fabrication and Characterization of Montmorillonite Clay/Agar-Based Magnetic Composite and Its Biological and Electrical Conductivity Evaluation.

Montmorillonite clay and agar are naturally occurring materials of significant importance in designing biocompatible materials tailored for applications in biotechnology and medicine. The introduction of magnetic properties has the potential to significantly boost their characteristics and expand their applications. In this study, we have successfully synthesized highly intercalated magnetic composites, incorporating magnetic iron oxide nanoparticles (MNPs), montmorillonite clay (MMT), and agar (AG), through a thermo-physicomechanical method. Three samples of MMT-AG with 2, 1.5, and 0.5% MNPs and three sample composites of MNPs-AG with 2, 1, and 0.5% MMT clay are prepared. The synthesized composites were characterized by SEM, XRD, TGA, DTA, and FTIR. SEM analysis revealed a uniform dispersion of MNPs and MMT in the composite. The XRD pattern confirmed the presence of MNPs in the composite site. The TGA and DTA results demonstrated improved thermal stability due to the MNP incorporation. FTIR spectra showed all of the constituents of agar, MNPs, and MMT clay. The swelling ratio was observed to range from 835% to 1739%. The swelling study indicated an increased hydrophobicity with the addition of MNPs to the composite. Antibacterial activities revealed a significant inhibition of Escherichia coli (E. coli) growth by ranging from 10 to 19 nm in the composite. The composite also exhibited a considerable antioxidant action, with IC50 values of 7.96, 46.55, and 57.58 μg/mL, and electrical properties just like conductors.

Design, Synthesis and Biological Evaluation of Novel Phenyl-Substituted Naphthoic Acid Ethyl Ester Derivatives as Strigolactone Receptor Inhibitor.

Strigolactones (SLs) are plant hormones that regulate several key agronomic traits, including shoot branching, leaf senescence, and stress tolerance. The artificial regulation of SL biosynthesis and signaling has been considered as a potent strategy in regulating plant architecture and combatting the infection of parasitic weeds to help improve crop yield. DL1b is a previously reported SL receptor inhibitor molecule that significantly promotes shoot branching. Here, we synthesized 18 novel compounds based on the structure of DL1b. We performed rice tillering activity assay and selected a novel small molecule, C6, as a candidate SL receptor inhibitor. In vitro bioassays demonstrated that C6 possesses various regulatory functions as an SL inhibitor, including inhibiting germination of the root parasitic seeds Phelipanche aegyptiaca, delaying leaf senescence and promoting hypocotyl elongation of Arabidopsis. ITC analysis and molecular docking experiments further confirmed that C6 can interact with SL receptor proteins, thereby interfering with the binding of SL to its receptor. Therefore, C6 is considered a novel SL receptor inhibitor with potential applications in plant architecture control and prevention of root parasitic weed infestation.

Total Synthesis, Structure Reassignment, and Biological Evaluation of the Anti-Inflammatory Macrolactone 13-Hydroxy-14-deoxyoxacyclododecindione.

Herein, the first total synthesis of natural 13-hydroxy-14-deoxyoxacyclododecindione along with the revision of the proposed configuration is reported. This natural product, initially discovered in 2018, belongs to the oxacyclododecindione family, renowned for their remarkable anti-inflammatory and antifibrotic activities. The synthetic route involves an esterification/Friedel-Crafts-acylation approach and uses various triol fragments. It allows the preparation of different stereoisomers, including the (revised) natural product, two threo-derivatives, and two Z-isomers of the endocyclic C═C double bond. Furthermore, a late-stage inversion of the C-13 stereocenter could transform the originally proposed structure into the revised natural product. With this comprehensive set of compounds and the previously prepared (13R,14S,15R)-isomer, deeper insights into their structural properties and biological activities were obtained. A detailed analysis of the final macrolactones using spectroscopy (NMR, IR, UV-vis) and X-ray crystallography gave new insights such as the significance of the optical rotation for the elucidation of their configuration and the light-induced E/Z double-bond photoisomerization. The pharmacological potential of the compounds was underlined by remarkably low IC50 values in biological assays addressing the inhibition of cellular inflammatory responses.

Thoughts on the Biological Evaluation of Biodegradable Cardiovascular Implants

In recent years, new degradable materials have been applied to cardiovascular implants. Cardiovascular implants with different physicochemical properties and degradation properties have special endpoints for their biological evaluation. In this study, the end points of biological evaluation of degradable cardiovascular implants were reviewed by taking vascular stents and occluders as examples.

Facile synthesis of Cu2S-NiS2 nanocomposite with highly active visible light photocatalyst for dye removal and biological evaluation

Earth abundant metal sulphides such as Cu2S and NiS2 are potential materials to be used as photocatalysts because of their advantageous optical and biological aspects. In this research, a low-cost, high-speed, one step combustion production of novel Cu2S-NiS2 nanocomposite (NCs) was successfully developed. They are integrally characterized and evaluated as photocatalysts for dye degradation and biological uses. The synthesized NCs were characterized by XRD, FTIR, SEM, TEM, EDAX, UV–Visible and PL. XRD data is well matched with JCPDS 03–1071 and 73–574 which correspond to Cu2S and NiS2 nanoparticles (NPs) respectively. FT-IR spectrum exhibits the existence of metal-sulphur bonding in Cu2S-NiS2 NCs. The optical energy band gap of Cu2S-NiS2 NCs was found 2.30 eV. Under visible light irradiation, the photocatalytic activity of Cu2S-NiS2 NCs on rose bengal dye was investigated. Cu2S-NiS2 NCs is more efficient photocatalyst than individual metal sulphide NPs. Also, an important aspect of this study was the exploration of the antimicrobial, antioxidant and antihemolytic properties of pure NPs and Cu2S-NiS2 NCs. The results from the biological screening exposed the fact that the Cu2S-NiS2 NCs demonstrated significantly higher pharmacological activities in comparison to pure NPs.

Synthesis, Characterization, in vitro Biological Evaluation of a Series of Benzothiazole Amides as Antibacterial Agents

A series of benzothiazole amides (VH01-06) were synthesized by using modified Schotten-Baumann reaction conditions, all the resultant compounds were obtained in good yields and purity. The molecular structure of the compounds was characterized using physical and spectral methods. The structures of the compounds were consistent with the analytical data obtained for FT-IR, 1H NMR, 13C NMR and HRMS ESI-Mass spectroscopic techniques. Further, compounds were subjected to the in vitro antibacterial activity screening against various strains that includes Gram-positive bacteria (methicillin-resistant Staphylococcus aureus (MRSA) ATCC 3359 and methicillin-sensitive Staphylococcus aureus (MSSA) ATCC 2592) and Gram-negative bacteria (Escherichia coli J53 R1, Escherichia coli ATCC 25922, Klebsiella pneumoniae ATCC 10031 and Klebsiella pneumonia BAA-1075). Based on the biological screening results, compounds VH01-06 were found to possesses limited antibacterial properties against selected strains, since the recorded activity was found at 100 µM concentration. While compound VH05 displayed specific activity against E. coli ATCC 25923 at 200 µg/mL.

Design, synthesis and biological evaluation of tanshinone IIA derivatives as NLRP3 inflammasome inhibitors

Natural product structures have long provided valuable pharmacophores and even candidates for drug discovery. Tanshinone scaffold showed moderately inhibitory activity in NLRP3 inflammasome/IL-1β pathway. Herein, we designed a series of derivatives on different regions of Tanshinone IIA (TNA) scaffold. The biological evaluation identified compound T10, a scaffold hybrid of TNA and salicylic acid, as a potent NLRP3 inflammasome inhibitor. Mechanistically, T10 inhibits the production of ROS and prevents NLRP3 inflammasome-dependent IL-1β production. In addition, treatment with T10 significantly attenuated inflammatory response in DSS-induced peritonitis. Our work describes a potential tanshinone-based derivative, which needs to be further structurally optimized as NLRP3 inflammasome inhibitors for treating inflammatory disorders.

Biological Activity Evaluation of Olive, Grape, and Fig at Various Mixing Ratios

Purpose: This study aimed to evaluate the antioxidation and enzymatic activity-related qualities of four mixtures prepared with different mixing ratios of olives (O), grapes (V), and figs (F), which are representative ingredients of the Mediterranean diet. Methods: Following mixtures were prepared: olives–figs (OF), grapes–figs (VF), and olives–grapes–figs (OVF). For mixture preparation, the ingredients were mixed in following ratios: olives-to-grapes, olives-to-figs, and grapes-to-figs at ratios of 1:1 (30 g of each) as well as olives-to-grapes-to-figs at a ratio of 1:1:1 (20 g of each). The antioxidant (total polyphenol and flavonoid contents along with 2,2-diphenyl-1-picrylhydrazyl [DPPH] and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) [ABTS] radical scavenging) and enzymatic (α-glucosidase inhibitory and angiotensin-converting enzyme [ACE] inhibitory) activities of the four aforementioned mixtures were measured. Results: OV and OVF mixtures showed the highest total polyphenol (27.25±0.22 mg TAE/g) and flavonoid contents (27.9 ± 2.14 mg QE/g), respectively. DPPH radical scavenging ability was highest in OV (92.86 ± 0.17%). The highest ABTS radical scavenging activity was registered in the OVF mixture (42.88±1.19%). α-glucosidase and ACE inhibitory activity measurements were highest in the OVF mixture (79.75±0.15% and 88.61±0.08%, respectively). Conclusion: Highest physiological activity levels (i.e., anti-oxidation and enzymatic activity) were observed in the olive, grape, and fig (1:1:1) mixture, hence, its regular consumption could improve metabolic syndrome.

Fragment-based drug discovery and biological evaluation of novel cannabinol-based inhibitors of oxytosis/ferroptosis for neurological disorders

The oxytosis/ferroptosis regulated cell death pathway is an emerging field of research owing to its pathophysiological relevance to a wide range of neurological disorders, including Alzheimer's and Parkinson's diseases and traumatic brain injury. Developing novel neurotherapeutics to inhibit oxytosis/ferroptosis offers exciting opportunities for the treatment of these and other neurological diseases. Previously, we discovered cannabinol (CBN) as a unique, potent inhibitor of oxytosis/ferroptosis by targeting mitochondria and modulating their function in neuronal cells. To further elucidate which key pharmacophores and chemical space are essential to the beneficial effects of CBN, we herein introduce a fragment-based drug discovery strategy in conjunction with cell-based phenotypic screens using oxytosis/ferroptosis to determine the structure-activity relationship of CBN. The resulting information led to the development of four new CBN analogs, CP1-CP4, that not only preserve the sub-micromolar potency of neuroprotection and mitochondria-modulating activities seen with CBN in neuronal cell models but also have better druglike properties. Moreover, compared to CBN, the analog CP1 shows improved in vivo efficacy in the Drosophila model of mild traumatic brain injury. Together these studies identify the key molecular scaffolds of cannabinoids that contribute to neuroprotection against oxytosis/ferroptosis. They also highlight the advantageous approach of combining in vitro cell-based assays and rapid in vivo studies using Drosophila models for evaluating new therapeutic compounds.

Anticancer and Antibacterial Evaluation of Pure Poly(o-Toluidine) for Tissue Engineering and Cancer Treatment

Chemical oxidative polymerization was employed to synthesize pure poly (ortho-toluidine) (POT). The synthesized POT was characterized using XRD, FT-IR, and SEM analyses. Additionally, the samples were subjected to biological evaluation. The antibacterial activity of POT was tested against both Gram-positive (S. aureus) and Gram-negative (E. coli) bacteria. Notably, E. coli displayed significant susceptibility to POT's antibacterial effects, especially at higher concentrations. Furthermore, in vitro anticancer experiments were conducted on MG-63 bone cancer cells to assess the cytotoxicity of POT. Pristine POT exhibited the highest level of cytotoxicity, as evidenced by an IC50 value of 83.15 g/ml. In summary, this investigation highlights the robust antibacterial and anticancer activities of POT. These findings suggest potential applications of POT in areas such as tissue engineering scaffolds, anticancer therapies, and various biomedical uses.

Design, synthesis, and biological evaluation of first-in-class FABP1 inhibitors for the treatment of NASH

The fatty acid-binding protein 1 (FABP1) is a fatty acid transporter protein that is considered as an emerging target for metabolic diseases. Despite forceful evidence that the inhibition of FABP1 is essential for ameliorating NASH, pharmacological control and validation of FABP1 are hindered by a lack of relevant inhibitors as pharmacological tool. Therefore, the development of effective FABP1 inhibitors is a current focus of research. Herein, we firstly reported the comprehensive structure-activity relationship (SAR) study of novel FABP1 inhibitors derived from high throughput screening of our in-house library, which resulting in the identification of the optimal compound 44 (IC50 = 4.46 ± 0.54 μM). Molecular docking studies revealed that 44 forms stable hydrogen bonds with amino acids around the active pocket of FABP1. Moreover, 44 alleviated the typical histological features of fatty liver in NASH mice, including steatosis, lobular inflammation, ballooning and fibrosis. Additionally, 44 has been demonstrated to have lipid metabolism regulating, anti-oxidative stress and hepatoprotective properties. This study might be provided a promising insight into the field of NASH and inspiration for the development of FABP1 inhibitors.

Sertraline-Induced Hypoglycemia in Drug-Induced Liver Injury

Sertraline, a selective serotonin reuptake inhibitor, is a medication recommended as a third line treatment of cholestatic liver injury pruritis. We report a case of a young male who developed liver injury secondary to self-administration of anabolic steroids and who complained of persistent pruritis leading to a treatment by sertraline. Two days later, the patient was admitted to the hospital with a severe hypoglycemia, while the liver function tests were in amelioration. Clinical and biological evaluation were in favor of sertraline-induced hypoglycemia, a side effect rarely reported in non-diabetic patients, and in the context of hepatic injury.

Synthesis, characterization, biological evaluation, and molecular docking studies of new 1,3,4-oxadiazole-thioether derivative as antioxidants and cytotoxic agents

Oxadiazoles and their derivatives with thioether functionalities represent a new and exciting class of physiologically active heterocyclic compounds. Several molecules with these moieties play a vital role in pharmaceuticals because of their diverse biological activities. This paper describes a new class of 1,3,4- oxadiazole-2-thioethers with acetophenone, coumarin, and N-phenyl acetamide residues (S-alkylation), with the hope that the addition of various biologically active molecules will have a synergistic effect on anticancer activity. The structure of the synthesized title compounds was determined by the combined methods of IR, proton-NMR, carbon-13-NMR, and mass spectrometry. Furthermore, all the newly prepared molecules were assessed for their antioxidant activity. Furthermore, four compounds were assessed for their molecular docking interactions and cytotoxicity activity. The synthesized derivatives have shown moderate antioxidant activity compared to the standard BHA (butylated hydroxy anisole). The IC50 of the titled molecules (11b, 11c, 13b, and 14b) observed for in vitro anti-cancer activities were 11.20, 15.73, 59.61, and 27.66 g/ml at 72-h treatment time against the A549 cell lines, respectively. The tested compounds' biological evaluation showed that 11b is the most effective molecule in the series. In conclusion, the findings of this study suggest that the tested compounds, 1,3,4-oxadiazole-2-thioether derivative, have shown high cytotoxicity against human lung cancer diseases, which may serve for subsequent studies in the formulation of cancer-based drugs and future outlook for researchers.

Synthesis, DFT Studies, and Biological Evaluation of New Quinazoline-1,3,4-Thiadiazole Derivatives as Anti-proliferative Agents

Synthesis, DFT Studies, and Biological Evaluation of New Quinazoline-1,3,4-Thiadiazole Derivatives as Anti-proliferative Agents

Discovery of novel thiazolidinone-1,2,3-triazole hybrids with (D)-Limonene skeleton as anticancer agents: Design, synthesis and biological evaluation

In the present study, a series of natural bioactive (D)-Limonene-based 1,2,3-triazole 14a-e hybrids were synthesized by copper (II)-catalyzed [3 + 2] cycloaddition reaction. Synthetic products are characterized by spectroscopic techniques (1H- and 13C NMR). Our objective is to evaluate the anticancer activity against human cancer cell lines HT-1080, A-549, MCF-7 and MDA-MB-231. Indeed, we found that the majority of 1,2,3-triazole hybrids 14a-e showed average cytotoxic activity towards all conquering cells tested with IC50 values between 13.03 ± 0.67 and 41.66 ± 1.98 μM, except in the case of 14d, which represents IC50 values 13.03 ± 0.67 μM and 15.98 ± 2.03 μM respectively against HT-1080 and A-549 cells.

Antioxidant Activity and DFT Calculations of Metal Complexes Derived from a Schiff Base Ligand: Synthesis, Characterization, and Biological Evaluation

AbstractMetal complexes derived from Schiff bases are known to have a wide range of applications, spanning the areas of material and medicinal sciences. Herein, a Schiff base ligand, (Z)‐2‐(((4‐chlorophenyl)imino)methyl)naphthalen‐1‐ol HL, was synthesized via a condensation reaction between 2‐hydroxy‐1‐naphthaldehyde and 4‐chloroaniline using methanol as a solvent in the presence of a catalytic amount of formic acid. The obtained ligand was further reacted with Mn(II), Ni(II), and Cu(II) using their acetate salts in a 1 : 2 stoichiometric ratio of metal to ligand to afford complexes C1–C3, respectively. Physicochemical and analytical techniques consisting of FTIR, UV‐Vis, elemental (CHN and metal content), TGA, HRMS, 1H, and 13 C NMR spectroscopy were deployed to establish the formation of the compounds. Results show that the ligand coordinated with the metal ions through the oxygen and nitrogen atoms of the phenolate and azomethine moieties, respectively, forming ON‐type complexes. Furthermore, the free ligand and its complexes were evaluated for their antioxidant activity compared to the standard (ascorbic acid) using an in vitro DPPH radical scavenging assay. From this investigation, C1 demonstrated higher radical scavenging activity than the free ligand, the complexes, and the standard (ascorbic acid). But the ligand has better scavenging activity than C2 and C3 at higher concentrations. DFT was also used to examine the electronic properties of the compounds, and the data obtained corroborated well with the experimental study.