Synthesis and evaluation of imidazole-bearing chalcones as a potential treatment for pulmonary aspergillosis

Pulmonary aspergillosis (PA) is a category of respiratory illnesses that significantly impacts the lives of immunocompromised individuals. However, new classifications of secondary infections like influenza associated aspergillosis (IAA) and COVID-19 associated pulmonary aspergillosis (CAPA) only exacerbate matters by expanding the demographic beyond the immunocompromised. Meanwhile anti-fungal resistant strains of Aspergillus are causing current treatments to act less effectively. Symptoms can range from mild (difficulty breathing, and expectoration of blood) to severe (multi organ failure, and neurological disease). Millions are affected yearly, and mortality rates range from 20-90% making it imperative to develop novel medicines to curtail this evolving group of diseases. Chalcones and imidazoles are current antifungal pharmacophores used to treat PA. Chalcones are a group of plant-derived flavonoids that have a variety of pharmacological effects, such as, antibacterial, anticancer, antimicrobial, and anti-inflammatory activities. Imidazoles are another class of drug that possess antibacterial, antiprotozoal, and anthelmintic activities. The increase in antifungal resistant Aspergillus and Candida species make it imperative for us to synthesize novel pharmacophores for therapeutic use. Our objective was to synthesize a chalcone and imidazole into a single pharmacophore and to evaluate its effectiveness against three different fungi from the Aspergillus or Candida species. The chalcones were synthesized via the Claisen-Schmidt aldol condensation of 4-(1H-Imizadol-1-yl) benzaldehyde with various substituted acetophenones using aqueous sodium hydroxide in methanol. The anti-fungal activity of the synthesized chalcones were evaluated via a welldiffusion assay against Aspergillus fumigatus, Aspergillus niger, and Candida albicans. The data obtained suggests that chalcone derivatives with electron-withdrawing substituents are moderately effective against Aspergillus and has the potential for further optimization as a treatment for pulmonary aspergillosis. This project was supported by grants from the National Institutes of Health (NIH), National Institute of General Medicine Sciences (NIGMS), IDeA Networks of Biomedical Research Excellence (INBRE), Award number: P20GM103466. The content is solely the responsibility of the authors and do not necessarily represent the official views of the NIH.Copyright © 2023 The American Society for Biochemistry and Molecular Biology, Inc.

Phytochemistry and Pharmacology of Indian Traditional Plant Hyssop (Hyssopus officinalis L.): A Review

Hyssopus officinalis is a traditional medicinal plant that belongs to the family Lamiaceae, which has been used for centuries for various purposes like carminative, expectorant, and cough reliever. It has been used for the treatment of numerous diseases in patients such as ulcers, asthma, jaundice, leprosy, dropsy, bronchitis, COPD, diabetes, AIDS, bacterial and fungal infections as an herbal remedy due to its fewer side effects and is more efficacies than other traditional medicine. Major classes of chemical compounds found in H. officinalis essential oil are bicyclic monoter-penes, monoterpenoids, acyclic monoterpenes, phenolic monoterpenoids, monocyclic monoterpenes, monocyclic sesquiterpenes, tricyclic sesquiterpenes, bicyclic sesquiterpenes, tricyclic sesquiterpe-noids, straight chain saturated hydrocarbons. Some of the major chemical constituents present in the H. officinalis are beta-pinene, alpha-pinene, 1, 8-cineole, apigenin, diosmin, caffeic acid, rosmarinic acid, cis-pinocamphone, trans-pinocamphone, iso-pinocamphone, pinocarvone, which are responsible for its various pharmacological activity. Various studies have been performed on the pharmacological activity of its extract, such as antioxidant, antimicrobial, anti-diabetic, anticancer, antiviral, anti-inflammatory, analgesic, anti-leishmanial, anthelmintic, anti-protozoal, and anti-anxiety. Recently, it is used as an anticancer agent and has been demonstrated by studying its cytotoxic and apoptotic effects on breast cancer and colon cancer cells. It is used as a potent antibacterial and antifungal agent being studied on the antibiotic-resistant bacterial and fungal strains recently, which can be further useful in developing herbal medicine against AMR. It is an excellent natural antioxidant due to the presence of polyphenolic compounds, and H. officinalis is used in various food industries as a source of natural antioxidants, which has minimum side effects as compared to artificial antioxi-dants. Furthermore, the pharmacological activity of these individual chemical constituents in H. officinalis extract still needs to be investigated for identifying the effectiveness of this plant in the natural treatment of various diseases. This review aims to collect various data regarding the traditional herbal plant hyssop (Hyssopus officinalis), including its photochemistry, chemical structures of the phyto-constituents and pharmacological profile, along with all the pharmacological models. This plant has significant importance in the health industry, so further studies are required on its effective usage against various emerging health problems, including COVID-19, cancer, diabetes, AMR.Copyright © 2023 Bentham Science Publishers.

A New Role for Old Friends: Effects of Helminth Infections on Vaccine Efficacy.

Vaccines are one of the most successful medical inventions to enable the eradication or control of common and fatal diseases. Environmental exposure of hosts, including helminth infections, plays an important role in immune responses to vaccines. Given that helminth infections are among the most common infectious diseases in the world, evaluating vaccine efficiency in helminth-infected populations may provide critical information for selecting optimal vaccination programs. Here, we reviewed the effects of helminth infections on vaccination and its underlying immunological mechanisms, based on findings from human studies and animal models. Moreover, the potential influence of helminth infections on SARS-CoV-2 vaccine was also discussed. Based on these findings, there is an urgent need for anthelmintic treatments to eliminate helminth suppressive impacts on vaccination effectiveness during implementing mass vaccination in parasite endemic areas.

Antiviral Activity of Approved Antibacterial, Antifungal, Antiprotozoal and Anthelmintic Drugs: Chances for Drug Repurposing for Antiviral Drug Discovery.

Drug repurposing process aims to identify new uses for the existing drugs to overcome traditional de novo drug discovery and development challenges. At the same time, as viral infections became a serious threat to humans and the viral organism itself has a high ability to mutate genetically, and due to serious adverse effects that result from antiviral drugs, there are crucial needs for the discovery of new antiviral drugs, and to identify new antiviral effects for the exciting approved drugs towards different types of viral infections depending on the observed antiviral activity in preclinical studies or clinical findings is one of the approaches to counter the viral infections problems. This narrative review article summarized mainly the published preclinical studies that evaluated the antiviral activity of drugs that are approved and used mainly as antibacterial, antifungal, antiprotozoal, and anthelmintic drugs, and the preclinical studies included the in silico, in vitro, and in vivo findings, additionally some clinical observations were also included while trying to relate them to the preclinical findings. Finally, the structure used for writing about the antiviral activity of the drugs was according to the families of the viruses used in the studies to form a better image for the target of antiviral activity of different drugs in the different kinds of viruses and to relate between the antiviral activity of the drugs against different strains of viruses within the same viral family.

Albatrellus confluens (Alb. & Schwein.) Kotl. & Pouz.: Natural Fungal Compounds and Synthetic Derivatives with In Vitro Anthelmintic Activities and Antiproliferative Effects against Two Human Cancer Cell Lines.

Neglected tropical diseases affect the world's poorest populations with soil-transmitted helminthiasis and schistosomiasis being among the most prevalent ones. Mass drug administration is currently the most important control measure, but the use of the few available drugs is giving rise to increased resistance of the parasites to the drugs. Different approaches are needed to come up with new therapeutic agents against these helminths. Fungi are a source of secondary metabolites, but most fungi remain largely uninvestigated as anthelmintics. In this report, the anthelmintic activity of Albatrellus confluens against Caenorhabditis elegans was investigated using bio-assay guided isolation. Grifolin (1) and neogrifolin (2) were identified as responsible for the anthelmintic activity. Derivatives 4-6 were synthesized to investigate the effect of varying the prenyl chain length on anthelmintic activity. The isolated compounds 1 and 2 and synthetic derivatives 4-6, as well as their educts 7-10, were tested against Schistosoma mansoni (adult and newly transformed schistosomula), Strongyloides ratti, Heligmosomoides polygyrus, Necator americanus, and Ancylostoma ceylanicum. Prenyl-2-orcinol (4) and geranylgeranyl-2-orcinol (6) showed promising activity against newly transformed schistosomula. The compounds 1, 2, 4, 5, and 6 were also screened for antiproliferative or cytotoxic activity against two human cancer lines, viz. prostate adenocarcinoma cells (PC-3) and colorectal adenocarcinoma cells (HT-29). Compound 6 was determined to be the most effective against both cell lines with IC50 values of 16.1 µM in PC-3 prostate cells and 33.7 µM in HT-29 colorectal cells.

In silico identification of excretory/secretory proteins and drug targets in monogenean parasites.

The Excretory/Secretory (ES) proteins of parasites are involved in invasion and colonization of their hosts. In addition, since ES proteins circulate in the extracellular space, they can be more accessible to drugs than other proteins, which makes ES proteins optimal targets for the development of new and better pharmacological strategies. Monogeneans are a group of parasitic Platyhelminthes that includes some pathogenic species problematic for finfish aquaculture. In the present study, 8297 putative ES proteins from four monogenean species which genomic resources are publicly available were identified and functionally annotated by bioinformatic tools. Additionally, for comparative purposes, ES proteins in other parasitic and free-living platyhelminths were identified. Based on data from the monogenean Gyrodactylus salaris, 15 ES proteins are considered potential drug targets. One of them showed homology to 10 cathepsins with known 3D structure. A docking molecular analysis uncovered that the anthelmintic emodepside shows good affinity to these cathepsins suggesting that emodepside can be experimentally tested as a monogenean's cathepsin inhibitor.

Ivermectin: An Anthelmintic, an Insecticide, and Much More.

Here we tell the story of ivermectin, describing its anthelmintic and insecticidal actions and recent studies that have sought to reposition ivermectin for the treatment of other diseases that are not caused by helminth and insect parasites. The standard theory of its anthelmintic and insecticidal mode of action is that it is a selective positive allosteric modulator of glutamate-gated chloride channels found in nematodes and insects. At higher concentrations, ivermectin also acts as an allosteric modulator of ion channels found in host central nervous systems. In addition, in tissue culture, at concentrations higher than anthelmintic concentrations, ivermectin shows antiviral, antimalarial, antimetabolic, and anticancer effects. Caution is required before extrapolating from these preliminary repositioning experiments to clinical use, particularly for Covid-19 treatment, because of the high concentrations of ivermectin used in tissue-culture experiments.