Distinct Mechanisms of Cytotoxicity in Novel Nitrogenous Heterocycles: Future Directions for a New Anti-Cancer Agent.

Electron-rich, nitrogenous heteroaromatic compounds interact more with biological/cellular components than their non-nitrogenous counterparts. The strong intermolecular interactions with proteins, enzymes, and receptors confer significant biological and therapeutic properties to the imidazole derivatives, giving rise to a well-known and extensively used range of therapeutic drugs used for infections, inflammation, and cancer, to name a few. The current study investigates the anti-cancer properties of fourteen previously synthesized nitrogenous heterocycles, derivatives of imidazole and oxazolone, on a panel of cancer cell lines and, in addition, predicts the molecular interactions, pharmacokinetic and safety profiles of these compounds. METHOD: The MTT and CellTiter-Glo® assays were used to screen the imidazole and oxazolone derivatives on six cancer cell lines: HL60, MDA-MB-321, KAIMRC1, KMIRC2, MCF-10A, and HCT8. Subsequently, in vitro tubulin staining and imaging were performed, and the level of apoptosis was measured using the Promega ApoTox-Glo® triplex assay. Furthermore, several computational tools were utilized to investigate the pharmacokinetics and safety profile, including PASS Online, SEA Search, the QikProp tool, SwissADME, ProTox-II, and an in silico molecular docking study on tubulin to identify the critical molecular interactions. RESULTS: In vitro analysis identified compounds 8 and 9 to possess the most significant potent cytotoxic activity on the HL60 and MDA-MB-231 cell lines, supported by PASS Online anti-cancer predictions with pa scores of 0.413 and 0.434, respectively. In addition, compound 9 induced caspase 3/7 dependent-apoptosis and interfered with tubulin polymerization in the MDA-MB-231 cell line, consistent with in silico docking results, identifying binding similarity to the native ligand colchicine. All the derivatives, including compounds 8 and 9, had acceptable pharmacokinetics; however, the safety profile was suboptimal for all the tested derivates except compound 4. CONCLUSION: The imidazole derivative compound 9 is a promising anti-cancer agent that switches on caspase-dependent apoptotic cell death and modulates microtubule function. Therefore, it could be a lead compound for further drug optimization and development.

Effectiveness of oral antibiotics in managing extended-spectrum B-lactamase urinary tract infections: A retrospective analysis.

Background: Urinary tract infections caused by extended-spectrum beta-lactamase organisms pose a significant concern worldwide. Given the escalating prevalence of drug resistance and the limited data on the effectiveness of oral antibiotics in treating these infections, this study aimed to assess the clinical outcomes in adult patients with extended-spectrum beta-lactamase urinary tract infections treated with oral antibiotics. Methods: A retrospective observational cohort study was conducted at King Abdulaziz Medical City, Saudi Arabia, from January 2018 to December 2021. It included patients ⩾18 years with complicated or uncomplicated urinary tract infections from extended-spectrum beta-lactamase Enterobacterales and treated with oral antibiotics as step-down or mainstay therapy. All-cause clinical failure within 30 days post-discharge was evaluated as the efficacy outcome. Statistical analyses were performed using SPSS software. Results: Out of 643 screened patients, 152 patients met the inclusion criteria. The patients were divided into oral step-down therapy (51.3%) and oral-only (48.7%) groups. The majority (69.1%) were females, with a mean age of 62 years. Complicated urinary tract infections were diagnosed in (75.5%) of cases, and the predominant pathogen was E. coli (79.6%). Clinical failure was observed in 23.1% in the oral step-down group and 13.5% in the oral-only group, with no significant difference (p = 0.128). Total antibiotics duration was significantly lower in the oral-only group (8 days vs. 12.2 days; p < 0.001). Binary logistic regression identified elder age, diabetes mellitus history, and prior extended-spectrum beta-lactamase infection as predictors of clinical failure. Conclusion: This study suggests that both step-down or primary oral antibiotic treatment yielded similar clinical outcomes in managing patients with extended-spectrum beta-lactamase urinary tract infections. Further prospective studies are required to validate these findings.

Natural Products as Novel Neuroprotective Agents; Computational Predictions of the Molecular Targets, ADME Properties, and Safety Profile.

Neurodegenerative diseases (NDs) are one of the most challenging public health issues. Despite tremendous advances in our understanding of NDs, little progress has been made in establishing effective treatments. Natural products may have enormous potential in preventing and treating NDs by targeting microglia; yet, there have been several clinical concerns about their usage, primarily due to a lack of scientific evidence for their efficacy, molecular targets, physicochemical properties, and safety. To solve this problem, the secondary bioactive metabolites derived from neuroprotective medicinal plants were identified and selected for computational predictions for anti-inflammatory activity, possible molecular targets, physicochemical properties, and safety evaluation using PASS online, Molinspiration, SwissADME, and ProTox-II, respectively. Most of the phytochemicals were active as anti-inflammatory agents as predicted using the PASS online webserver. Moreover, the molecular target predictions for some phytochemicals were similar to the reported experimental targets. Moreover, the phytochemicals that did not violate important physicochemical properties, including blood-brain barrier penetration, GI absorption, molecular weight, and lipophilicity, were selected for further safety evaluation. After screening 54 neuroprotective phytochemicals, our findings suggest that Aromatic-turmerone, Apocynin, and Matrine are the most promising compounds that could be considered when designing novel neuroprotective agents to treat neurodegenerative diseases via modulating microglial polarization.

The Role of Myrrh Metabolites in Cancer, Inflammation, and Wound Healing: Prospects for a Multi-Targeted Drug Therapy.

BACKGROUND: Myrrh extract is a well-known medicinal plant with significant therapeutic benefits attributed to the activity of its diverse metabolites. It has promising activity against cancer and inflammatory diseases, and could serve as a potential therapeutic alternative since most therapeutic agents have severe side effects that impair quality of life. METHOD: The current study identified the active metabolites from the myrrh resin methanolic extract. Then, the extracts were tested for in vitro anti-inflammatory and anti-cancer activity using cancer cell lines and Tamm-Horsfall Protein 1 (Thp-1)-like macrophage cell lines. Furthermore, using an in vivo rat model, the extracts' anti-inflammatory and wound-healing activity was investigated. In addition, in silico predictions of the myrrh constituents highlighted the pharmacokinetic properties, molecular targets, and safety profile, including cytochrome P 450 (CYP) inhibition and organ toxicity. RESULTS: Nine secondary metabolites were identified, and computational predictions suggested a good absorption profile, anticancer, anti-inflammatory, and wound-healing effects. The myrrh extract had moderate cytotoxic activity against both HL60 and K562 leukemia cell lines and the KAIMRC1 breast cancer cell line. Myrrh caused a dose-dependent effect on macrophages to increase the reactive oxygen species (ROS) levels, promote their polarization to classically activated macrophages (M1) and alternatively activated macrophages (M2) phenotypes, and consequently induce apoptosis, highlighting its ability to modulate macrophage function, which could potentially aid in several desired therapeutic processes, including the resolution of inflammation, and autophagy which is an important aspect to consider in cancer treatment. The topical application of myrrh improved wound healing, with no delayed inflammatory response, and promoted complete re-epithelization of the skin, similar to the positive control. In conclusion, we provide evidence for the methanolic extract of myrrh having cytotoxic activity against cancer cells and anti-inflammatory wound-healing properties, which may be attributed to its role in modulating macrophage function. Furthermore, we suggest the active constituents responsible for these properties, which warrants further studies focusing on the precise roles of the active metabolites.

Imidazole as a Promising Medicinal Scaffold: Current Status and Future Direction.

Various imidazole-containing compounds have been tested for their medical usefulness in clinical trials for several disease conditions. The rapid expansion of imidazole-based medicinal chemistry suggests the promising and potential therapeutic values of imidazole-derived compounds for treating incurable diseases. Imidazole core scaffold contains three carbon atoms, and two nitrogen with electronic-rich characteristics that are responsible for readily binding with a variety of enzymes, proteins, and receptors compared to the other heterocyclic rings. Herein, we provide a thorough overview of the current research status of imidazole-based compounds with a wide variety of biological activities including anti-cancer, anti-microbial, anti-inflammatory and their potential mechanisms including topoisomerase IIR catalytic inhibition, focal adhesion kinase (FAK) inhibition, c-MYC G-quadruplex DNA stabilization, and aurora kinase inhibition. Additionally, a great interest was reported in the discovery of novel imidazole compounds with anti-microbial properties that break DNA double-strand helix and inhibit protein kinase. Moreover, anti-inflammatory mechanisms of imidazole derivatives include inhibition of COX-2 enzyme, inhibit neutrophils degranulation, and generation of reactive oxygen species. This systemic review helps to design and discover more potent and efficacious imidazole compounds based on the reported derivatives, their ADME profiles, and bioavailability scores that together aid to advance this class of compounds.

Metabolites Profiling, In Vitro, In Vivo, Computational Pharmacokinetics and Biological Predictions of Aloe perryi Resins Methanolic Extract.

BACKGROUND: Aloe perryi is a traditional herb that has various biological and pharmacological properties such as anti-inflammatory, laxative, antiviral, antidiabetic, and antitumor effects, which have not been deliberated before. The current investigation aims to evaluate in vitro cytotoxicity against several cancer cell lines in addition to in vivo anti-inflammatory activities of Aloe perryi extract using a rat animal model. Moreover, the pharmacokinetic properties of bioactive constituents and possible biological targets were assessed and evaluated. The methanolic extract of Aloe perryi was prepared by maceration, to tentatively identify the biomolecules of the Aloe perryi extract, analytical LC-QTOF-MS method was employed for Aloe perryi methanolic extract. The cytotoxic activity was examined in six cancer cell lines using Titer-Glo assay and the IC50s were calculated in addition to in silico target predictions and in vivo anti-inflammatory activity assessment. Subsequently, the pharmacokinetics of the identified active components of Aloe perryi were predicted using SwissADME, and target prediction using the Molinspiration webserver. The cytotoxic activity on HL60 and MDA-MB-231 was moderately affected by the Aloe perryi extract with IC50 of 63.81, and 89.85 µg/ml, respectively, with no activity on other cells lines. Moreover, the Aloe perryi extract exhibited a significant increase in wound contraction, hair growth, and complete re-epithelization when compared with the negative control. The pharmacokinetic properties of the bioactive constituents suggested a good pharmaceutical profile for the active compounds and nuclear receptors and enzymes were the two main possible targets for these active compounds. Our results demonstrated the promising activity of Aloe perryi extract with cytotoxic and anti-inflammatory properties, indicating a potential therapeutic utility of this plant in various disease conditions.