Drugs Drug Candidates, Volume 2, Issue 3 (September 2023) – 11 articles

Based on the demonstrated and reported trypanocidal, leishmanicidal, and antiplasmodial activities of two menthol prodrugs, it was decided to proceed with preformulation studies, which are of key relevance in the drug discovery process. The aim of this study is to examine the stability and permeability of two new menthol prodrugs with antiparasitic activity. To determine the stability of menthol and its prodrugs, the corresponding studies were carried out in buffered solutions at pH values of 1.2, 5.8, and 7.4 at 37 °C. In silico permeability studies were performed using the free PerMM software and then in vitro permeability studies were performed using a biomimetic artificial membrane (BAM). Permeability studies conducted in silico predicted that both menthol and its prodrugs would pass through biological membranes via flip-flop movement. This prediction was subsequently confirmed by in vitro BAM permeability studies, where it was observed that the menthol prodrugs (1c and 1g) exhibited the highest P_app (apparent permeability) value compared to the parent compound. The study reveals that menthol prodrugs exhibit stability at a pH of 5.8 and possess sufficient in vitro permeability values as preformulation parameters. Full article

The Warburg effect (or aerobic glycolysis), which was first described in 1926 by Otto Heinrich Warburg, consists of the change in glucose metabolism in cancer cells. In normal cells, glucose metabolism finalizes in the mitochondria through oxidative phosphorylation (OXPHOS) in the presence of oxygen. However, the Warburg effect describes a change in the glucose metabolism in cancer cells, consuming excess glucose and converting it into lactate independently of the presence of oxygen. During this process, a wide variety of enzymes can modify their expression and activity to contribute to the mechanism of deregulated cancer metabolism. Therefore, the modulation of enzymes regulating aerobic glycolysis is a strategy for cancer treatment. Although numerous enzymes play a role in regulating aerobic glycolysis, hexokinase 2 (HK2), pyruvate dehydrogenase kinase (PDK), pyruvate kinase (PK), and lactate dehydrogenase (LDH) are worth mentioning. Numerous modulators of these enzymes have been described in recent years. This review aims to present and group, according to their chemical structure, the most recent emerging molecules targeting the above-mentioned enzymes involved in the Warburg effect in view of the future development of cancer treatments. Full article

ACE inhibitors, sartans, and sacubitril are among the most important drugs for the prevention of cardiovascular mortality and morbidity. At the same time, they are known to cause non-allergic bradykinin-mediated angioedema, a potentially fatal swelling of the mucosa and/or submucosa and deeper skin without signs of urticaria or pruritus, occurring mainly in the head and neck region. In contrast with hereditary angioedema, which is also mediated by bradykinin, angioedema triggered by these drugs is by far the most common subtype of non-allergic angioedema. The molecular mechanisms underlying this type of angioedema, which are discussed here, are not yet sufficiently understood. There are a number of approved drugs for the prevention and treatment of acute attacks of hereditary angioedema. These include inhibitors of bradykinin synthesis that act as kallkrein inhibitors, such as the parenterally applied plasma pool, and recombinant C1 esterase inhibitor, ecallantide, lanadelumab, and the orally available berotralstat, as well as the bradykinin receptor type 2 antagonist icatibant. In contrast, no diagnostic tools, guidelines, or treatments have yet been approved for the diagnosis and treatment of acute non-allergic drug-induced angioedema, although it is more common and can take life-threatening courses. Approved specific drugs and a structured diagnostic workflow are needed for this emergency diagnosis. Full article

The endocannabinoid system is found throughout the CNS and the body where it impacts many important physiological processes. Expectations were high that targeting cannabinoid receptors would prove therapeutically beneficial; pharmaceutical companies quickly seized on the appetitive and metabolic effects of cannabinoids to develop a drug for the treatment of weight loss. Alas, the experience with first-in-class cannabinoid type-1 receptor (CB₁R) antagonist rimonabant is a now-classic cautionary tale of the perils of drug development and the outcome of rimonabant’s fall from grace dealt a blow to those pursuing therapies involving CB₁R antagonists. And this most commercially compelling application of rimonabant has now been partially eclipsed by drugs with different mechanisms of action and greater effect. Still, blocking CB₁ receptors causes intriguing metabolic effects, some of which appear to occur outside the CNS. Moreover, recent years have seen a startling change in the legal status of cannabis, accompanied by a popular embrace of ‘all things cannabis’. These changes combined with new pharmacological strategies and diligent medicinal chemistry may yet see the field to some measure of fulfillment of its early promise. Here, we review the story of rimonabant and some of the therapeutic niches and strategies that still hold promise after the fall. Full article

Bacteriophages (phages) are viruses of bacteria and have been used as antibacterial agents now for over one-hundred years. The primary pharmacodynamics of therapeutic phages can be summed up as follows: phages at a certain concentration can reach bacteria at a certain rate, attach to bacteria that display appropriate receptors on their surfaces, infect, and (ideally) kill those now-adsorbed bacteria. Here, I consider the rate at which phages reach bacteria, during what can be dubbed as an ‘extracellular search’. This search is driven by diffusion and can be described by what is known as the phage adsorption rate constant. That constant in turn is thought to be derivable from knowledge of bacterial size, virion diffusion rates, and the likelihood of phage adsorption given this diffusion-driven encounter with a bacterium. Here, I consider only the role of bacterial size in encounter rates. In 1932, Schlesinger hypothesized that bacterial size can be described as a function of cell radius (R, or R¹), as based on the non-phage-based theorizing of Smoluchowski (1917). The surface area of a cell—what is actually encountered—varies however instead as a function R². Here, I both provide and review evidence indicating that Schlesinger’s assertion seems to have been correct. Full article

A series of new 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene compounds were designed, synthesized, and evaluated in vitro against two parasites (Plasmodium falciparum and Leishmania donovani). The biological results showed antimalarial activity with IC₅₀ values in the sub and μM range. The in vitro cytotoxicity of these new aza polyaromatic derivatives was also evaluated on human HepG2 cells. The 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene 1m was found as one of the most potent and promising antimalarial candidates with a ratio of cytotoxic to antiprotozoal activities of 83.67 against the P. falciparum CQ-sensitive strain 3D7. In addition, derivative 1r was also identified as the most interesting antimalarial compound with a selectivity index (SI) of 17.28 on the W2 P. falciparum CQ-resistant strain. It was previously described that the telomeres of P. falciparum could be considered as potential targets of these kinds of aza heterocycles; thus, the ability of these new derivatives to stabilize the parasitic telomeric G-quadruplexes was measured through a FRET melting assay. Full article

Trypanosomatids are mainly responsible for leishmaniasis, sleeping sickness, and Chagas disease, which are the most challenging among the neglected tropical diseases due to the problem of drug resistance. Although problems of target deconvolution and polypharmacology are encountered, a target-based approach is a rational method for screening drug candidates targeting a biomolecule that causes infections. The present study aims to summarize the latest information regarding potential inhibitors of squalene synthase and farnesyl phosphate synthase with anti-Trypanosomatidae activity. The information was obtained by referencing textbooks and major scientific databases from their inception until April 2023. Based on in vitro experiments, more than seventy compounds were reported to inhibit squalene synthase and farnesyl diphosphate synthase. Among these compounds, more than 30 were found to be active in vitro against Trypanosomatidae, inferring that these compounds can be used as scaffolds to develop new drugs against trypanosomatid-related infections. Overall, natural and synthetic products can inhibit enzymes that are crucial for the survival and virulence of trypanosomatids. Moreover, in vitro experiments have confirmed the activity of more than half of these inhibitors using cell-based assays. Nevertheless, additional studies on the cytotoxicity, pharmacokinetics, and lead optimization of potent anti-Trypanosomatid compounds should be investigated. Full article

The Met protein is a cell surface receptor tyrosine kinase predominantly expressed in epithelial cells. Aberrant regulation of MET is manifested by numerous mechanisms including amplification, mutations, deletion, fusion of the MET proto-oncogene, and protein overexpression. They represent the common causes of drug resistance to conventional and targeted chemotherapy in numerous cancer types. There is also accumulating evidence that MET/HGF signaling drives an immunosuppressive tumor microenvironment and dampens the efficacy of cancer immunotherapy. Substantial research effort has been invested in designing Met-targeting drugs with different mechanisms of action. In this review, we summarized the current preclinical and clinical research about the development of Met-targeting drugs for cancer therapeutics. Early attempts to evaluate Met-targeted therapies in clinical trials without selecting the appropriate patient population did not produce satisfactory outcomes. In the era of personalized medicine, cancer patients harboring MET exon 14 alterations or MET amplification have been found to respond well to Met-inhibitor therapy. The application of Met inhibitors to overcome drug resistance in cancer patients is discussed in this paper. Given that kinases play critical roles in cancer development, numerous kinase-mediated signaling pathways are attractive targets for cancer therapy. Existing kinase inhibitors have also been repurposed to new kinase targets or new indications in cancer. On the other hand, non-oncology drugs have also been repurposed for treating cancer through kinase inhibition as one of their reported anticancer mechanisms. Full article

Alzheimer’s disease (AD), an ongoing neurodegenerative disorder among the elderly, is signalized by amnesia, progressive deficiency in cognitive roles, and behavioral deformity. Over the last ten years, its pathogenesis still remains unclear despite several efforts from various researchers across the globe. There are certain factors that seem to be involved in the progression of the disease such as the accumulation of β-amyloid, oxidative stress, the hyperphosphorylation of tau protein, and a deficit of acetylcholine (ACh). Ongoing therapeutics are mainly based on the cholinergic hypothesis, which suggests that the decrease in the ACh levels leads to the loss of memory. Therefore, increasing the cholinergic function seems to be beneficial. Acetylcholinesterase inhibitors (AChEIs) inhibit the enzyme by avoiding the cleavage of acetylcholine (ACh) and increasing the neurotransmitter acetylcholine (ACh) levels in the brain areas. Thus, the cholinergic deficit is the root cause of Alzheimer’s disease (AD). Currently, drugs such as tacrine, donepezil, rivastigmine, and galantamine have been launched on the market for a cholinergic approach to AD to increase neurotransmission at cholinergic synapses in the brain and to improve cognition. These commercialized medicines only provide supportive care, and there is a loss of medicinal strength over time. Therefore, there is a demand for investigating a novel molecule that overcomes the drawbacks of commercially available drugs. Therefore, butyrylcholinesterase (BChE), amyloid-β (Aβ), β-secretase-1 (BACE), metals Cu(II), Zn(II), or Fe(II), antioxidant properties, and the free radical scavenging capacity have been primarily targeted in the preceding five years along with targeting the AChE enzyme. A desired, well-established pharmacological profile with a number of hybrid molecules incorporating substructures within a single scaffold has been investigated. From distinct chemical categories such as acridine, quinoline, carbamate, huperzine, and other heterocyclic analogs, the main substructures used in developing these molecules are derived. The optimization of activity through structural modifications of the prototype molecules has been followed to develop the Structure Activity Relationship (SAR), which in turn facilitates the development of novel molecules with expected AChE inhibitory activity together with many more pharmacological properties. The present review outlines the current drug candidates in the advancement of these AChEIs in the last two years. Full article

Green nanotechnology is a promising technology that has a wide range of applications in pharmaceuticals today because they offer a higher surface-area-to-volume ratio. Algal-based nanoparticles (NPs) are the subject of intense research interest today for their potential to treat and prevent infections caused by infectious microorganisms that are antibiotic resistant. Algae contain a variety of therapeutically potential bioactive ingredients, including chlorophyll, phycobilin, phenolics, flavonoids, glucosides, tannins, and saponins. As a result, NPs made from algae could be used as therapeutic antimicrobials. Due to their higher surface-area-to-volume ratios compared to their macroscopic components, metallic nanoparticles are more reactive and have toxic effects on their therapy. For pharmaceutical and biomedical applications, green synthesis restricts the use of physical and chemical methods of metallic nanoparticle synthesis, and it can be carried out in an environmentally friendly and relatively low-cost manner. The majority of macroalgae and some microalgae have latent antimicrobial activity and are used in the synthesis of metallic nanoparticles. A potential application in the field of nanomedicine and the establishment of a potential pharmacophore against microorganisms may result from the synthesis of algal-based NPs. Only a few studies have been done on the potential antimicrobial, antifungal, and antibacterial activity of algae-based NPs. As a result, the study will concentrate on the environmentally friendly synthesis of various NPs and their therapeutic potential, with a focus on their antibacterial activity. Thus, the aim of this study is to review all the literature available on the synthesis and characterization of the algal nanoparticles and their potential application as an antibacterial agent. Full article

The kallikrein–kinin system consists of the two kininogen substrates present in the blood plasma, and two serine proteases: the plasma and tissue kallikreins. The action of the latter on kininogens produces small peptides, the kinins, short-lived, but endowed by powerful pharmacologic actions on blood vessels and other tissues. Many recent and exciting therapeutic developments in the field are briefly summarized. Notably, various novel strategies are being clinically developed to inhibit the formation of bradykinin or block its receptors in the management of hereditary angioedema. The interventions include orally bioavailable drugs, biotechnological proteins, and gene therapy. These approaches are currently explored in a variety of other inflammatory and thrombotic disorders. Harnessing controlled kinin formation is also of potential therapeutic interest, as shown by the clinical development of recombinant tissue kallikrein for ischemic stroke and renal disease. The biomarkers of kinin-mediated disorders, frequently implicating edemas, include the consumption of kininogen(s), plasma kallikrein activity, and the detection of circulating kinin metabolites such as fragments BK_1–5 and BK_2–9. Novel opportunities to clinically apply the underexploited drugs of the kallikrein–kinin system are briefly reviewed. This personal perspective is offered by an observer of and a participant in drug characterization throughout the last four decades. Full article