Current Drug Discovery Technologies - Volume 20, Issue 2, 2023

COVID-19, aka Coronavirus Disease 2019, triggered by new severe acute respiratory syndrome coronavirus-2 or SARS-CoV-2, is now a public health emergency due to its rapid spread, high transmission efficiency, and severe viral pandemic that is significantly increasing the number of patients and associated deaths. Currently, no specific treatment is available for this highly contagious virus. The unavailability of effective and specific treatments and the severity of this epidemic situation potentiate medicinal chemists’ in supporting new prophylactic or therapeutic interventions against COVID-19. This study discusses the therapeutic potential of hesperidin, a traditionally used herbal medicine with an exceptional safety profile. Recent studies on hesperidin advocate its promising potential in the prevention and management of COVID-19. This paper also discusses the recent clinical studies based on the previously documented antiviral activity of hesperidin. Herein, we propose the detailed preclinical and clinical manifestations of hesperidin based on its multifaceted bioactivities to develop a novel anti-COVID-19 lead.

Aims and Background: Natural preservatives are a viable alternative to replace chemical preservatives that have potential toxicity and carcinogenic effects. Objective: To prove the effectiveness in increasing the microbiological stability of Minas Frescal cheese with the addition of a bacteriocin obtained from Latilactobacillus sakei as a natural preservative. Methods: A new broad-spectrum bacteriocin was evaluated for its functional activity in vitro and in situ when applied in the formulation of Minas Frescal cheese. A commercial bacteriocin was used as a positive control. Results: The inhibitory action of the bacteriocin studied was confirmed, with a reduction of 42.86% in the count of coagulase-positive Staphylococcus in relation to the negative control, at the end of the 30 days of study. For the group of thermotolerant coliforms, the bacteriocin studied showed greater efficiency than the commercial preservative. In vitro analyzes showed the inhibitory action of bacteriocin, above 87% inhibition against S. aureus, E. coli and Salmonela enteritidis, and approximately 90% against Listeria monocytogenes. Conclusion: It was concluded that the bacteriocin produced by the Latilactobacillus sakei strain has great potential for application in foods such as Minas Frescal cheese.

Background: In the past few decades, considerable progress has been made in CNS drug discovery, and various new CNS agents have been developed. Pyrimidine is an important scaffold in the area of medicinal chemistry. Recently, pyrimidine-containing compounds have been successfully designed as potent CNS agents. Substantial research has been carried out on pyrimidine-bearing compounds to treat different disorders of CNS in various animal models. Methods: Utilizing various databases, including Google Scholar, PubMed, Science Direct, and Web of Science, the literature review was conducted. The specifics of significant articles were discussed with an emphasis on the potency of pyrimidines derivatives possessing CNS activity. Results: Recent papers indicating pyrimidine derivatives with CNS activity were incorporated into the manuscript. (46) to (50) papers included different pyrimidine derivatives as 5-HT agonist/antagonists, (62) to (67) as adenosine agonist/antagonist, (70) to (75) as anticonvulsant agents, (80) to (83) as cannabinoid receptor agonists, (102) to (103) as nicotinic and (110) as muscarinic receptor agonists. The remaining papers (113) to (114) represented pyrimidine-based molecular imaging agents. Conclusion: Pyrimidine and its derivatives have been studied in detail to evaluate their efficacy in overcoming multiple central nervous system disorders. The article covers the current updates on pyrimidine-based compounds as potent CNS and molecular imaging agents and will definitely provide a better platform for the development of potent pyrimidine-based CNS drugs in the near future.

Background: SARS-CoV-2 main protease (M^pro or 3CL^pro) and papain-like protease (PL^pro) are common viral targets for repurposed drugs to combat COVID-19 disease. Recently, several antidepressants (such as fluoxetine, venlafaxine and citalopram) belonging to the Selective Serotonin Reuptake Inhibitors (SSRIs) and the Serotonin-Norepinephrine Reuptake Inhibitors (SNRI) classes have been shown to in vitro inhibit viral replication. Aim: Investigate a possible action of fluoxetine and derivatives on SARS-CoV-2 protease sites. Methods: Molecular docking was performed using AutoDock Vina. Both protease structures and different drug conformations were used to explore the possibility of SARS-CoV-2 inhibition on a M^pro or PL^pro related pathway. Drug structures were obtained by optimization with the Avogadro software and MOPAC using the PM6 method. Results were analysed on Discovery Studio Visualizer. Results: The results indicated that M^pro interacted in a thermodynamically favorable way with fluoxetine, venlafaxine, citalopram, atomoxetine, nisoxetine and norfluoxetine in the region of the active site, whether PL^pro conformers did not come close to the active site. Conclusion: In an in silico perspective, it is likely that the SSRIs and other anti-depressants could interact with M^pro and cause the enzyme to malfunction. Unfortunately, the same drugs did not present similar results on PLpro crystal, therefore, no inhibition is expected in an in vitro trial. Anyway, in vitro tests are necessary for a better understanding of the links between SARS-CoV-2 proteases and antidepressants.

Background: In the present study, a new series of 1,2,4-triazole linked to pyrazole derivatives (8a-j) of 4-(((7-amino-7H-[1,2,4]triazolo[4,3-b][1,2,4]triazol-6-yl)methyl)amino)-1,5-dimethyl- 2-phenyl-1H-pyrazol-3(2H)-one were synthesized and assessed for their antibacterial and anticancer activity. Objective: Encouraged by these results, these analogues 4-(((7-amino-7H-[1,2,4]triazolo[4,3- b][1,2,4]triazol-6-yl)methyl)amino)-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-ones 8 have been synthesized and their inhibitory potential activity against different bacterial microorganisms and cancer cell lines was discussed. Methods: All the synthesized final scaffolds were characterized by ¹H NMR, ¹³C NMR, IR, mass and elemental analysis. All the synthesized 1,2,4–triazole linked to pyrazole compounds were evaluated for their antimicrobial sensitivity by using the agar dilution technique. The anticancer activity of these compounds has been assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay and docking results are described by Autodock 4.2. Results: In vitro analysis suggests that compounds 8h, 8f, and 8b demonstrated excellent antibacterial activity against S. aureus, P. aeruginosa, S. epidermidis with MICs of 8, 8, 11 μg/mL respectively, while the remaining compounds showed moderate to good inhibitory potential. Some of them exhibited potent cytotoxicity against MCF-7 and P388 cancer cell lines and compounds 8c, 8f, and 8d reveal the highest potency against MCF-7 with IC50 values 2.8 ± 0.4, 3.1 ± 0.4, 3.5 ± 0.2 μM, respectively. Especially 8c, 8i and 8f showed better interaction patterns with amino acids Ala197 (N–N), Lys168 (N–N), Asn163 (O–N) at 3.13, 3.09, 3.00 A° as reported in DNA (Topo II) complex (1ZXM). Conclusion: New findings have established the fact that fused 1,2,4-triazoles linked to pyrazole contributed great significance in the field of medicinal chemistry due to their various biological properties.

Background: In this study, zinc oxide nanoparticles (ZnO-NPs) were biologically synthesized from Abelmoschus esculentus L. (Okra) mucilage fraction (OM). Methods: Analytical techniques were employed to study the formation and properties of OM-ZnO NPs, including their morphology, shape, size distribution, and surface charges. Additionally, OM-ZnO NPs were assessed for their antimicrobial, antioxidant, and cytotoxic properties. Results: UV-visible spectroscopy confirmed the formation of OM-ZnO NPs, evident by the appearance of an SPR peak at 368.8 nm. The FTIR spectroscopy demonstrated that OM functional groups contribute to the formation and stability of the NPs. Micrographs from TEM and SEM showed that OM-ZnO NPs ranged from 15-40 nm in diameter, whereas hydrodynamic diameter and surface charge values obtained from Zeta and DLS were 72.8 nm and 14.6 mv, respectively. XRD analysis indicated the OM-ZnO NPs were crystalline with a wurtzite structure and a crystallite size of 27.3 nm, while EDX revealed a zinc: oxygen ratio of 67.5:34. Further, the OM-ZnO NPs demonstrated significant antimicrobial activity in response to different types of bacteria. In the antioxidant assay, the OM-ZnO NPs scavenged DPPH with 68.6% of the efficiency of ascorbic acid (100%). Conclusion: The present study demonstrated the cytotoxic efficacy of MO-ZnO NPs against MCF7 cells with an IC50 of 43.99 μg/ml. Overall, the green synthesis of ZnO NPs by OM was successful for many biological applications, such as antimicrobial, antioxidant, and anticancer. Moreover, OM-ZnO NPs can be applied as a biologically-derived nanotherapeutic agent.

The treatment measures of malignant carcinomas are most important for human health. In recent years the use of targeted therapy based on small molecule compounds and identical immunoglobulin has been the most frequently used tool to combat cancerous cells. But there are still several limitations in their clinical development and applications, including their ability to bind multiple molecular target sites, both cell surface receptors and intracellular proteins, promoting a greater risk of toxicity. PROTAC is a novel technology that maintains a balance between protein synthesis and degradation and uses molecules instead of conventional enzyme inhibitors, containing two active domains and a linker to destroy unwanted selective protein (like kinase, skeleton protein and regulatory protein). PROTACs are heterobifunctional nano molecules with a size range of about 10 nanometres that eliminate the protein complexes formed by protein-protein interaction through large and flat surfaces generally defined as “undruggable” in conventional drug delivery systems, which include around 85% of proteins present in humans, suggesting their wide application in the field of drug development. Such peptide-based PROTACs have successfully shown targets' destruction in cultured cells (e.g., MetAP-2, and FKBP12^F36V, receptors for estrogens and androgen). However, some obstacles prevent this technology from transferring from the laboratory to its actual clinical utility, such as delivery system and bioavailability. The scope of the presented review is to give an overview of novel PROTAC technology with its limitations, advantages, mechanism of action, and development of photocontrolled PROTACs and to summarize its futuristic approach to targeting proteins in cancer cells.

Spirulina or Arthrospira, a Cyanobacterium from the class Cyanophyceae, with a wide range of properties, has been applied for over 400 years. The present study aimed to review available investigations surrounding the clinical and pharmacological properties of Spirulina that have been carried out so far. Databases including Scopus, PubMed, Google Scholar, and Web of Science were searched for relevant literature using the keywords: (Spirulina), (pharmacology), and (clinical). About 130 papers that studied the pharmacological characteristics of Spirulina in animal models, as well as clinical trials, were selected from the beginning to 29 July 2021. According to this review, antioxidative, anti-inflammatory, anti-neoplastic, hypolipidemic, antiviral, immunomodulatory, antimicrobial, anti-atherogenic, anti-diabetic, and radio-protective functions are attributed to Spirulina. Moreover, Spirulina's positive influence on several organs, including hair, skin, liver, CNS, lung, and genitourinary tract, are ascribed to different components of various species of Spirulina such as Spirulina platensis, Spirulina fusiformis, and Spirulina maxima. Although so many studies have been accomplished on every aspect of Spirulina in recent years, the lack of a comprehensive investigation surrounding this microalga encouraged us to prepare this paper. Therefore, the present study could be considered an up-to-date overview of the clinical, pharmacological, and molecular aspects of Spirulina, resulting in more occupational research on this valuable organism.