Drugs and Drug Candidates

Respiratory viruses present significant global health challenges due to their rapid evolution, efficient transmission, and zoonotic potential. These viruses primarily spread through aerosols and droplets, infecting respiratory epithelial cells and causing diseases of varying severity. While traditional intramuscular vaccines are effective in reducing severe illness and mortality, they often fail to induce sufficient mucosal immunity, thereby limiting their capacity to prevent viral transmission. Mucosal vaccines, which specifically target the respiratory tract’s mucosal surfaces, enhance the production of secretory IgA (sIgA) antibodies, neutralize pathogens, and promote the activation of tissue-resident memory B cells (BrMs) and local T cell responses, leading to more effective pathogen clearance and reduced disease severity. Bacillus subtilis spore surface display (BSSD) technology is emerging as a promising platform for the development of mucosal vaccines. By harnessing the stability and robustness of Bacillus subtilis spores to present antigens on their surface, BSSD technology offers several advantages, including enhanced stability, cost-effectiveness, and the ability to induce strong local immune responses. Furthermore, the application of BSSD technology in drug delivery systems opens new avenues for improving patient compliance and therapeutic efficacy in treating respiratory infections by directly targeting mucosal sites. This review examines the potential of BSSD technology in advancing mucosal vaccine development and explores its applications as a versatile drug delivery platform for combating respiratory viral infections. Full article

Background: Staphylococcus aureus is a pathogen that has become resistant to different antibiotics, which makes it a threat to human health. Although the first penicillin-resistant strain appeared in 1945, nowadays, there are just a few alternatives to fight it. To circumvent this issue, novel approaches to develop drugs to target proteins of the bacteria cytoskeleton, essential for bacteria’s binary fission, are being developed. FtsZ and FtsA are two proteins that are key for the initial stages of binary fission. On one side, FtsZ forms a polymeric circular structure called the Z ring; meanwhile, FtsA binds to the cell membrane and then anchors to the Z ring. According to the literature, this interaction occurs within the C-terminus domain of FtsZ, which is mainly disordered. Objective: In this work, we studied the binding of FtsZ to FtsA using computational chemistry tools to identify the interactions between the two proteins to further use this information for the search of potential protein-protein binding inhibitors (PPBIs). Methods: We made a bioinformatic analysis to obtain a representative sequence of FtsZ and FtsA of Staphylococcus aureus. With this information, we built homology models of the FtsZ to carry out the molecular docking with the FtsA. Furthermore, alanine scanning was conducted to identify the key residues forming the FtsZ–FtsA complex. Finally, we used this information to generate a pharmacophore model to carry out a virtual screening approach. Results: We identified the key residues forming the FtsZ-FtsA complex as well as five molecules with high potential as PPBIs. Full article

Fragment libraries have a major significance in drug discovery due to their role in de novo design and enumerating large and ultra-large compound libraries. Although several fragment libraries are commercially available, most are derived from synthetic compounds. The number of fragment libraries derived from natural products is still being determined. Still, they represent a rich source of building blocks to generate pseudo-natural products and bioactive synthetic compounds inspired by natural products. In this work, we generated and analyzed a fragment library of natural products from Colombia, a highly diverse geographical region where fragment libraries are yet to be reported. We also generated and reported fragment libraries of three novel natural product libraries and, as a reference, the most updated version of FDA-approved drugs. In line with the principles of open science, the fragment libraries developed in this study are freely available. Full article

Pomolic acid (3-beta,19alpha-Dihydroxy-urs-12-en-28-oic acid, PA) is a naturally occurring pentacyclic triterpenoid. Derived from the mevalonate pathway through cyclization of 2,3-oxidosqualene, it has been widely found in several plant species. In the mid-1960s, PA was identified as the genuine aglycone of triterpenoid saponins from Sanguisorba officinalis, and studies on its biological activities began in 1989. Since then, several pharmacological properties have been described for this compound, including antitumoral activity. PA induced cell death in tumors, such as lung, brain, breast, and sensitive and resistant leukemia. Additionally, PA modulates resistant proteins and events involved in metastasis. Even though PA constitutes an important candidate for new treatment against several cancers, its availability hampers the evolution of PA studies toward clinical evaluation. This review discusses the limitations of PA availability, the recent approaches to improve it, and other aspects of the antitumoral studies on PA activity. Full article

Background: Ovarian cancer (OC) is the most prevalent gynecological malignancy in women, often diagnosed at an advanced stage due to the absence of specific clinical biomarkers. Notch signaling, particularly Notch3, is frequently activated in OC and contributes to its oncogenic role. Despite its known association with poor clinical outcomes, the biomarker potential of Notch3 remains inadequately explored. Methods: We investigated the biomarker potential of Notch3 in OC using multiple databases, including ONCOMINE, GEPIA, Human Protein Atlas, UALCAN, Kaplan–Meier Plotter, and LinkedOmics. We analyzed Notch3 expression levels, survival correlations, and clinicopathological parameters. Results: Notch3 expression was significantly upregulated in OC, as well as other cancers. Correlation analysis demonstrated that high Notch3 mRNA levels were associated with poor overall survival (OS) (p < 0.05) and relapse-free survival (p < 0.05) in OC patients. Human Protein Atlas data showed elevated Notch3 protein levels in OC tissues compared to healthy controls. Clinicopathological analysis indicated significant associations between Notch3 expression and patient age (p < 0.5), TP53 mutation status (p < 0.5), and cancer stage (p < 0.1). Additionally, genes such as WIZ, TET1, and CHD4 were found to be co-expressed with Notch3 in OC. Notch3 expression also correlated with immune cell infiltration in OC. Conclusions: Our bioinformatics analysis highlights Notch3 as a potential biomarker for poor prognosis in OC. However, further in vitro and in vivo studies, along with validation using larger tissue samples, are necessary to confirm its biomarker utility. Full article

Background/Objectives: Elevated plasma homocysteine levels constitute a risk factor for vascular and cardiovascular disorders. Ferulic acid (FA), a polyphenol is tested on L-methionine-induced hyperhomocysteinemia (hHcy). The present study investigated the protective effect of ferulic acid (FA) on hyperhomocysteinemia (hHcy) induced changes in hemodynamic, biochemical, anti-oxidant, anti-inflammatory parameters as well as histopathological changes in abdominal aorta and heart. Methodology: The Wistar rats were divided into six groups (n = 6) and treated orally for 36 days. The rats were treated with Met (1 gm/kg) to induce Hcy. They were treated with either standard (Vit. B12 + Folic acid; 15 + 70 mg) or test FA (20/40/60 mg/kg, respectively) post-Met treatment. Homocysteine, cholesterol, lactate dehydrogenase (LDH), creatinine kinase (CK-MB), and liver enzymes were estimated in blood followed by the measurement of hemodynamic parameters. The liver was estimated for antioxidant parameters and nitric oxide (NO). Heart and abdominal aorta were studied histopathologically. Result: Diseased rats showed increased Hcy, cholesterol, LDH, CK-MB, alanine transaminase (ALT), aspartate transaminase (AST), malondialdehyde (MDA), NO, and reduced glutathione (GSH). Following FA treatment, these parameters returned to normal. Atherosclerotic lesions in the aorta were observed in the hHcy group; however, in the FA treatment groups, they were lessened. Conclusions: Ferulic acid reduces oxidative and nitrosive stress, thereby reducing hypercyteinemia and improving the lipid profile. It might be acting by increasing the activity of methylation dependent on S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH), which in turn prevents the formation of Hcy and reduces hHcy. The docking study supports these findings. Full article

Background/Objectives: Alzheimer’s disease (AD), a complex neurogenerative disorder, manifests as dementia and concomitant neuropsychiatric symptoms, including apathy, depression, and circadian disruption. The pathology involves a profound degeneration of the hippocampus and cerebral cortex, leading to the impairment of both short-term and long-term memory. The cholinergic hypothesis is among the various theories proposed, that assume the loss of the cholinergic tract contributes to the onset of AD and proves clinically effective in managing mild to moderate stages of the disease. This study explores the potential therapeutic efficacy of sulfonamide-based butyrylcholinesterase inhibitors in mitigating scopolamine-induced amnesia in rats. Methods: Behavioral assessments utilizing Y-maze, Barnes maze, and neurochemical assays were conducted to evaluate the effectiveness of the test compounds. Results: Results demonstrated a significant reduction in the impact of scopolamine administration on behavioral tasks at a dose of 20 mg/kg for both compounds. Correspondingly, neurochemical assays corroborated these findings. In silico docking analysis on rat butyrylcholinesterase (BChE) was performed to elucidate the binding mode of the compounds. Subsequent molecular dynamics studies unveiled the formation of stable complexes between the test compounds and rat BChE. Conclusions: These findings contribute valuable insights into the potential therapeutic role of sulfonamide-based butyrylcholinesterase inhibitors in addressing memory deficits associated with AD, emphasizing their in silico molecular interactions and stability. Full article

The review explores the critical role of chirality in the pharmacology of antidepressant drugs, focusing on how the stereochemistry of these compounds influences their biological activity and therapeutic outcomes. Antidepressants, especially modern classes such as selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs), often possess chiral centers that result in enantiomers with distinct pharmacodynamic and pharmacokinetic profiles. The review systematically examines various chiral antidepressants, including racemic mixtures and enantiomerically pure drugs, highlighting the differential effects of each enantiomer on neurotransmitter reuptake inhibition and the potential clinical implications. By examining specific examples of chiral antidepressants, the review illustrates the differences in pharmacokinetics and pharmacodynamics between enantiomers and racemic mixtures, emphasizing the clinical advantages of using enantiomerically pure compounds. Understanding and leveraging chirality in drug design and therapy is crucial for optimizing antidepressant treatments, offering insights into future research directions that could enhance patient outcomes by tailoring medication more precisely to individual biological profiles. Full article

Microwaves in the presence of enzymes can contribute to the preparation of a variety of medicinally active compounds. Microwave-induced enzymatic reactions are influenced by variables such as frequency, field strength, waveform, duration, and modulation. The activation of enzymes under microwave irradiation allows the study of simple and complex reactions that have never before been reported under these conditions. By combining enzyme catalysis with microwave technology and solvent-free chemical reactions, it is possible to prepare drug-related molecules. This review presents the most interesting microwave reactions performed by enzymes toward medicinally active molecules. Full article

By taking into account our previously described series of 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene compounds, we have now designed, prepared, and evaluated in vitro against Plasmodium falciparum a novel series of structural analogues of these molecules, i.e., the 1,3,5-tris[(4-(substituted-aminomethyl)phenoxy)methyl]benzene derivatives. The pharmacological data showed antimalarial activity with IC₅₀ values in the sub and μM range. The in vitro cytotoxicity of these new nitrogen polyphenoxymethylbenzene compounds was also evaluated on human HepG2 cells. The 1,3,5-tris[(4-(substituted-aminomethyl)phenoxy)methyl]benzene derivative 1m was found as one of the most potent and promising antimalarial candidates with favorable cytotoxic to antiprotozoal properties in the P. falciparum strains W2 and 3D7. In conclusion, this 1,3,5-tris[(4-(pyridin-3-ylmethylaminomethyl)phenoxyl)methyl]benzene 1m (IC₅₀ = 0.07 μM on W2, 0.06 μM on 3D7, and 62.11 μM on HepG2) was identified as the most promising antimalarial derivative with selectivity indexes (SI) of 887.29 on the W2 P. falciparum chloroquine-resistant strain, and of 1035.17 on the chloroquine-sensitive and mefloquine decreased sensitivity strain 3D7. It has been previously described that the telomeres of P. falciparum could represent potential targets for these types of polyaromatic compounds; therefore, the capacity of our novel derivatives to stabilize the parasitic telomeric G-quadruplexes was assessed using a FRET melting assay. However, with regard to the stabilization of the protozoal G-quadruplex, we observed that the best substituted derivatives 1, which exhibited some interesting stabilization profiles, were not the most active antimalarial compounds against the two Plasmodium strains. Thus, there were no correlations between their antimalarial activities and selectivities of their respective binding to G-quadruplexes. Full article

Commonly known as wild pepper, Piper capense (P. capense) is a culinary herb mainly used as a secret in preparation of “Nkui” and “Nah poh” in Bayangam, West Cameroon. However, it also has many interesting pharmacological properties, which is why the people of sub-Saharan Africa so highly prize it for the treatment of multiple human pathologies. This study aimed to highlight the traditional uses, phytochemical composition, biological activities, and toxicological profile of the P. capense plant, to draw the attention of pharmaceutical companies to its enormous potential for the development of future phyto- or pharmaceutical products. Documentary research was meticulously carried out in the Web of Sciences, Scopus, Pubmed/Medline, and Google Scholar databases according to PRISMA 2020 guidelines. The results show that extracts and compounds isolated from Piper capense have interesting anticancer, antibacterial, antimalarial, hypoglycemic, anti-epileptic, and antidepressant activities. Methanolic extracts and essential oils from P. capense exhibit no harmful effects when directly applied to normal human hepatocytes, umbilical cord cells, intestinal cells, and keratinocyte cell lines. Additionally, methanolic extracts administered acutely or subchronically at low doses (≤250 mg/kg body weight) in Wistar rats also demonstrate no adverse effects. In conclusion, given its interesting activities, P. capense is a viable option for developing new antimalarial, anticancer, antibacterial, hypoglycemic, anti-epileptic, and antidepressant drugs. However, many avenues still need to be explored before translation into drugs. Full article

Docetaxel (DTX) and betulinic acid (BA) co-encapsulated poly-lactic co-glycolic acid (PLGA) nanoparticles (NPs) were developed for enhanced lung cancer activity in vitro. Poly (lactic-co-glycolic acid) (PLGA) was used as an encapsulating polymer along with polyvinyl alcohol (PVA) as a stabilizing base to formulate NPs with the double-emulsion solvent evaporation method to study the size and potential, along with the surface morphology and in vitro release, of NPs. Cell culture studies like in vitro cellular uptake, apoptosis, and cell cycle arrest were performed in an in vitro cytotoxicity study to access the NP’s effect in the A549 human lung cancer cell line. The emulsification solvent evaporation technique produced smooth spherical nanoparticles of small sizes with a relatively narrow size distribution (147.2 ± 12.29 nm). On the A549 cell line, the formulation showed higher cytotoxicity (6.43 ± 0.11, 4.21 ± 0.32, and 1.17 ± 0.23 µmol for 24, 48, and 72 h, respectively) compared to the free drug due to an increase in vitro cellular uptake. Apoptosis and cell cycle analysis also confirmed the effectiveness of the prepared NPs. In vitro studies have proven the tumor-targeting potential of DTX-BA-NPs in A549 cell lines and could be future medication for lung cancer treatment. Full article

In this paper, we report on the use of a purpose-built hybrid solid-state microwave and radiofrequency generator operating at frequencies of 2.45 GHz and/or 480 kHz for cancer ablation in various tissues. The hybrid generator was tested ex vivo on chicken breast and bovine liver and has demonstrated that the high accuracy of the power delivered to the sample can be achieved by controlling the emitted power versus the temperature profile of the treated sample. In particular, the hybrid generator incorporates control systems based on impedance or reflected power measurements that allow controlled ablation without causing unwanted carbonization and without including areas where tissue damage is not desired. The results of the ex vivo tests showed that radiofrequency ablation (RFA) could be effective for performing controlled ablations with minimally invasive probes, such as cardiac pathologies, small lesions, and tissues with particular composition, while microwave ablation (MWA) could be optimal for performing large ablations in highly vascularized tissues, such as liver cancer, where it is necessary to achieve higher temperatures. Full article

Fungal infections are a significant threat to human health and the environment. The emergence of multidrug-resistant strains of fungi and the growing prevalence of azole resistance in invasive fungal infections exacerbate the problem, with efflux pumps being a major cause of antifungal resistance and a prime target for several counteractive strategies. In Candida albicans, the ATP-binding cassette superfamily transporter CaCdr1p is the predominant efflux pump involved in azole resistance. Marine organisms have unique phenotypic characteristics to survive in challenging environments, resulting in biologically active compounds. The cyclodepsipeptides unnarmicin A and C have shown promising results as inhibitors of rhodamine 6G efflux in cells expressing CaCdr1p. Herein, a series of unnarmicin analogues were designed and docked against a CaCdr1p efflux pump based on the cryogenic electron microscopy structure available to select the most promising compounds. Analogue 33 was predicted to be the best considering its high affinity for the efflux pump and pharmacokinetic profile. These results pave the way for further synthesis and in vitro biological studies of novel unnarmicins seeking a synergistic effect with fluconazole. Full article

Antibiotic resistance is a critical public health issue. Among the multi-drug resistant microorganisms in question, Pseudomonas aeruginosa has been designated by the WHO as a priority threat. Its virulence is orchestrated through quorum sensing (QS). This sophisticated communication network relies on the release and perception of autoinducers acting as population density indicators. Therefore, the interest of a quorum silencing pharmacological approach has unfolded to quench bacterial pathogenicity without impairing growth. In this article, we reported the development of a family of indazole–quinolone hybrids as anti-virulence agents. These new biaromatic compounds were designed as potential specific QS quenchers against P. aeruginosa. Our transdisciplinary research methodology included their synthesis using palladocatalyzed cross-coupling reactions, as well as their in silico physicochemical and in vitro biological evaluation. The hit 7-chloro-2-indazolyl-4-quinolone Ie shows a promising anti-biofilm and anti-pyocyanin efficiency (35% inhibition at 25 µM and 35% inhibition at 100 µM, respectively) without an anti-pseudomonal bacteriostatic effect. It also demonstrated a moderate eukaryotic cytotoxicity. Its anti-QS properties have been investigated using metabolomic and molecular modelling studies. Full article

The indole scaffold is considered a privileged framework in the design and synthesis of several active pharmaceutical ingredients, particularly as promising anticancer agents. Its presence in several bioactive natural compounds has caught the attention of the scientific community, which has been committed to unveiling its biosynthetic pathways and generating multiple derivatives with innovative synthetic routes. The large variety of structural derivatives enhances their use in multiple bioapplications and pharmacological activities. In this review, the reader will have easy access to some examples of natural and synthetic indole derivatives with antimicrobial, antidepressant, anti-inflammatory, antiviral, antimigraine, and antiemetic activity. However, the main topic of this review is related to cancer and the importance of indole derivatives as promising anticancer drugs. Two of the reasons why cancer is considered a massive problem worldwide are attributed to the struggle to develop target-specific drugs while avoiding drug resistance. Among countless drugs targeting specific proteins involved in tumorigenesis, prompting life quality in the treatment of several cancer types, protein kinases, desoxyribonucleic acid topoisomerases, and P-glycoprotein have been shown to be the main targets when it comes to the development of novel anticancer agents. Furthermore, indole and its derivatives are also studied regarding affinity to other targets related to cancer. This review aims to highlight the utility of the indole scaffold in anticancer drug design, inspiring the creation and synthesis of new derivatives that target specific proteins and address drug resistance challenges. Full article

In our previous study, we documented the anti-melanogenic efficacy of calebin-A (CBA), which is a curcuminoid analog. The effects of its newly synthesized analogs, i.e., bisdemethoxy calebin (BD), demethoxycalebin-1 (DA1), demethoxycalebin-2 (DA2), and tetrahydrocalebin-A (THCBA), on melanogenesis have not been examined yet. Herein, we evaluated these four CBA analogs to determine their impacts on the enzymatic activity of mushroom tyrosinase. Additionally, we examined their effects on melanogenesis and the tyrosinase activity in B16F10 mouse and MNT-1 human melanoma cells. The antioxidant activity of the analogs was also assessed. Our results revealed that BD was ineffective, while DA1 and DA2 showed similar antioxidant activities, with THCBA exhibiting the greatest antioxidant activity. Next, the diphenolase activity assay results revealed that DA1 showed the most excellent inhibitory efficacy, DA2 and BD showed similar inhibition profiles, and THCBA was ineffective. In addition, the results of the monophenolase activity showed a similar pattern, except that THCBA suppressed the activity. The four analogs were evaluated for any cytotoxicity over a 48 h duration in B16F10 and HaCaT keratinocytes, where DA1 exerted cytotoxicity at the concentration of 50 µM. Based on this, the analogs were evaluated over a 10–50 µM concentration range, while DA1 was evaluated over 10–35 µM. BD showed the greatest efficacy at multiple concentrations in significantly diminishing melanogenesis in hormone-stimulated B16F10 cells, while DA1 and DA2 suppressed melanin at 35 and 50 µM, respectively, and THCBA stimulated melanogenesis at 50 µM. In addition, BD and DA1 suppressed tyrosinase activity in B16F10 cells, with no effect in the case of DA2 and THCBA analogs. However, in MNT-1 cells, only DA1 showed efficacy in suppressing melanin production while the other three analogs were ineffective. Interestingly, BD and DA1 suppressed MNT-1 cell tyrosinase activity. Collectively, our results indicate that of the four analogs, DA1 merits further investigation as a potential compound for hyperpigmentation skin disorders. Additional research is necessary to delineate the molecular mechanisms underlying the melanogenesis-inhibitory effect of CBA analogs and examine their efficacy in diminishing melanogenesis in normal human melanocytes. Full article

Clotrimazole (CLZ), traditionally an antifungal agent, unveils promising avenues in cancer therapy, particularly in addressing bladder and prostate cancers. In vitro assessments underscore its remarkable efficacy as a standalone treatment, significantly diminishing cancer cell viability. Mechanistically, CLZ operates through multifaceted pathways, including the inhibition of Ca²⁺-dependent K⁺ channels, suppression of glycolysis-related enzymes, and modulation of the ERK-p65 signaling cascade, thus underscoring its potential as a versatile therapeutic agent. Our investigation sheds light on intriguing observations regarding the resilience of UM-UC-5 bladder cancer cells against high doses of paclitaxel (PTX), potentially attributed to heightened levels of the apoptosis-regulating protein Mcl-1. However, synergistic studies demonstrate that the combination of Doxorubicin (DOXO) and CLZ emerges as particularly potent, especially in prostate cancer contexts. This effectiveness could be associated with the inhibition of drug efflux mediated by multidrug resistance-associated protein 1 (MRP1), underscoring the importance of exploring combination therapies in cancer treatment paradigms. In essence, our findings shed light on the anticancer potential of CLZ, emphasizing the significance of tailored approaches considering specific cancer types and molecular pathways in drug repurposing endeavors. While further validation and clinical exploration are warranted, the insights gleaned from this study offer promising prospects for enhancing cancer therapy efficacy. Full article

Plants and plant extracts have long been acknowledged as valuable resources for the development of therapeutic formulations for various diseases. Among them, numerous plants and plant-derived products have demonstrated cytotoxic and/or anti-tumor properties. Saffron, particularly due to its major compounds, namely crocin, crocetin, and safranal, stands out as a promising candidate in this regard. Our research undertakes a literature review, reaffirming the antioxidant, anti-inflammatory, and, notably, anti-tumor properties of saffron and its major constituents. Additionally, this study examines relevant patent documents, highlighting innovative applications for saffron and its major compounds in cancer therapy. The review discusses the progress in purifying the compounds extracted from saffron and assesses their impact on cytotoxic trial outcomes, the potential synergies between certain saffron compounds and established cytotoxic molecules, and the limitations of the patents examined, particularly concerning reported clinical evidence. Researchers who focus on advances in oncology will know from our findings the evolution of the patent landscape regarding cytotoxic and/or anti-tumor therapeutic applications using saffron or its main compounds. Moreover, investigators can draw inspiration from patents leveraging traditional knowledge, particularly from Chinese medicine, to clarify specific active molecules and their mechanisms of action and can expedite the translation of these findings into clinically relevant interventions, potentially enhancing cancer therapy outcomes. Full article