The dissolution of p-methoxycinnamic acid-ß-cyclodextrin inclusion complex produced with microwave irradiation.

Background: p-methoxycinnamic acid (pMCA) is an ethyl pmethoxycinnamic derivative, which is the largest active ingredient in the rhizome of the kencur (Kaempferia galanga L) plant. Several studies reported that the compound has anti-inflammatory activity but has low solubility in water. The formation of a pMCA-ß- cyclodextrin (ßCD) inclusion complex with a molar ratio of 1:1 can increase its solubility. The formation of inclusion complexes with conventional methods requires a long time and the yield value is not optimal. Objective: This study aims to evaluate the dissolution of the pMCA-ßCD inclusion complex produced using the microwave irradiation method. Methods: The product was manufactured with chloroform solvent and a power of 400 watts (power 80%). It was then evaluated using the Differential Thermal Analysis (DTA) every 2 minutes until the 8th minute. The reaction was complete after 4 minutes of treatment with a yield of 96.5%. The obtained inclusion complexes were evaluated using DTA, FTIR, and PXRD. Subsequently, a dissolution test was carried out using a type 2 apparatus in distilled water medium of pH 6.8±0.05 at 37±0.5°C. Results: The results showed that there was a change in the melting temperature profile, infrared spectra, and crystallinity of the product. An 89.18% dissolution was also obtained within 60 minutes, which was twice that of pMCA compounds. Conclusion: From the results of the study, it can be concluded that the formation of pMCA-ßCD inclusion complexes using the microwave irradiation method is capable of providing high-yield values in a short time.

In vivo anticancer activity of benzoxazine and aminomethyl compounds derived from eugenol.

Background: Indonesia is the world's primary producer of clove. In order to find new utilization for clove and new biologically active compounds, eugenol, the main constituent of clove, has been converted to its derivatives. Objective: This study aims to examine in vivo anticancer activity of benzoxazine and aminomethyl compounds derived from eugenol. Methods: Fibrosarcoma was induced by injection of benzo(a)pyrene solution. The test compounds were given per oral at 20, 40, and 80 mg/Kg body weight, once a day for 30 days. Results: As a result, all the tested compounds showed activity in reducing the cancer incidence rate. All the tested compounds were also found to reduce tumor weight. Benzoxazine derivatives gave slightly better activity compared to aminomethyl derivatives. The strongest activity was exhibited by 6-allyl-3-(furan-2- ylmethyl)-8-methoxy-3,4-dihydro-2H-benzo(e)(1,3)oxazine. Conclusions: All four benzoxazine and aminomethyl compounds derived from eugenol that were tested exhibited anticancer activity in mice fibrosarcoma.

Chemoinformatics approach to design and develop vanillin analogs as COX-1 inhibitor.

Background: Coronary Heart Disease (CHD), commonly known as the silent killer, impacted the severity of COVID-19 patients during the pandemic era. Thrombosis or blood clots create the buildup of plaque on the coronary artery walls of the heart, which leads to coronary heart disease. Cyclooxygenase 1 (COX-1) is involved in the production of prostacyclin by systemic arteries; hence, inhibiting the COX-1 enzyme can prevent platelet reactivity mediated by prostacyclin. To obtain good health and well-being, the research of discovery of new drugs for anti-thrombotic still continue. Objective: This study aims to predict the potential of 17 compounds owned by the vanillin analog to COX-1 receptor using in silico. Methods: This research employed a molecular docking analysis using Toshiba hardware and AutoDock Tools version 1.5.7, ChemDraw Professional 16.0, Discovery Studio, UCSF Chimera software, SWISSADME and pKCSM, a native ligand from COX- 1 (PDB ID: 1CQE) was validated. Results: The validation result indicated that the RMSD was <2 Å. The 4-formyl-2-methoxyphenyl benzoate compound had the lowest binding energy in COX-1 inhibition with a value of -7.70 Å. All vanillin derivatives show good intestinal absorption, and the predicted toxicity indicated that they were non-hepatotoxic. All these compounds have the potential to be effective antithrombotic treatments when consumed orally. Conclusion: In comparison to other vanillin derivative compounds, 4-formyl-2-methoxyphenyl benzoate has the lowest binding energy value; hence, this analog can continue to be synthesized and its potential as an antithrombotic agent might be confirmed by in vivo studies.

In silico study of phytochemicals contained in Brucea javanica in inhibiting the InhA enzyme as antituberculosis.

Background: Currently Mycobacterium tuberculosis is found to be resistant to the treatment of tuberculosis with rifampin and isoniazid (INH) and often stated as multi-drug resistance (MDR). Knowledge and determination of biological properties of plant extracts is a source of drug candidates in various health fields. Therefore, natural products are important in the discovery of new drugs, especially in disease therapy, particularly for tropical diseases, tuberculosis. Brucea javanica, known as Buah Makasar, is found in many Asian countries including Indonesia. This plant fruit has a very bitter taste so it cannot be directly consumed and is often used as a traditional medicine to prevent some diseases, especially malaria. There has been no research on the effectiveness of Buah Makasar in tuberculosis. Objective: This study aims to identify compounds contained in Brucea javanica, namely bruceines, bruceosides and yadanziosides in inhibiting the InhA enzyme found in the wall of Mycobacterium tuberculosis. Methods: This in-silico study is using Molegro Virtual Docker (MVD) Ver. 5.5. We compared it to the native ligand, namely N-(4- Methylbenzoyl)-4-Benzylpiperidine (code: 4PI) and the reference drug standard, INH. Results: In-silico results show that yadanziosides found in Brucea javanica have the potential to inhibit the InhA enzyme. Bruceoside F (-190.76 Kcal/mol) has the lowest MolDock score among the 27 other compounds. It is also having lower MolDock score than the native ligand 4PI (-120.61 Kcal/mol) and INH (- 54.44 Kcal/mol). Conclusion: Brucea javanica can be considered as source of drug development for againts tuberculosis.

Synthesis, anti-angiogenic activity and prediction toxicity of (E)-3-(3-methoxyphenyl) propenoic acid.

Background: Anti-angiogenic medications, one of cancer chemo preventive mechanism were permitted for different cancers. Nevertheless, major primary and secondary resistance obstruct efficacy in several tumor types. Moreover, the improvement of safe and effective NSAIDs for angiogenesis inhibition is complicated, because of their serious toxicity. So, we require improving clinically appropriate strategies to boost efficacy of anti-angiogenic drugs with low risk of toxicity. Objectives: The present study aimed to synthesize the (E)-3- (3-methoxyphenyl)propenoic acid (3MPCA), to determine the anti-angiogenic activity and predict its toxicity. Methods: 3MPCA was obtained by Knoevenagel reaction using microwave irradiation at 400 Watt. The anti-angiogenesis experimental was performed using chorioallantois membrane of embryonated chicken eggs induced by b-FGF. The potency of 3MPCA was verified at dosage 30 and 60 ng and compared with celecoxib 60 ng. Toxicity prediction of 3MPCA was performed by ProTox II online program. Results: The results showed that 3MPCA was achieved in good yield (89%). Anti angogenic activity was showed by endothelial cells growth in neovascular capillaries of new blood vessel of chorioallantois membrane of embryonated chicken eggs. The endothelial cells growth decreased until 41.7-83%. The prediction LD50 was 1772mg/kg. Conclusion: (E)-3-(3-methoxyphenyl)propenoic acid can be obtained through Knovenagel reaction using microwave irradiation and it has potential as anti-angiogenesis inhibitor with low toxicity.

Potential Utilization of Phenolic Acid Compounds as Anti-Inflammatory Agents through TNF-α Convertase Inhibition Mechanisms: A Network Pharmacology, Docking, and Molecular Dynamics Approach.

Inflammation is a dysregulated immune response characterized by an excessive release of proinflammatory mediators, such as cytokines and prostanoids, leading to tissue damage and various pathological conditions. Natural compounds, notably phenolic acid phytocompounds from plants, have recently garnered substantial interest as potential therapeutic agents to bolster well-being and combat inflammation recently. Based on previous research, the precise molecular mechanism underlying the anti-inflammatory activity of phenolic acids remains elusive. Therefore, this study aimed to predict the molecular mechanisms underpinning the anti-inflammatory properties of selected phenolic acid phytocompounds through comprehensive network pharmacology, molecular docking, and dynamic simulations. Network pharmacology analysis successfully identified TNF-α convertase as a potential target for anti-inflammatory purposes. Among tested compounds, chlorogenic acid (-6.90 kcal/mol), rosmarinic acid (-6.82 kcal/mol), and ellagic acid (-5.46 kcal/mol) exhibited the strongest binding affinity toward TNF-α convertase. Furthermore, phenolic acid compounds demonstrated molecular binding poses similar to those of the native ligand, indicating their potential as inhibitors of TNF-α convertase. This study provides valuable insights into the molecular mechanisms that drive the anti-inflammatory effects of phenolic compounds, particularly through the suppression of TNF-α production via TNF-α convertase inhibition, thus reinforcing their anti-inflammatory attributes.

The thermodynamic study of p-methoxycinnamic acid inclusion complex formation, using ß-cyclodextrin and hydroxypropyl-ß-cyclodextrin.

OBJECTIVES: Cyclodextrin's ability to form an inclusion complex with a guest molecule is a function of two factors. The first is steric and depends on the relative size of cyclodextrin cavity to the guest molecule, while the second is the thermodynamic interaction between the different system components. This study therefore aims to determine the effect of ß-cyclodextrin and hydroxypropyl-ß-cyclodextrin as complex formers, on thermodynamic parameter values (ΔH, ΔG, and ΔS) in the formation of inclusion complex with p-methoxycinnamic acid (pMCA). METHODS: The pMCA complex formation with ß-cyclodextrin or hydroxypropyl-ß-cyclodextrin was determined in 0.02 pH 4.0 M acetate buffer and 0.02 M pH 7.0 phosphate buffer, with a 0.2 µ value at 32, 37, and 42 ± 0.5 °C. This experiment was carried out in a waterbath shaker until a saturated solution was obtained. Subsequently, pMCA concentration was determined using UV spectrophotometer at the maximum pMCA wavelength, at each pH. RESULTS: The result showed pMCA formed inclusion complex with ß-cyclodextrin or hydroxypropyl-ß-cyclodextrin and exhibited increased solubility with increase in ß-cyclodextrin or hydroxypropyl-ß-cyclodextrin concentration. This temperature rise led to a decrease in the complex's constant stability (K). Furthermore, the interaction showed a negative enthalpy (∆H<0) and is a spontaneous processes (∆G<0). At pH 4.0, an increase in the system's entropy occurred (∆S>0), however, at pH 7.0, the system's entropy decreased (∆S<0). CONCLUSIONS: The rise in pMCA solubility with increase in cyclodextrin solution concentration indicates an inclusion complex has been formed, and is supported by thermodynamic data.

Interactions of primaquine and chloroquine with PEGylated phosphatidylcholine liposomes.

This study aimed to analyze the interaction of primaquine (PQ), chloroquine (CQ), and liposomes to support the design of optimal liposomal delivery for hepatic stage malaria infectious disease. The liposomes were composed of hydrogenated soybean phosphatidylcholine, cholesterol, and distearoyl-sn-glycero-3-phosphoethanolamine-N-(methoxy[polyethyleneglycol]-2000), prepared by thin film method, then evaluated for physicochemical and spectrospic characteristics. The calcein release was further evaluated to determine the effect of drug co-loading on liposomal membrane integrity. The results showed that loading PQ and CQ into liposomes produced changes in the infrared spectra of the diester phosphate and carbonyl ester located in the polar part of the phospholipid, in addition to the alkyl group (CH2) in the nonpolar portion. Moreover, the thermogram revealed the loss of the endothermic peak of liposomes dually loaded with PQ and CQ at 186.6 °C, which is identical to that of the phospholipid. However, no crystallinity changes were detected through powder X-ray diffraction analysis. Moreover, PQ, with either single or dual loading, produced the higher calcein release profiles from the liposomes than that of CQ. The dual loading of PQ and CQ tends to interact with the polar head group of the phosphatidylcholine bilayer membrane resulted in an increase in water permeability of the liposomes.

In silico estrogen receptor alpha antagonist studies and toxicity prediction of Melia azedarach leaves bioactive ethyl acetate fraction.

The estrogen hormone dependent accounts for a major cause in the incidence of women breast cancer. Thus, their receptor, especially the estrogen receptor α (ER-α), is becoming a target in endocrine treatment. These ligand-inducible nuclear functions are regulated by an array of phytochemical and synthetic compounds, such as 17 ß-estradiol and tamoxifen (4-hydroxytamoxifen [4OHT]). The Chinaberry (Melia azedarach) leaves are known naturally for relieving internal and external diseases. Previous studies revealed the potency of Melia's ethanolic extract and ethyl acetate fractions as anticancer; furthermore, this study aimed to resolve possible ER-α antagonist's mechanism and safety from M. azedarach leaves ethyl acetate fraction contents. Melia's phytochemical content was analyzed with electrospray ionization liquid chromatography-mass spectrometry, while its ER-α antagonist's potency was investigated by in silico. The computational docking was used to 3ERT (a human ER-α-4OHT binding domain complex) with Autodock Vina and related programs. The results presented Energy binding (ΔG) of Melia's quercetin 3-O-(2'',6''-digalloyl)-ß-D-galactopyranoside was similar to 4OHT, and lower than its agonist 17 ß-estradiol. Furthermore, the toxicity prediction of these compounds were revealed safer than 4OHT. The Melia's leaves ethyl acetate fraction, therefore, is a potential pharmacological material for further studies.

Shallot skin profilling, computational evaluation of physicochemical properties, ADMET, and molecular docking of its components against P2Y12 receptor.

OBJECTIVES: Medicinal plants are a source of many compounds that are useful in the pharmaceutical field for novel drug development. Polyphenols and the flavonoid group in plants are known to have several activities, such as relieving cardio vascular disease (CVD). The outer skin of the shallot which is disposed of as waste is known to have an antiplatelet activity which was tested in vitro assay. To date, there is no study reported on the ADMET profile and physicochemical properties of the active component of the shallot skins. METHODS: The extraction of shallot skins was conducted by ultrasonic irradiation using ethanol. The phytochemical screenings were carried out by TLC and color reaction. The profiling of its active ingredient was presented by GC-MS, HPLC and spectrophotometry UV-vis. Whereas their physicochemical properties were analyzed by ChemDraw 17.00 program and the ADMET predictions were studied using pkCSM online tool. The MVD program was operated in the docking study on protein P2Y12 (PDB ID 4PXZ). RESULTS: The extract showed the presence of polyphenol, flavonoids, quercetin, natalensine-3,5-dinitrobenzoate; bis[2-(2-fluorophenyl)-6-fluoroquinolin-4-yl]amine, benzo[a]heptalene, N-(trifluoroacetyl) methyl-N-deacethyl-colchicine. The ADMET prediction data displayed that the compounds in the extract have good absorption so that they can be used in the oral and transdermal routes. Some components in the extract have lower MDS than clopidogrel. CONCLUSIONS: The ultrasonicated shallot skin extract can be used as additional resources of the active pharmaceutical ingredients and to have the potency to be developed as an oral or transdermal preparation.

Ferulic Acid Prevents Angiogenesis Through Cyclooxygenase-2 and Vascular Endothelial Growth Factor in the Chick Embryo Chorioallantoic Membrane Model.

OBJECTIVES: This study was designed to verify the antiangiogenic activity of ferulic acid (FA) and its potency to inhibit cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) expression in the chorioallantoic membrane (CAM) model. Moreover, we verified its mechanism of action by docking the molecule on COX-2, tyrosine kinase, and VEGF-2 proteins in silico. MATERIALS AND METHODS: An antiangiogenesis assay of FA at doses of 30, 60, and 90 µg was performed using the CAM of chicken eggs that were 9 days old and stimulated by 60 ng of basic fibroblast growth factor. Celecoxib (60 µg) was used as the reference drug. The inhibitory activity on VEGF and COX-2 expression was determined by immunohistochemistry assay. Molecular docking of FA was accomplished by Molegro Virtual Docker program ver. 5.5 on COX-2 enzyme (PDB ID 1CX2), tyrosine kinase receptor (PDB ID 1XKK), and VEGF-2 receptor (PDB ID 4ASD). RESULTS: FA at doses of 30, 60, and 90 µg significantly prevented angiogenesis in the CAM model, which was represented as inhibitory activity against endothelial cells of blood vessels (42.6-70.7%) and neovascularization (43.0-86.6%). The inhibitory activity of FA against VEGF expression was stronger than its action on COX-2 expression. Molecular docking on VEGF-2 receptor resulted in an RS value of FA of -73.844 kcal/mol and for celecoxib it was -94.557 kcal/mol. The RS value on tyrosine kinase of FA was -84.954 kcal/mol, while on celecoxib it was -93.163 kcal/mol. Docking on COX-2 receptor gave an RS value of FA of -73.416 kcal/mol, while for celecoxib it was -118.107 kcal/mol. CONCLUSION: Reductions in VEGF-2 and COX-2 expression due to treatment with FA at the dose range 30-90 µg appeared to be related to angiogenesis inhibition, which was shown by two parameters, namely inhibition of neovascularization and endothelial cell growth in blood vessels. It was concluded that FA is a promising antiangiogenic therapeutic agent especially at the early stage, and this activity can arise from inhibitory action on COX-2 and VEGF-2 proteins.

o-Hydroxycinnamic derivatives as prospective anti-platelet candidates: in silico pharmacokinetic screening and evaluation of their binding sites on COX-1 and P2Y12 receptors.

Background The high prevalence of thrombotic abnormalities has become a major concern in the health sector. This is triggered by uncontrolled platelet aggregation, which causes complications and death. The problem becomes more complicated because of the undesirable side effects of the drugs currently in use, some of which have reportedly become resistant. This study aims to evaluate the potency of o-hydroxycinnamic acid derivatives (OCA1a-22a) and their pharmacokinetic properties and toxicity for them to be developed as new antiplatelet candidates. Methods In silico analysis of pharmacokinetics was carried out using pKCSM. Molecular docking of the compounds OCA 1a-22a was performed using the Molegro Virtual Docker. In silico evaluation of the potency of biological activity was done by measuring the bonding energy of each tested compound to the target receptor i.e. COX-1 and P2Y12, as the Moldock score (MDS). Results pKCSM analyses showed that more than 90% of OCA 1a-22a are absorbed through the intestine and distributed in plasma. Most tested compounds are not hepatotoxic, and none is mutagenic. An evaluation of the COX-1 receptor showed that OCA 2a-22a have lower binding energy compared to aspirin, which is the COX-1 inhibitor used today. So, it can be predicted that OCA 2-22a have stronger activity. Interactions with P2Y12 show lower MDS than aspirin, but slightly higher than ibuprofen, which is the standard ligand. Conclusions ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile prediction shows that OCA 1a-22a have the potential to be developed as oral preparations. OCA 1a-22a have strong potential to interact with COX-1 and P2Y12 receptors, so they are prospective anti-platelet candidates.

Anti-aging properties of Curcuma heyneana Valeton & Zipj: A scientific approach to its use in Javanese tradition.

ETHNOPHARMACOLOGICAL RELEVANCE: Temu giring, the rhizome of Curcuma heyneana Valeton & Zipj (C. heyneana), is native to tropical regions, especially in Indonesia. It is traditionally used as a skin care, for cosmetic and body freshness, in Javanese and Balinese women, and has many other bioactivities such as antioxidant, anticancer and antiinflammatory. AIM OF THE STUDY: The purpose of this study was to determine the antiaging activity of C. heyneana to prove its traditional use. MATERIALS AND METHODS: The antioxidant activity was determined using the DPPH free radical method, and anti-aging activity was examined using in vitro assays such as tyrosinase inhibitor and collagenase inhibitor. In vivo tests were performed by observing histomorphologic changes in rat skin exposed to Ultraviolet (UV) rays. The total curcuminoid contents and chromatographic profiles were determined by Thin Layer Chromatography (TLC) - densitometry. RESULTS: In all in vitro assays, all of the extracts showed a dose-dependent manner in the final concentration range from 62.5 to 500 µg/mL for DPPH assay and 31.25 to 250 µg/mL for tyrosinase inhibition and collagenase inhibition assay. Curcuminoid (CUR), the active principle of Curcuma genus shows antioxidant, tyrosinase inhibitor and collagenase inhibitor activity greater than all C. heyneana extracts. The in vivo assay results showed that the topical application of the crude extract of C. heyneana produced significant improvement effects on the UV-induced skin structure damage. The total CUR content was correlated with the anti-aging activity of Curcuma heyneana. CONCLUSIONS: The results show that C. heyneana contains antioxidant compounds and has potent anti-aging activity, indicating that it can be used as an anti-aging drug candidate or as a phyto-cosmeceutical.