Newly synthesized benzimidazole hydrazone derivatives 1-26 were evaluated for their α-glucosidase inhibitory activity. Compounds 1-26 exhibited varying degrees of yeast α-glucosidase inhibitory activity with IC50 values between 8.40 ± 0.76 and 179.71 ± 1.11 μM when compared with standard acarbose. In this assay, seven compounds that showed highest inhibitory effects than the rest of benzimidazole series were identified. All the synthesized compounds were characterized by different spectroscopic methods adequately. We further evaluated the interaction of the active compounds with enzyme with the help of docking studies.
Phytochemical investigation on the stem bark of Shorea maxwelliana yielded five oligostilbenoids identified as α-viniferin (1), maximol A (2), vaticanol A (3), suffruticosol A (4) and vaticanol G (5). Chemotaxonomy of isolated compounds was discussed briefly. Major compounds were tested for neurotoxic and cytotoxic activities. Neurotoxicity for all tested compounds did not pose any toxic effect against cultured cell (cell viability range ±100-94%). Compounds 2-5 possessed active cyctotoxic activity against HL60 cell line with IC50 values range of 2.7-78 µg mL(-1).
Biscoumarin analogs 1-18 have been synthesized, characterized by EI-MS and (1)H NMR and evaluated for α-glucosidase inhibitory potential. All compounds showed variety of α-glucosidase inhibitory potential ranging in between 13.5±0.39 and 104.62±0.3μM when compared with standard acarbose having IC50 value 774.5±1.94μM. The binding interactions of the most active analogs were confirmed through molecular docking. The compounds showed very good interactions with enzyme. All synthesized compounds 1-18 are new. Our synthesized compounds can further be studied to developed lead compounds.
A library of novel 2,5-disubtituted-1,3,4-oxadiazoles with benzimidazole backbone (3a-3r) was synthesized and evaluated for their potential as β-glucuronidase inhibitors. Several compounds such as 3a-3d, 3e-3j, 3l-3o, 3q and 3r showed excellent inhibitory potentials much better than the standard (IC50=48.4±1.25μM: d-saccharic acid 1,4-lactone). All the synthesized compounds were characterized satisfactorily by using different spectroscopic methods. We further evaluated the interaction of the active compounds and the enzyme active site with the help of docking studies.
Apoptotic cell death is the cause of the loss of insulin-producing β-cells in all forms of diabetes mellitus. The identification of small molecules capable of protecting cytokine-induced apoptosis could form the basis of useful therapeutic interventions. Here in, we present the discovery and synthesis of new benzimidazole derivatives, capable of rescuing pancreatic β-cells from cytokine-induced apoptosis. Three hydrazone derivatives of benzimidazole significantly increased the cellular ATP levels, reduced caspase-3 activity, reduced nitrite production and increased glucose-stimulated insulin secretion in the presence of proinflammatory cytokines. These findings suggest that these compounds may protect β-cells from the harmful effects of cytokines and may serve as candidates for therapeutic intervention for diabetes.
Thiourea derivatives having benzimidazole 1-17 have been synthesized, characterized by 1H NMR, 13C NMR and EI-MS and evaluated for α-glucosidase inhibition. Identification of potential α-glucosidase inhibitors were done by in vitro screening of 17 thiourea bearing benzimidazole derivatives using Baker's yeast α-glucosidase enzyme. Compounds 1-17 exhibited a varying degree of α-glucosidase inhibitory activity with IC50 values between 35.83±0.66 and 297.99±1.20μM which are more better than the standard acarbose (IC50=774.5±1.94μM). Compound 10 and 14 showed significant inhibitory effects with IC50 value 50.57±0.81 and 35.83±0.66μM, respectively better than the rest of the series. Structure activity relationships were established. Molecular docking studies were performed to understand the binding interaction of the compounds.
A new flavanone derivative, malaysianone A (1), four prenylated flavanones, 6-prenyl-3'-methoxyeriodictyol (2), nymphaeol B (3), nymphaeol C (4) and 6-farnesyl-3',4',5,7-tetrahydroxyflavanone (5), and two coumarins, 5,7-dihydroxycoumarin (6) and scopoletin (7), were isolated from the dichloromethane extract of the inflorescences of Macaranga triloba. The structures of these compounds were elucidated based on spectroscopic methods including nuclear magnetic resonance (NMR-1D and 2D), UV, IR and mass spectrometry. The cytotoxic activity of the compounds was tested against several cell lines, with 5 inhibiting very strongly the growth of HeLa and HL-60 cells (IC(50): 1.3 μg/ml and 3.3 μg/ml, respectively). Compound 5 also showed strong antiplasmodial activity (IC(50): 0.06 μM).
A new oligostilbenoid tetramer, malaysianol B (1), was isolated from the acetone extract of the stem bark of Dryobalanops lanceolata along with seven oligostilbenoids tetramers; hopeaphenol (2), stenophyllol A (3), nepalensinol B (4), vaticanol B (5) and C (6), upunaphenol D (7), and flexuosol A (8). The structures of the isolated compounds were established on the basis of their spectroscopic data evidence. The antibacterial activity of the isolated compounds was evaluated using resazurin microtitre-plate assay.
A new resveratrol trimer, malaysianol A (1), five known resveratrol oligomers: laevifonol (2), ampelopsin E (3), α-viniferin (4), ε-viniferin (5), diptoindonesin A (6), and bergenin (7) have been isolated from the acetone extract of the stem bark of Dryobalanops aromatica by combination of vacuum and radial chromatography techniques. Their structures were established on the basis of their spectroscopic evidence and comparison with the published data. The cytotoxic activity of the compounds was tested against several cell lines in which compound 4 was found to inhibit strongly the growth of HL-60 cell line.
Breast cancer is the most common and the second leading cause of cancer-related deaths in women. It has two distinctive hallmarks: rapid abnormal growth and the ability to invade and metastasize. During metastasis, cancer cells are thought to form actin-rich protrusions, called invadopodia, which degrade the extracellular matrix. Current breast cancer treatments, particularly chemotherapy, comes with adverse effects like immunosuppression, resistance development and secondary tumour formation. Hence, naturally-occurring molecules claimed to be less toxic are being studied as new drug candidates. Ampelopsin E, a natural oligostilbene extracted from Dryobalanops species, has exhibited various pharmacological properties, including anticancer and anti-inflammatory activities. However, there is yet no scientific evidence of the effects of ampelopsin E towards metastasis. Scratch assay, transwell migration and invasion assays, invadopodia and gelatin degradation assays, and ELISA were used to determine the effects of ampelopsin E towards the invasiveness of MDA-MB-231 cells. Strikingly in this study, ampelopsin E was able to halt migration, transmigration and invasion in MDA-MB-231 cells by reducing formation of invadopodia and its degradation capability through significant reduction (p < 0.05) in expression levels of PDGF, MMP2, MMP9 and MMP14. In conclusion, ampelopsin E reduced the invasiveness of MDA-MB-231 cells and was proven to be a potential alternative in treating TNBC.
Four isoprenylated flavonols, including two new compounds, macainermisins A-B (1-2), and two known compounds, sinoflavonoid P (3), broussoflavonol F (4), were isolated from the leaves of Macaranga inermis. A combination of HRESIMS, UV, 1D, and 2D NMR spectra elucidated the structures of 1-2. Flavonols (1-4) were evaluated against three cancer cells. Compound 1 showed high cytotoxicity against WiDR with an IC50 value of 0.93 µM, and compound 2 was active towards HeLa and WiDR (IC50 values of 0.90 and 0.94 µM), and compound 3 showed high activity towards 4T1 and HeLa (IC50 values of 0.83 and 0.98 µM).
Novel series of disulfide and sulfone hybrid analogs (1-20) were synthesized and characterized through EI-MS and (1)H NMR and evaluated for β-glucuronidase inhibitory potential. All synthesized analogs except 13 and 15 showed excellent β-glucuronidase inhibitory potential with IC50 value ranging in between 2.20-88.16μM as compared to standard d-saccharic acid 1,4 lactone (48.4±1.25μM). Analogs 19, 16, 4, 1, 17, 6, 10, 3, 18, 2, 11, 14 and 5 showed many fold potent activity against β-glucuronidase inhibitor. Structure activity relationship showed that substitution of electron withdrawing groups at ortho as well as para position on phenyl ring increase potency. Electron withdrawing groups at meta position on phenyl ring showed slightly low potency as compared to ortho and para position. The binding interactions were confirmed through molecular docking studies.
Bisindolylmethane thiosemicarbazides 1-18 were synthesized, characterized by 1H NMR and ESI MS and evaluated for urease inhibitory potential. All analogs showed outstanding urease inhibitory potentials with IC50 values ranging between 0.14 ± 0.01 to 18.50 ± 0.90 μM when compared with the standard inhibitor thiourea having IC50 value 21.25 ± 0.90 μM. Among the series, analog 9 (0.14 ± 0.01 μM) with di-chloro substitution on phenyl ring was identified as the most potent inhibitor of urease. The structure activity relationship has been also established on the basis of binding interactions of the active analogs. These binding interactions were identified by molecular docking studies.
Thirty-two (32) bis-indolylmethane-hydrazone hybrids 1-32 were synthesized and characterized by 1HNMR, 13CNNMR and HREI-MS. All compounds were evaluated in vitro for β-glucuronidase inhibitory potential. All analogs showed varying degree of β-glucuronidase inhibitory potential ranging from 0.10 ± 0.01 to 48.50 ± 1.10 μM when compared with the standard drug d-saccharic acid-1,4-lactone (IC50 value 48.30 ± 1.20 μM). Derivatives 1-32 showed the highest β-glucuronidase inhibitory potentials which is many folds better than the standard drug d-saccharic acid-1,4-lactone. Further molecular docking study validated the experimental results. It was proposed that bis-indolylmethane may interact with some amino acid residues located within the active site of β-glucuronidase enzyme. This study has culminated in the identification of a new class of potent β-glucuronidase inhibitors.
Due to the great biological importance of β-glucuronidase inhibitors, here in this study, we have synthesized a library of novel benzothiazole derivatives (1-30), characterized by different spectroscopic methods and evaluated for β-glucuronidase inhibitory potential. Among the series sixteen compounds i.e.1-6, 8, 9, 11, 14, 15, 20-23 and 26 showed outstanding inhibitory potential with IC50 value ranging in between 16.50 ± 0.26 and 59.45 ± 1.12 when compared with standard d-Saccharic acid 1,4-lactone (48.4 ± 1.25 µM). Except compound 8 and 23 all active analogs showed better potential than the standard. Structure activity relationship has been established.
Muntingia calabura (Elaeocarpaceae) is one of the most common roadside trees in Malaysia. Its leaves, barks, flowers and roots have been used as a folk remedy for the treatment of fever, incipient cold, liver disease, as well as an antiseptic agent in Southeast Asia. The aim of this study is to isolate and identify the antibacterial and cytotoxic compounds from the leaves of Muntingia calabura L.
Hylocereus undatus foliage is believed to contain antioxidants similar to its peel. Numerous studies have been conducted to determine the total phenolic content (TPC) and antioxidant activity on the Hylocereus undatus pulps and peels; however, similar studies on its foliage have yet to be investigated. In this study, Hylocereus undatus foliage and peels were extracted using two different solvents namely; chloroform and methanol through Folin-Ciocalteu method and Diphenyl-1-Ipicrylhydrazyl (DPPH) free radical scavenging assay for TPC and antioxidant activity, respectively. As for TPC, results revealed that the peels gave higher TPC in both methanol (48.15 mg GAE/100g extract) and chloroform (18.89 mg GAE/100g extract) extractions than foliage (30.3 mg GAE/100g extract and 5.92 mg GAE/100g extract, respectively). However, when a comparison was made between foliage and peels in terms of its scavenging effects in DPPH assay, the peels contained more antioxidants (18.71%) than foliage (38.3%) in the chloroform solvent extracts. This study shows that Hylocereus undatus foliage has a similar antioxidant activity as its peels and is potentially a natural antioxidant in food applications.
Treatments for skin injuries have recently advanced tremendously. Such treatments include allogeneic and xenogeneic transplants and skin substitutes such as tissue-engineered skin, cultured cells, and stem cells. The aim of this paper is to discuss the general overview of the quality assurance and quality control implemented in the manufacturing of cell and tissue product, with emphasis on our experience in the manufacturing of MyDerm®, an autologous bilayered human skin substitute. Manufacturing MyDerm® requires multiple high-risk open manipulation steps, such as tissue processing, cell culture expansion, and skin construct formation. To ensure the safety and efficacy of this product, the good manufacturing practice (GMP) facility should establish a well-designed quality assurance and quality control (QA/QC) programme. Standard operating procedures (SOP) should be implemented to ensure that the manufacturing process is consistent and performed in a controlled manner. All starting materials, including tissue samples, culture media, reagents, and consumables must be verified and tested to confirm their safety, potency, and sterility. The final products should also undergo a QC testing series to guarantee product safety, efficacy, and overall quality. The aseptic techniques of cleanroom operators and the environmental conditions of the facility are also important, as they directly influence the manufacturing of good-quality products. Hence, personnel training and environmental monitoring are necessary to maintain GMP compliance. Furthermore, risk management implementation is another important aspect of QA/QC, as it is used to identify and determine the risk level and to perform risk assessments when necessary. Moreover, procedures for non-conformance reporting should be established to identify, investigate, and correct deviations that occur during manufacturing. This paper provides insight and an overview of the QA/QC aspect during MyDerm® manufacturing in a GMP-compliant facility in the Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia.
The genus Jatropha (Euphorbiaceae) comprises of about 170 species of woody trees, shrubs, subshrubs or herbs in the seasonally dry tropics of the Old and the New World. They are used in medicinal folklore to cure various diseases of 80% of the human population in Africa, Asia and Latin America. Species from this genus have been popular to cure stomachache, toothache, swelling, inflammation, leprosy, dysentery, dyscrasia, vertigo, anemia, diabetis, as well as to treat HIV and tumor, opthalmia, ringworm, ulcers, malaria, skin diseases, bronchitis, asthma and as an aphrodisiac. They are also employed as ornamental plants and energy crops. Cyclic peptides alkaloids, diterpenes and miscellaneous compounds have been reported from this genus. Extracts and pure compounds of plants from this genus are reported for cytotoxicity, tumor-promoting, antimicrobial, antiprotozoal, anticoagulant, immunomodulating, anti-inflammatory, antioxidant, protoscolicidal, insecticidal, molluscicidal, inhibition AChE and toxicity activities.
The genus Dillenia is comprised of about 100 species of evergreen and deciduous trees or shrubs of disjunct distribution in the seasonal tropics of Madagascar through South and South East Asia, Malaysia, North Australia, and Fiji. Species from this genus have been widely used in medicinal folklore to treat cancers, wounds, jaundice, fever, cough, diabetes mellitus, and diarrhea as well as hair tonics. The plants of the genus also produce edible fruits and are cultivated as ornamental plants. Flavonoids, triterpenoids, and miscellaneous compounds have been identified in the genus. Their extracts and pure compounds have been reported for their antimicrobial, anti-inflammatory, cytotoxic, antidiabetes, antioxidant, antidiarrheal, and antiprotozoal activities. Mucilage from their fruits is used in drug formulations.