Drugs and Drug Candidates

Sebetralstat is a novel, potent, and selective oral plasma kallikrein inhibitor drug candidate in clinical development for the on-demand treatment of hereditary angioedema (HAE). Upon binding, sebetralstat induces a conformational change in the active site of plasma kallikrein, which contributes to its high potency (K_i 3 nM) and selectivity (>1500 fold) against other serine proteases. Its physiochemical properties promote both rapid dissolution in the stomach and rapid absorption in the upper intestine that contribute to its fast and efficient absorption. A single oral administration of sebetralstat rapidly provides near-complete inhibition of plasma kallikrein and blockade of high-molecular-weight kininogen cleavage as early as 15 min, which drives its clinical efficacy. In a phase 2 clinical trial, sebetralstat significantly reduced the time to beginning of symptom relief (p < 0.0001) with median times of 1.6 h (95% CI: 1.5–3.0) with sebetralstat versus 9.0 h (4.0–17.2) with placebo. KONFIDENT (NCT05259917) is a phase 3 clinical trial assessing the on-demand use of sebetralstat for HAE. If successful, this trial could support the approval of sebetralstat as the first noninvasive, on-demand treatment option to rapidly halt HAE attacks and provide fast symptom relief. Full article

Zilucoplan is a synthetic macrocyclic peptide approved by the Food and Drug Administration (FDA), in October 2023, for the treatment of generalized myasthenia gravis. It is considered as an orphan drug that causes the inhibition of terminal complement cascade activation with a dual mechanism of action preventing the formation of the membrane attack complex (MAC) and the destruction of the neuromuscular junction. This drug has been demonstrated to be able to treat the generalized myasthenia gravis without significant adverse effects, with good efficacy, safety, and tolerability profile. Zilucoplan is not only innovative and promising in the therapeutics of generalized myasthenia gravis, but it could also be beneficial for the treatment of other diseases as well as a model for synthesis of analogues to improve pharmacological profile. Full article

Fractionation of the stem bark of Enantia chlorantha Oliv yields three alkaloids, palmatine (1), jatrorrhizine (2), columbamine (3), and β-Sitosterol (4). In this investigation, density functional theory (DFT) calculations were carried out to evaluate the electronic structure and properties of 1–4 by DFT-B3LYP/6-31G level of theory using Gaussian 09 software. The highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO), HOMO-LUMO energy difference (band gap), hardness (η), softness (S), dipole moment (μ), electronegativity (χ), hydrophobicity (logP), topological surface area (TPSA), and energy gap (Eg) were calculated. The in vitro cytotoxicity of the compounds was investigated against MCF-7 and HCT116 cancer cell lines using Wi-38 cells as a control. The compounds inhibited the proliferation of the MCF-7 and HCT116 cell lines and induced apoptosis via upregulation of caspase-3, Bax, PARP cleavage, and downregulation of Bcl-2. DFT analyses revealed that compounds 1 and 3 have smaller energy gaps, 0.072 and 0.071eV, respectively, with the highest dipole moments; hence, these compounds are more chemically reactive and exhibit better modulation of caspase-3 enzyme and inhibitory activities of the MCF-3 and HCT116 cell lines. The antimicrobial and antiparasitic evaluation of 1–4 showed moderate efficacy against the bacterial strains and moderate antiparasitic activity against Cichlidogyrus tilapia. Full article

Despite various efforts, a successful selective delivery system for chemotherapeutic agents for lung cancer is still lacking. Dry powder inhaler (DPI) systems based on proliposomes (PLMs) could be a potential system for the efficient delivery of paclitaxel to lungs. PLM-based DPI prepared with a freeze-drying method can therefore be an alternative. Paclitaxel-loaded PLM-based DPI (PTX-PLM-DPI) powders were prepared using the method of thin film deposition on a carrier followed by freeze drying. These were prepared using soya phosphatidylcholine (SPC) and cholesterol as the lipids and mannitol as the carrier. The reconstituted liposomes were evaluated in terms of size, morphology, drug entrapment, release and cytotoxicity. The DPI powders were evaluated for their flow property, surface topography, dose uniformity and in vitro lung deposition. Stable and free-flowing PTX-PLM-DPI powder was obtained that could be reconstituted into homogenous liposomal vesicles < 200 nm as confirmed by TEM and SEM studies. The liposomes showed drug entrapment of 92.64 ± 1.4% and diffusion-controlled release of up to 28% in 24 h. These liposomes showed better dose-dependent cytotoxicity in A549 cells in comparison to paclitaxel suspension with IC₅₀ values of 46 ± 0.87 ng/mL and 154.9 ± 3.64 ng/mL, respectively. In vitro lung deposition studies of the PTX-PLM-DPI showed sufficient deposition with the fine particle fraction (FPF) of 50.86 ± 2.8% of particles with an aerodynamic diameter less than 5 µ. Hence, it canbe concluded that PLM-based DPI prepared by freeze drying can be a promising, stable, safe and free-flowing system for the enhanced lung delivery of paclitaxel. Full article

Shigellosis is a pathological condition that affects the digestive system and possibly causes diarrhoea. Shigella species, which are responsible for this disease, are highly contagious and spread through contaminated food and water. The increasing development of resistance by Shigella species necessitates the urgent need to search for new therapies against diarrhoea-causing shigellosis. The scientific validation of medicinal plants, such as Diospyros gilletii, which is used for the traditional treatment of diarrhoeal conditions is worthwhile. The present study aims to investigate the antibacterial activity of extracts from D. gilletii against selected Shigella species. Extracts from D. gilletii stem bark were prepared by maceration using various solvents. The antibacterial activity of D. gilletii extracts was evaluated in Shigella dysenteriae, S. flexneri, S. boydii, and S. sonnei using a microdilution method, whereas a cytotoxicity test was performed on Vero and Raw cells using resazurin-based colorimetric assays. Bacterial membrane-permeability studies were evaluated using propidium iodide (PI)- and 1-N-phenyl-naphthylamine (NPN)-uptake assays, whereas inhibition and eradication tests on bacterial biofilms were carried out by spectrophotometry. As a result, methanol, ethanol and hydroethanol (water: ethanol; 30:70, v/v) extracts of D. gilletii inhibited the growth of S. boydii, S. flexneri and S. sonnei, with minimum inhibitory concentration (MIC) values ranging from 125 to 500 µg/mL, without toxicity to Vero and Raw cells. Time-kill kinetics revealed bactericidal orientation at 2 MIC and 4 MIC and a bacteriostatic outcome at 1/2 MIC. The mechanistic basis of antibacterial action revealed that D. gilletii extracts inhibited and eradicated Shigella biofilms and promoted the accumulation of NPN and PI within the inner and outer membranes of bacteria to increase membrane permeability, thereby causing membrane damage. This novel contribution toward the antibacterial mechanisms of action of D. gilletii extracts against Shigella species substantiates the use of this plant in the traditional treatment of infectious diarrhoea. Full article

High rates of resistance to antibiotics are associated with healthcare-related infections, thus demonstrating the urgent need for effective antimicrobials against these maladies. The present study aims to determine the chemical composition of essential oil (EO) from Clausena anisata leaves and evaluate their antibacterial activity against selected nosocomial bacteria. To this end, one kilogram (1 kg) of fresh leaves of C. anisata was washed and boiled with 500 mL of distilled water for 2−4 h using a Clevenger apparatus. The oil was then collected in an Erlenmeyer, dried using anhydrous sodium sulfate, bottled in a tinted glass bottle and refrigerated at 4 °C before analysis. Next, the as-prepared oil was analyzed using gas chromatography-mass spectrometry (GC-MS). The essential oil was further tested against a panel of selected nosocomial bacteria, including Staphylococcus and Klebsiella species, among others, by microdilution using a resazurin assay to determine the minimum inhibitory and minimum bactericidal concentrations (MICs and MBCs, respectively). As a result, 0.77% of EO was extracted from fresh leaves of C. anisata. The GC-MS analysis revealed that the as-prepared essential oil contained E-anethole (70.77%), methyl isoeugenol (13.85%), estragole (4.10%), γ-terpinene (3.33%), myrcene (2.82%) and sabinene (0.77%), with E-anethole being the major constituent. Twenty-two compounds were identified in the EO of C. anisata leaves through gas chromatography. Upon antibacterial testing against selected nosocomial pathogens, the E-anethole-rich essential oil exhibited MIC and MBC values ranging from 3.91 to 125 µg/mL and 7.81 to 125 µg/mL, respectively, indicative of a bactericidal orientation of the plant’s essential oil (MIC/MBC ratio < 4). This novel contribution highlights the scientific validation of the use of C. anisata leaves in the traditional treatment of various infectious diseases. However, toxicity and pharmacokinetic studies, mechanistic bases of the antibacterial action, and in vivo antibacterial experiments of the E-anethole-rich EO of C. anisata should be investigated to successfully use this plant in the treatment of infectious diseases. Full article

The Group for the Promotion of Pharmaceutical Chemistry in Academia (GP₂A) held its 31st annual conference in August 2023 at the Faculty of Pharmacy of Aix-Marseille University, Marseille, France. There were 8 keynote presentations, 10 early career researcher oral presentations and 23 poster presentations. Among them, four awards were delivered, two for best oral communications and two for the best poster presentations. Full article

For thousands of years, nature has been a source of medical substances, and an astounding numeral of contemporary remedies have been identified from natural origins. Plants have long been used as folk herbal medicines to treat various disorders, and their different natural products have inspired the design, discovery, and development of new drugs. With the invention of recent molecular targets based on proteins, there is a growing need for fresh chemical diversification in screening. Natural products will play a vital part in supplying this need via the continuous exploration of global biodiversity, the majority of which remains unexplored. Even though drug discovery from medicinal plants remains an important source of novel therapeutic leads, various hurdles exist, including identifying and executing suitable high-throughput screening bioassays, scaling up the supply of bioactive molecules, and acquiring plant materials. Investigating these natural resources takes multi-disciplinary, nationwide, and global partnerships in design, synthesis, discovery, and drug development techniques. This review article discusses current advancements and future approaches for discovering natural items such as health- and wellness-promoting remedies. It also summarizes strategies to unify the therapeutic use of plant-derived natural products worldwide to support future drug discoveries derived from plant sources. Full article

Cissus populnea Guill. & Perr. (Vitaceae) is used in traditional medicine to treat microbial infections, venereal diseases and infertility, among others. The aim of this research is to isolate and characterize the antimicrobial constituent(s) from the stem of C. populnea. The n-butanol fraction of C. populnea, being most active, was subjected to silica gel column chromatography, which led to the isolation of white solid and white crystalline substances coded compounds C1 and C4C5, respectively. Spectral analysis (1D and 2D-NMR) of the isolated compounds and comparison with the literature data indicated C1 to be Bis-(2-ethyloctyl)-phthalate and C4C5 to be a mixture of stigmasterol and β-sitosterol; C4C5 exhibited a zone of inhibition ranging from 24 to 29 mm against the test organisms with Candida albicans being the most sensitive organism while Trichophyton rubrum was the least sensitive organism. Of the standard drugs, ciprofloxacin had 27–37 mm while fluconazole and fulcin exhibited zones of inhibition ranging from 34 mm to 29–32 mm, respectively. The MIC and MBC/MFC values for C4C5 ranges from 12.5 to 25.0 µg/cm³ and 25.0 to 50.0 µg/cm³ against methicillin-resistant Staphylococcus aureus, Staphylococcus. aureus, Escherichia coli, Candida albicans, Trichophyton rubrum and Trichophyton mentagrophyte, respectively. In conclusion, Bis-(-(2-ethyloctyl)-phthalate) and a mixture of stigmasterol and β-sitosterol were identified for the first time from the stem of C. populnea. Full article

The drug discovery and development process is very lengthy, highly expensive, and extremely complex in nature. Considering the time and cost constraints associated with conventional drug discovery, new methods must be found to enhance the declining efficiency of traditional approaches. Artificial intelligence (AI) has emerged as a powerful tool that harnesses anthropomorphic knowledge and provides expedited solutions to complex challenges. Advancements in AI and machine learning (ML) techniques have revolutionized their applications to drug discovery and development. This review illuminates the profound influence of AI on diverse aspects of drug discovery, encompassing drug-target identification, molecular properties, compound analysis, drug development, quality assurance, and drug toxicity assessment. ML algorithms play an important role in testing systems and can predict important aspects such as the pharmacokinetics and toxicity of drug candidates. This review not only strengthens the theoretical foundation and development of this technology, but also explores the myriad challenges and promising prospects of AI in drug discovery and development. The combination of AI and drug discovery offers a promising strategy to overcome the challenges and complexities of the pharmaceutical industry. Full article

This review was performed to determine the potential of drugs that can remove or decrease the requirements for blood transfusion among beta (β)-thalassemia patients. A comprehensive literature search was conducted to identify clinical trials and studies using PubMed Central, Google Scholar, PubMed, and ScienceDirect archived articles published from 1996 to November 2023. According to this review, clinical trials for a number of drugs, including luspatercept, sotatercept, mitapivat, etavopivat, hydroxyurea, rapamycin, decitabine, thalidomide, and quercetin, have been performed as part of efforts to improve the cure strategy for β-thalassemia. Of these drugs, luspatercept and sotatercept have exhibited particularly promising results and have been granted US Food and Drug Administration (FDA) approval for use in β-thalassemia patients. The mode of action for the drugs luspatercept and sotatercept involves the stimulation of hemoglobin (Hb) production or enhancement of its functionality, thereby decreasing reliance on blood transfusions and enhancing the overall quality of life. In this way, drugs like luspatercept and sotatercept present an opportunity to notably decrease the necessity for blood transfusions in β-thalassemia patients, improving their standard of living and overall prognosis. However, more research is needed to evaluate the effectiveness and safety of these drugs in the long run. Full article

Cerebral ischemia represents a particular condition among neurological diseases due to its high frequency, high associated mortality, and the permanent disability in patients that survive it. Numerous studies in animal models have demonstrated the protective properties of resveratrol against cerebral ischemia. Resveratrol is a soluble molecule in polar solvents with high membrane permeability; however, it is rapidly metabolized at the liver and is also a substrate of the ATP binding cassette transporters located at the blood–brain barrier. These circumstances reduced bioavailability of resveratrol to the brain. In this review, we examined nasal resveratrol’s formulations including nanocarriers such as nanostructured lipid carriers, nanoemulsions, nanoparticles, bilosomes, cubosomal, and transferosomes that are directly transported to the brain. An intranasal administration route evades resveratrol transformation due to liver metabolism. Components of nanoformulations increased resveratrol absorption to the brain by enhancing permeation through specific approaches and also maintaining stability during storage. Both characteristics improved the delivery of resveratrol with conserved antioxidant capacity and protective properties for neurological models. Although demonstration that the nanoformulations prevents resveratrol’s blood–brain barrier retention is missing, properties of resveratrol’s nanoformulation encourage testing in clinical trials; however, regulatory approval for a novel nanocarrier in nasal drug delivery is complicated and needs approval. Full article

Ongoing therapy for human parasite infections has a few known drugs but with serious side effects and the problem of drug resistance, impelling us to discover novel drug candidates with newer mechanisms of action. Universally, this has boosted the research in the design and development of novel medicinal agents as antiparasitic drugs with a novel mode of action. Histone deacetylase inhibitors (HDACis) are used in a vast variety of diseases due to their anti-inflammatory properties. Drug repurposing strategies have already approved HDACis as cancer therapeutics and are now under investigation for many parasitic infections. Along with the expression of the gene, histone deacetylase (HDAC) enzymes also act as a slice of great multi-subunit complexes, targeting many non-histones, changing systemic and cellular levels signaling, and producing different cell-based specified effects. Zinc (Zn²⁺)- and nicotinamide adenine dinucleotide (NAD⁺)-dependent HDACs of parasites play pivotal roles in the alteration of gene expression of parasites. Some of them are already known to be responsible for the survival of several parasites under odd circumstances; thus, targeting them for therapeutic interventions will be novel for potential antiparasitic targets. This point of view outlines the knowledge of both class-I and class-II HDACis and sirtuin inhibitors that emerged to be the key players in the treatment of human parasitic disorders like Leishmaniasis, Schistosomiasis, Malaria, Trypanosomiasis, and Toxoplasmosis. This review also focuses on repurposing opportunities and challenges in HDAC inhibitors that are preceded by their clinical development as potent new antiparasitic drugs. Full article

COVID-19 has claimed around 7 million lives (from December 2019–November 2023) worldwide and continues to impact global health. SARS-CoV-2, the virus causing COVID-19 disease, is characterized by a high rate of mutations, which contributes to its rapid spread, virulence, and vaccine escape. While several vaccines have been produced to minimize the severity of the coronavirus, and diverse treatment regimens have been approved by the US FDA under Emergency Use Authorization (EUA), SARS-CoV-2 viral mutations continue to derail the efforts of scientists as the emerging variants evade the recommended therapies. Nonetheless, diverse computational models exist that offer an opportunity for the swift development of new drugs or the repurposing of old drugs. In this review, we focus on the use of various virtual screening techniques like homology modeling, molecular docking, molecular dynamics simulations, QSAR, pharmacophore modeling, etc., in repurposing SARS-CoV-2 therapeutics against major variants of SARS-CoV-2 (Alpha, Beta, Gamma, Delta, and Omicron). The results have been promising from the computer-aided drug design (CADD) studies in suggesting potential compounds for the treatment of COVID-19 variants. Hence, in silico therapeutic studies represent a transformative approach that holds great promise in advancing our fight against the ever-evolving landscape of SARS-CoV-2 and its variants. Full article

The natural product Desmosdumotin D (hereafter referred to as Des-D), isolated from the plant Desmos dumosus, showed potent anti-HIV activity. However, the subsequent pharmacological activity and clinical studies are limited due to the low content of Des-D in the plant. Therefore, the total synthesis path of Des-D was optimized in this paper, and the total yield was increased from 4.4% to 11.9%. Additionally, twelve analogues were obtained following the synthesis route of Des-D. The anti-HIV activity evaluation results in vitro showed that Des-D had the highest activity, with an IC₅₀ value of 13.6 μM, and compounds 17 and 11 had the lowest anti-HIV activity, with IC₅₀ values of 101.3 μM and 161.0 μM, respectively. Through the molecular docking of compounds Des-D and 17 with HIV-IN, the results show that phenolic hydroxyl groups and two benzene rings interact with HIV-IN and are possible pharmacodynamic groups. Full article

The development of antimicrobial resistance has increased the prevalence of infectious diseases, causing a global health problem that accounts for over 4.95 million deaths worldwide annually. The side effects associated with current antibiotics prompt a crucial need to search for effective and safe antimicrobial agents. In this study, silver nanoparticles (AgNPs) were prepared by chemical reduction method using silver nitrates as a metallic precursor and Croton macrostachyus bark aqueous extract as a reducing and capping agent. The nanoparticles were further functionalized using C. macrostachyus-based activated carbon (CAC) to generate nanocomposites (CAC-AgNPs). The nanomaterials were characterized by ultraviolet-visible (UV–vis) absorption spectra and Fourier transform infrared (FTIR) spectra. The antibacterial activity of the as-prepared nanomaterials was evaluated against an array of bacterial strains by microdilution method, whereas their cytotoxicity profile was evaluated using Vero cells (human mammalian cells). Antibacterial mechanistic studies of active nanomaterials were carried out through bacterial growth kinetics, nucleic acid leakage tests, and catalase inhibition assays. As a result, the as-prepared nanomaterials exhibited antibacterial activity against an array of bacterial strains (minimum inhibitory concentration (MIC) range: 62.5 to 500 µg/mL), the most susceptible being Escherichia coli and Staphylococcus aureus. Cytotoxicity studies of the nanomaterials on Vero cells revealed that the nanocomposite (median cytotoxic concentration (CC₅₀): 213.6 µg/mL) was less toxic than its nanoparticle (CC₅₀ value: 164.75 µg/mL) counterpart. Antibacterial mechanistic studies revealed that the nanomaterials induced (i) bacteriostatic activity vis à vis E. coli and S. aureus and (ii) inhibition of catalase in these bacteria. This novel contribution regarding the antibacterial mechanisms of action of silver nanocomposites from C. macrostachyus-based activated carbon may contribute to our understanding of the antibacterial action of these biomaterials. Nevertheless, more chemistry and in vivo experiments as well as in depth antibacterial mechanistic studies are warranted for the successful utilization of these antibacterial biomaterials. Full article

The high frequency of infectious diseases has spurred research into effective tactics to combat microorganisms that are resistant to several drugs. The overproduction of the transmembrane efflux pump protein NorA, which may export hydrophilic fluoroquinolones, is a common mechanism of resistance in S. aureus strains. This work evaluated the antimicrobial activity of the ethanolic extract from the leaves of Croton heliotropiifolius (EECH) against different bacterial and fungal strains, as well as investigating its modulating effect on the resistance to norfloxacin in a Staphylococcus aureus SA1199B overproducing the NorA efflux pump. Microdilution assays were used to assess the EECH’s antibacterial efficacy. The MIC of norfloxacin or ethidium bromide (EtBr) against the SA1199B strain was determined in the presence or absence of the EECH in order to assess the modifying influence on drug resistance. The EECH showed no activity against the Gram-positive and Gram-negative bacterial strains tested. The EECH also showed no antifungal activity against Candida albicans ATCC 10231. On the other hand, the extract reduced the MIC values for norfloxacin against SA1199B at subinhibitory concentrations. In addition, the EECH also reduced the MIC values of EtBr at subinhibitory concentrations, suggesting the occurrence of phytochemicals that inhibit efflux pumps. Molecular docking showed that retusin, a flavonoid found in the extract, could compete with norfloxacin at the orthosteric site of the NorA, indicating that it could be a potential efflux pump inhibitor. However, isolated retusin did not enhance the activity of norfloxacin or EtBr and it did not inhibit the EtBr efflux, showing that it is not a NorA inhibitor. Even though C. heliotropiifolius is a source of phytochemicals that function as adjuvants for norfloxacin, isolated retusin cannot be used in conjunction with norfloxacin to treat infections brought on by S. aureus that overproduces NorA. Full article