Anhydroparthenin as a dual-target inhibitor against Sterol C-24 methyltransferase and Sterol 14-α demethylase of Leishmania donovani: A comprehensive in vitro and in silico study.

Parthenium hysterophorus plant has a diverse chemical profile and immense bioactive potential. It exhibits excellent pharmacological properties such as anti-cancer, anti-inflammatory, anti-malarial, microbicidal, and anti-trypanosomal. The present study aims to evaluate the anti-leishmanial potential and toxicological safety of anhydroparthenin isolated from P. hysterophorus. Anydroparthenin was extracted from the leaves of P. hysterophorus and characterized through detailed analysis of 1H, 13C NMR, and HRMS. Dye-based in vitro and ex vivo assays confirmed that anhydroparthenin significantly inhibited both promastigote and amastigote forms of the Leishmania donovani parasites. Both the cytotoxicity experiment and hemolytic assay revealed its non-toxic nature and safety index in the range of 10 to 15. Further, various mechanistic assays suggested that anhydroparthenin led to the generation of oxidative stress, intracellular ATP depletion, alterations in morphology and mitochondrial membrane potential, formation of intracellular lipid bodies, and acidic vesicles, ultimately leading to parasite death. As a dual targeting approach, computational studies and sterol quantification assays confirmed that anhydroparthenin inhibits the Sterol C-24 methyl transferase and Sterol 14-α demethylase proteins involved in the ergosterol biosynthesis in Leishmania parasites. These results suggest that anhydroparthenin could be a promising anti-leishmanial molecule and can be developed as a novel therapeutic stratagem against leishmaniasis.

Semisynthesis of Novel Dispiro-pyrrolizidino/thiopyrrolizidino-oxindolo/indanedione Natural Product Hybrids of Parthenin Followed by Their Cytotoxicity Evaluation.

Natural products possess unique and broader intricacies in the chemical space and have been essential for drug discovery. The crucial factor for drug discovery success is not the size of the library but rather its structural diversity. Although reports on the number of new structurally diverse natural products (NPs) have declined recently, researchers follow the next logical step: synthesizing natural product hybrids and their analogues using the most potent tool, diversity-oriented synthesis (DOS). Here, we use weed Parthenium hysterophorus as a source of parthenin for synthesis of novel dispiro-pyrrolizidino/thiopyrrolizidino-oxindolo/indanedione natural product hybrids of parthenin via chemo-, regio-, and stereoselective azomethine ylide cycloaddition. All synthesized compounds were characterized through a detailed analysis of one-dimensional (1D) and two-dimensional (2D) NMR and HRMS data, and the stereochemistries of the compounds were confirmed by X-ray diffraction analysis. All compounds were evaluated for their cytotoxicity against four cell lines (HCT-116, A549, Mia-Paca-2, and MCF-7), and compound 6 inhibited the HCT-116 cells with an IC50 of 5.0 ± 0.08 µM.

Two new cycloartane type triterpenes from Dysoxyllum binectariferum.

Dysoxyllum binectariferum is an important medicinal plant known for various biological activities like anti-inflammatory, CNS depressants, contraceptive, analgesic, immunomodulatory, antimalarial, antifeedant, leishmanicidal and antiviral. It is a rich source of rohitukine, a basic skeleton of flavopiridol. Phytochemical investigation of chloroform extracts of Dysoxyllum binectariferum leaves, lead to the isolation of beddomeilactone (1) and two new cycloartane type triterpenoids beddomeilactol (2) and binectarilactone-A (3) with modified A ring. Compounds were assessed for their in-vitro α-glucosidase inhibitory activity. Compound 1 was found to be most potent, showing IC50 of 17.99 ± 0.26 µg/ml which is comparable to the positive control acarbose.

Photoprotective effect of 18ß-glycyrrhetinic acid derivatives against ultra violet (UV)-B-Induced skin aging.

Excessive exposure to sun can harm the skin, causing sunburn, photo-aging, and even skin cancer. Different benzylidene derivatives (A02-A18 and A19-A34) of 18ß-Glycyrrhetinic acid (A01) were designed and synthesized in an effort to discover photo-protective compounds against UV-B -induced skin aging. The synthesized derivatives were subjected to cellular viability test using MTT assay in primary Human Dermal Fibroblasts (HDFs). The results indicate A01, A05, A15, A22, A23, A25, A26, A28, A29, A32, A33, and A34 significantly enhanced cell viability of HDFs. Compound A33 at 10 and 25 µM showed a significant photo-protective effect against UV-B (10 mJ/cm2) -induced damage in HDFs. A33 at 25 µM significantly restored the UV-B -induced damage via its potent anti-oxidant, anti-apoptotic effects and ability to prevent collagen degradation. These findings pave the way for further development of A33 as a photo-protective skin agent.