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Crotofolane Diterpenoids and Other Constituents Isolated from Croton kilwae.

ABSTRACT: Six new crotofolane diterpenoids (1-6) and 13 known compounds (7-19) were isolated from the MeOH-CH₂Cl₂ (1:1, v/v) extracts of the leaves and stem bark of Croton kilwae. The structures of the new compounds were elucidated by extensive analysis of spectroscopic and mass spectrometric data. The structure of crotokilwaepoxide A (1) was confirmed by single-crystal X-ray diffraction, allowing for the determination of its absolute configuration. The crude extracts and the isolated compounds were investigated for antiviral activity against respiratory syncytial virus (RSV) and human rhinovirus type-2 (HRV-2) in HEp-2 and HeLa cells, respectively, for antibacterial activity against the Gram-positive Bacillus subtilis and the Gram-negative Escherichia coli, and for antimalarial activity against the Plasmodium falciparum Dd2 strain. ent-3β,19-Dihydroxykaur-16-ene (7) and ayanin (16) displayed anti-RSV activities with IC₅₀ values of 10.2 and 6.1 μM, respectively, while exhibiting only modest cytotoxic effects on HEp-2 cells that resulted in selectivity indices of 4.9 and 16.4. Compounds 2 and 5 exhibited modest anti-HRV-2 activity (IC₅₀ of 44.6 μM for both compounds), while compound 16 inhibited HRV-2 with an IC₅₀ value of 1.8 μM. Compounds 1-3 showed promising antiplasmodial activities (80-100% inhibition) at a 50 μM concentration.

SUBMITTER: Mahambo ET

PROVIDER: S-EPMC9972476 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Crotofolane Diterpenoids and Other Constituents Isolated from Croton kilwae.

Mahambo Emanuel T ET Uwamariya Colores C Miah Masum M Clementino Leandro da Costa LDC Alvarez Luis Carlos Salazar LCS Di Santo Meztler Gabriela Paula GP Trybala Edward E Said Joanna J Wieske Lianne H E LHE Ward Jas S JS Rissanen Kari K Munissi Joan J E JJE Costa Fabio T M FTM Sunnerhagen Per P Bergström Tomas T Nyandoro Stephen S SS Erdelyi Mate M

Journal of natural products 20230207 2

Six new crotofolane diterpenoids (1-6) and 13 known compounds (7-19) were isolated from the MeOH-CH2Cl2 (1:1, v/v) extracts of the leaves and stem bark of Croton kilwae. The structures of the new compounds were elucidated by extensive analysis of spectroscopic and mass spectrometric data. The structure of crotokilwaepoxide A (1) was confirmed by single-crystal X-ray diffraction, allowing for the determination of its absolute configu ...[more]

PMID: 36749598

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Project description:Leishmania is a parasitic protozoon responsible for the neglected tropical disease Leishmaniasis. Approximately, 350 million people are susceptible and close to 70,000 death cases globally are reported annually. The lack of effective leishmanicides, the emergence of drug resistance and toxicity concerns necessitate the pursuit for effective antileishmanial drugs. Natural compounds serve as reservoirs for discovering new drugs due to their chemical diversity. Hardwickiic acid (HA) isolated from the stembark of Croton sylvaticus was evaluated for its leishmanicidal potential against Leishmania donovani and L. major promastigotes. The susceptibility of the promastigotes to HA was determined using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide/phenazine methosulfate colorimetric assay with Amphotericin B serving as positive control. HA showed a significant antileishmanial activity on L. donovani promastigotes with an IC50 value of 31.57± 0.06 µM with respect to the control drug, amphotericin B with IC50 of 3.35 ± 0.14 µM). The cytotoxic activity was observed to be CC50 = 247.83 ± 6.32 µM against 29.99 ± 2.82 µM for curcumin, the control, resulting in a selectivity index of SI = 7.85. Molecular modeling, docking and dynamics simulations of selected drug targets corroborated the observed antileishmanial activity of HA. Novel insights into the mechanisms of binding were obtained for trypanothione reductase (TR), pteridine reductase 1 (PTR1), and glutamate cysteine ligase (GCL). The binding affinity of HA to the drug targets LmGCL, LmPTR1, LdTR, LmTR, LdGCL, and LdPTR1 were obtained as -8.0, -7.8, -7.6, -7.5, -7.4 and -7.1 kcal/mol, respectively. The role of Lys16, Ser111, and Arg17 as critical residues required for binding to LdPTR1 was reinforced. HA was predicted as a Caspase-3 stimulant and Caspase-8 stimulant, implying a possible role in apoptosis, which was shown experimentally that HA induced parasite death by loss of membrane integrity. HA was also predicted as antileishmanial molecule corroborating the experimental activity. Therefore, HA is a promising antileishmanial molecule worthy of further development as a biotherapeutic agent.

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Crotofolane Diterpenoids and Other Constituents Isolated from Croton kilwae.

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Crotofolane Diterpenoids and Other Constituents Isolated from <i>Croton kilwae</i>.

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