New Dipterocarpol-Based Molecules with α-Glucosidase Inhibitory and Hypoglycemic Activity.

Dammarane triterpenoids are affordable and bioactive natural metabolites with great structural potential, which makes them attractive sources for drug development. The aim of the study was to investigate the potency of new dipterocarpol derivatives for the treatment of diabetes. Two dammaranes (dipterocarpol and its 20(24)-diene derivative) were modified by a Claisen-Schmidt aldol condensation to afford C2(E)-arylidenes in good yields. The majority of the synthesized compounds exhibited an excellent-to-moderate inhibitory effect toward α-glucosidase (from S. saccharomyces), among them eight compounds showed IC50 values less than 10 µM. 3-Oxo-dammarane-2(E)-benzylidenes (holding p-hydroxy- 3 l and p-carbonyl- 3 m substituents) demonstrated the most potent α-glucosidase inhibition with IC50 0.753 and 0.204 µM, being 232- and 857-times more active than acarbose (IC50 174.90 µM), and a high level of NO inhibition in Raw 264.7 cells with IC50 of 1.75 and 4.57 µM, respectively. An in vivo testing of compound 3 m (in a dose of 20 mg/kg) on a model of streptozotocin-induced T1DM in rats showed a pronounced hypoglycemic activity, the ability to reduce effectively the processes of lipid peroxidation in liver tissue and decrease the excretion of glucose and pyruvic acid in the urine. Compound 3 m reduced the death of diabetic rats and preserved their motor activity.

Synthetic modifications of abietane diterpene acids to potent antimicrobial agents.

Among abietane type semisynthetic diterpenoids, a series of quinopimaric and maleopimaric acid derivatives modified at the carboxyl and carbonyl groups, and in ring E were synthesised to obtain new compounds with antimicrobial potency against Mycobacterium tuberculosis H37Rv and key ESKAPE pathogens. It was found that compound 8 exhibited low toxicity to human embryonic kidney cell line HEK-293 (> 32 µg/mL) and showed significant bacteriostatic activity against methicillin-resistant Staphylococcus aureus (MRSA) (MIC ≤ 0.25 µg/mL) and excellent antifungal activity against Cryptococcus neoformans var. grubii (MICs ≤0.25 µg/mL) being ≈4 and ≈30 fold more active than vancomycin and fluconazole. It also showed moderate activity against fungus Candida albicans (MIC ≤ 0.25 µg/mL). Compound 9 inhibited M. tuberculosis H37Rv with MIC of 1.25 µg/mL. The docking studies suggest possible interactions of the leading compounds with the molecular targets.

The Introduction of Hydrazone, Hydrazide, or Azepane Moieties to the Triterpenoid Core Enhances an Activity Against M. tuberculosis.

BACKGROUND: Triterpenoids exhibit a wide spectrum of antimicrobial activity. OBJECTIVE: The objective of this study was to synthesize a series of nitrogen derivatives based on lupane, oleanane, and ursane triterpenoids with high antitubercular activity. METHODS: Isonicotinoylhydrazones were prepared via the reaction of 3-oxotriterpenic acids or betulonic aldehyde with isoniazid (INH) in yields of 54-72%. N-Acylation of betulonic or azepanobetulinic acids led to lupane C28 hydrazides and dihydrazides. The derivatives were evaluated for their in vitro antimycobacterial activities against Mycobacterium tuberculosis (MTB) H37RV and single-drug resistance (SDR)-TB in the National Institute of Allergy and Infectious Diseases, USA. Molecular docking was performed to evaluate the possible binding modes of investigated compounds in the active site of Diterpene synthase (Rv3378c). RESULTS: The obtained compounds are represented by C3 or C28 conjugates with hydrazine hydrate or INH. Some compounds demonstrated from high minimum inhibitory concentration (MIC ≤ 10 µg/mL) to excellent (MICs from 0.19 to 1.25 µg/mL) activity against MTB H37RV. Two lupane conjugates with INH were the leading compounds against MTB H37RV and some SDR-strains with MICs ranged from 0.19 to 1.70 µg/mL. Molecular docking of active compounds to diterpene synthase showed that these moieties accommodate the active site of the enzyme. CONCLUSION: It was revealed that the conjugation of lupanes with INH at C3 is more effective than at C28 and the lupane skeleton is preferable among oleanane and ursane types. The replacement of native hexacarbocyclic A ring to seven-member azepane ring is favorably for inhibition of both MTB H37RV and SDR-strains. These data could possibly mean that the antitubercular activity against INH-resistant strains (INH-R) came from both triterpenoid and isoniazid parts of the hybrid molecules. Azepanobetulin showed the highest activity against both INH-R strains in comparison with other triterpenoids and INH. Thus, the introduction of hydrazone, hydrazide (dihydrazide), or azepane moieties into the triterpenoid core is a promising way for the development of new anti-tubercular agents.

Newly synthesised oxime and lactone derivatives from Dipterocarpus alatus dipterocarpol as anti-diabetic inhibitors: experimental bioassay-based evidence and theoretical computation-based prediction.

Dipterocarpus alatus-derived products are expected to exhibit anti-diabetes properties. Natural dipterocarpol (1) was isolated from Dipterocarpus alatus collected in Quang Nam province, Vietnam; afterwards, 20 derivatives including 13 oxime esters (2 and 3a-3m) and 7 lactones (4, 5, 6a-6e) were semi-synthesised. Their inhibitory effects towards diabetes-related proteins were investigated experimentally (α-glucosidase) and computationally (3W37, 3AJ7, and PTP1B). Except for compound 2, the other 19 compounds (3a-3m, 4, 5, and 6a-6d) are reported for the first time, which were modified at positions C-3, C-24 and C-25 of the dipterocarpol via imidation, esterification, oxidative cleavage and lactonisation reactions. A framework based on docking-QSARIS combination was proposed to predict the inhibitory behaviour of the ligand-protein complexes. Enzyme assays revealed the most effective α-glucosidase inhibitors, which follow the order 5 (IC50 of 2.73 ± 0.05 µM) > 6c (IC50 of 4.62 ± 0.12 µM) > 6e (IC50 of 7.31 ± 0.11 µM), and the computation-based analysis confirmed this, i.e., 5 (mass: 416.2 amu; polarisability: 52.4 Å3; DS: -14.9 kcal mol-1) > 6c (mass: 490.1 amu; polarisability: 48.8 Å3; DS: -13.7 kcal mol-1) > 6e (mass: 549.2 amu; polarisability: 51.6 Å3; DS: -15.2 kcal mol-1). Further theoretical justifications predicted 5 and 6c as versatile anti-diabetic inhibitors. The experimental results encourage next stages for the development of anti-diabetic drugs and the computational strategy invites more relevant work for validation.

Synthesis and antimycobacterial activity of triterpeni≿ A-ring azepanes.

A series of A-ring azepanones and azepanes derived from betulonic, oleanonic and ursonic acids was synthesized and evaluated for their in vitro antimycobacterial activities against M. tuberculosis (MTB) H37Rv and SDR-TB in the National Institute of Allergy and Infectious Diseases. Triterpenic A-azepano-28-hydroxy-derivatives were synthesized by the reduction with LiAlH4 of triterpenic azepanones available from the Beckmann rearrangement of the corresponding C3-oximes. Modification of azepanes at NH-group and atoms С12, C20, C28 and C29 of triterpenic core led to the derivatives with oxo, epoxy, aminopropyl, oximino and acyl substituents. The primary assay of tested triterpenoids against MTB H37Rv demonstrated their MIC values ranged from 3.125 to >200 µM. Ursane type A-azepano-28-cinnamoates were the most active being 2 and 4 times more efficient than the initial 28-hydroxy-derivative. The follow-up testing revealed A-azepano-28-cinnamoyloxybetulin as a leader compound with MIC 2 and MBC 4 µM against MTB H37Rv and MICs 4, 1 and 1 µM against INH, RIF and OFX resistant strains, respectively. Five oleanane and ursane azepanes pronounced better activity than isoniazid against INH-R1 and rifampicin against INH-R2 strains. This work opens a new direction in the design and synthesis of new antitubercular agents basing on azepanotriterpenoids.

Inhibition of Alpha-Glucosidase by Synthetic Derivatives of Lupane, Oleanane, Ursane and Dammarane Triterpenoids.

A variety of new and earlier synthesized lupane, oleanane, ursane and dammarane triterpenoids have been investigated for their inhibitory activity against α-glucosidase. 2,3-Indole-21 ß-acetyl-20ß,28-epoxy-18α,19ßH-ursane and 3-oxo-3A-homo-3a-aza-20(S)-hydroxydammar-24(25)-ene were synthesized for the first time. The compounds 3, 4, 8-11 and 14 demonstrated strong in vitro inhibitory activity towards α-glucosidase with IC50 values of 37.5-115.1 µM. 3-Deoxy-3a-homo-3a-aza-28-cinnamoyloxy-20(29)-lupene, with an IC50 of 6.67 µM was 60-fold more active than the market drug acarbose.

Synthesis and antiviral activity of maleopimaric and quinopimaric acids' derivatives.

A series of maleopimaric and quinopimaric acids' derivatives modified in the E-ring, at the carbonyl- and carboxyl-groups were synthesized and evaluated for their activity in vitro against respiratory viruses (influenza; rhinovirus; adenovirus; and SARS), papilloma virus, and hepatitis B and C viruses. The antiviral screening of levopimaric acid diene adducts derivatives was carried out with minimal effect on SARS and influenza type B viruses. Excellent antiviral activity of the ozonolysis product of maleopimaric acid and dihydroquinopimaric methyl-(2-methoxycarbonyl)ethylene amide was found toward papilloma virus (HPV-11 strain) with the selectivity index of SI 30 and 20, respectively. Methyl (2-methoxycarbonyl)ethylene-, 1ß-hydroxy-5'-kaprolaktamo- and 4ß-hydroxy-4α,14α-epoxy-13(15)-ene-dihydroquinopimaric acid derivatives have also shown activity against replication of HCV nucleic acid and low toxicity.

Synthesis and anticancer activity of quinopimaric and maleopimaric acids' derivatives.

A series of quinopimaric and maleopimaric acids' derivatives modified in the E-ring, at the carbonyl- and carboxyl-groups were synthesized and their in vitro cytotoxic activity was evaluated at the National Cancer Institute, USA. Methyl esters of dihydroquinopimaric, 1a,4a-dehydroquinopimaric, 2,3-epoxyquinopimaric, 1-ethylenketal-dihydroquinopimaric, 1-ethylenketal-4-hydroxyiminodihydroquinopimaric acids displayed an activity on renal cancer, leukemia, colon cancer and breast cancer cell lines in concentration 10(−5) M. Methyl 1,4-dihydroxyiminodihydroquinopimarate showed both a potent and broad spectrum of cytotoxic activity against NSC lung cancer, colon cancer, breast cancer, renal cancer and leukemia and revealed in vivo antineoplastic activity towards mouse solid transplantable mammary carcinoma Ca755 and colon adenocarcinoma AKATOL. The information about antineoplastic activity of the studied quinopimaric and maleopimaric acids' derivatives will be used for hit to lead optimization in these chemical series.

One-pot synthesis of hollongdione from dipterocarpol.

A one-pot synthesis of a hybrid triterpenoid-steroid molecule, hollongdione (22,23,24,25,26,27-hexanordammar-3,20-dion), was achieved in a yield of 89%, based on the selective dehydration of dipterocarpol following ozonolysis. The structure of hollongdione was confirmed by X-ray analysis for the first time. Dammar-20(22),24(25)-dien inhibited the growth of Mycobacterium tuberculosis (strain H37Rv) in vitro with a MIC of 50 µg/mL.

An efficient oxyfunctionalization of quinopimaric acid derivatives with ozone.

An access to oxyfunctionalized quinopimaric acid derivatives is reported. The ozonolysis of methyl dihydroquinopimarate occurs through 1,2-cycloaddition of ozone to the bridging double bond followed by intermolecular rearrangements and formation of nontrivial 4beta-hydroxy-4alpha,14alpha-epoxy-13(15)-ene derivative 2. The oxidation of methyl furfurilydene dihydroquinopimarate with ozone led to anhydride 5 and unexpected carboxymethyl substituted cyclopentane lactone 6. The structure of compound 6 was confirmed by X-Ray analysis of its methyl ester.