The predominance of endothelium-derived relaxing factors and beta-adrenergic receptor pathways in strong vasorelaxation induced by 4-hydroxybenzaldehyde in the rat aorta.

4-hydroxybenzaldehyde (4HB), known as ρ-hydroxybenzaldehyde, is commonly present in traditional Chinese medicine herb, most frequently used for hypertension treatment. This research aims to determine the potency of 4HB's vasorelaxant action. In the study, the vasodilation effect of 4HB was evaluated using in vitro isolated rat aortic rings assay. The aortic rings were pre-incubated with respective antagonists before being pre-contracted with phenylephrine (PE) and challenged with various concentrations of 4HB for mechanistic action studies. Rmax (maximal vasodilation) and pEC50 (negative logarithm of half-maximal effective concentration) values of each experiment were determined for comparison purposes. 4HB caused vasodilation on endothelium-intact aortic rings which pre-contracted with PE (pEC50 = 3.53 ± 0.05, Rmax = 100.95 ± 4.25%) or potassium chloride (pEC50 = 2.96 ± 0.13, Rmax = 72.13 ± 4.93%). The vasodilation effect of 4HB was significantly decreased in the absence of an endothelium (pEC50 = 2.21 ± 0.25, Rmax = 47.96 ± 4.16%). The atropine, 4-aminopyridine, Nω-nitro-L-arginine methyl ester, glibenclamide, and propranolol significantly reduced the vasorelaxation effect of 4HB. Besides that, 4HB blocked the voltage-operated calcium channel (VOCC) and regulated the intracellular Ca2+ release from the sarcoplasmic reticulum (SR) in the aortic ring. Thus, the results indicated that 4HB exerted its vasodilatory effect via cGMP and ß2 pathways, M3-dependent PLC/IP3 pathways, and potassium and calcium channels.

Discovery of trans-3,4,4'-trihydroxystilbene as new lead vasorelaxant agent for antihypertensive drug development.

AIMS: The structure-vasorelaxant activity relationships (SARs) assessment in previous study has found that trans-3,4,4'-trihydroxystilbene (344OH) could potentially act as a vasorelaxing agent with demonstration of over 2-fold maximal relaxation (Rmax) compared to its analogue, resveratrol. The present study focuses on the mechanism of actions and pathways employed by 344OH and compared to its analogue to further speculate the SAR of stilbenoids towards vasorelaxation. MATERIALS AND METHODS: The 344OH employed in present study was synthesized based on the protocol in previous study. The vascular responses towards the cumulative addition of 344OH were evaluated using in vitro rat aortic rings assays. KEY FINDINGS: The pEC50 and Rmax values were found to be 4.33 ± 0.05 and 106 ± 3.99%, respectively. Results showed that the vasorelaxation of 344OH were predominated by G-protein-coupled muscarinic- (M3) and ß2-adrenergic receptors, followed by PGI2/AC/cAMP- and NO/sGC/cGMP-dependent pathways. It was also identified that 344OH employed voltage-activated- (Kv), calcium-activated- (Kca) and inwardly-rectifying (Kir) potassium channels and act as an antagonist for both VOCC and IP3R while regulating the action potential in the vasculature. SIGNIFICANCE: The different position of hydroxyl substituent located in A-ring of the stilbenoid backbone in 344OH compared to resveratrol resulted in a significant difference in mechanistic actions that lead to 344OH's fast-acting and less time-dependent vasorelaxation behaviour. This has substantially increased the potential of 344OH to be developed as an effective antihypertensive drug in future. Present findings further strengthen our inferences where the SARs study approach should be carried out as the mainstream methodology in future drug development research.

One-step synthesis of M13 phage-based nanoparticles and their fluorescence properties.

Fluorescent carbon nanoparticles have been gaining more attention in recent years for their excellent fluorescence properties and simple synthesis routes. Different carbon sources have been reported for fluorescent carbon nanoparticle synthesis but the use of virus particles as a carbon source is scarce. Herein, we report the utilization of M13 bacteriophage particles as the carbon source to synthesize phage-based nanoparticles through facile, one-step microwave heating. M13 bacteriophage is a nanosized filamentous virus particle with a single-stranded DNA genome encapsulated by a large number of coat proteins. These amino acid rich building blocks provide a substantial amount of carbon source for the synthesis of fluorescent nanoparticles. The resulting nanoparticles from M13 bacteriophage showed good water solubility and exhibited bright blue luminescence. The selectivity and sensitivity of the phage-based nanoparticles towards Fe(iii) ions showed a quenching effect with a linear correlation and a detection limit of 8.0 µM. This process highlights the potential application of virus particles as a source for the synthesis of fluorescent carbon nanoparticles and the sensing application.

In vitro study and structure-activity relationship analysis of stilbenoid derivatives as powerful vasorelaxants: Discovery of new lead compound.

The development of vasorelaxant as the antihypertensive drug is important as it produces a rapid and direct relaxation effect on the blood vessel muscles. Resveratrol (RV), as the most widely studied stilbenoid and the lead compound, inducing the excellent vasorelaxation effect through the multiple signalling pathways. In this study, the in vitro vascular response of the synthesized trans-stilbenoid derivatives, SB 1-8e were primarily evaluated by employing the phenylephrine (PE)-precontracted endothelium-intact isolated aortic rings. Herein we report trans-3,4,4'-trihydroxystilbene (SB 8b) exhibited surprisingly more than 2-fold improvement to the maximal relaxation (Rmax) of RV. This article also highlights the characterization of the aromatic protons in terms of their unique splitting patterns in 1H NMR.

Synthesis, characterization, and anti-cancer activity of new chalcone derivatives containing naphthalene and fluorine moieties.

In recent years, chalcones and their derivatives have become the focus of global scientists due to increasing evidence reported towards their potency in antitumor and anti-cancer. Here, the chalcones designed and synthesized in our present study were derived from the derivatives of naphthaldehyde and acetophenone. Both these precursors have been reported in demonstrating a certain degree of anticancer property. Also, the substituents on these precursors such as hydroxyl, methoxy, prenyl, and chloro were shown able to enhance the anticancer efficiency. Hence, it is the interest of the current study to investigate the anticancer potential of the hybrid molecules (chalcones) consisting of these precursors with different alkoxy substituents and with or without the fluorine moiety. Two series of chalcone derivatives were designed, synthesized, and characterized using the elemental analysis, IR, 1 H and 13 C NMR spectroscopy, subsequently evaluated for their anti-cancer activity. Interestingly, the results showed that the fluorinated chalcones 11-15 exhibited stronger cytotoxic activity towards the breast cancer cell lines (4T1) compared to non-fluorinated chalcone derivatives. Remarkably, the selectivity index obtained for these fluorinated chalcones derivatives against the breast cancer 4T1 cell line was higher than those exhibited by cisplatin, which is one of the most frequently deployed chemotherapy agents in current medical practice. These findings could provide an insight towards the potential of fluorinated chalcones being developed as an anti-cancer agent with moderate activity towards breast cancer cell and low inhibition of fibroblast cell at a concentration of 100 µM.

Overview of Neurological Mechanism of Pain Profile Used for Animal "Pain-Like" Behavioral Study with Proposed Analgesic Pathways.

Pain is the most common sensation installed in us naturally which plays a vital role in defending us against severe harm. This neurological mechanism pathway has been one of the most complex and comprehensive topics but there has never been an elaborate justification of the types of analgesics that used to reduce the pain sensation through which specific pathways. Of course, there have been some answers to curbing of pain which is a lifesaver in numerous situations-chronic and acute pain conditions alike. This has been explored by scientists using pain-like behavioral study methodologies in non-anesthetized animals since decades ago to characterize the analgesic profile such as centrally or peripherally acting drugs and allowing for the development of analgesics. However, widely the methodology is being practiced such as the tail flick/Hargreaves test and Von Frey/Randall-Selitto tests which are stimulus-evoked nociception studies, and there has rarely been a complete review of all these methodologies, their benefits and its downside coupled with the mechanism of the action that is involved. Thus, this review solely focused on the complete protocol that is being adapted in each behavioral study methods induced by different phlogogenic agents, the different assessment methods used for phasic, tonic and inflammatory pain studies and the proposed mechanism of action underlying each behavioral study methodology for analgesic drug profiling. It is our belief that this review could significantly provide a concise idea and improve our scientists' understanding towards pain management in future research.

New flavonoid-based compound synthesis strategy for antihypertensive drug development.

Hypertension is one of the leading causes of mortality in relation to the cardiovascular conditions and easily the most overlooked and poorly managed disease in mankind. With well over 200 drugs available in the market globally, there is still an urgency to search for antihypertensive alternatives due to the subpar efficacy and unwarranted side effects of the current choices. Present studies reported over 250 types of plant-derived compounds were being investigated for potential pharmacological effects on the vasculature in the last 3 decades. There were numerous literatures that claimed various compounds exhibiting vasorelaxant properties to a certain extent with low numbers of these compounds being successfully adapted into the current medicinal practice for treatment of hypertension. The issue is the scarcity of reviews that summarizes the discovery of this field and the lack of thorough comparison of these compounds to identify which of these vasodilators should be the next face of hypertension management. Thus, this review is aiming towards identifying the relationship between a major class of plant-derived compounds, flavonoid's activity as a vasodilator with their signalling pathways and their structural characteristics according to their vasorelaxant properties. Interestingly, we found that both nitric oxide and voltage-operated calcium channels pathways, and two of the flavonoid's structural characteristics play crucial roles in eliciting strong vasorelaxant effects. We have faith that the insights of this review will serve as a reference for those researching similar topics in the future and potentially lead to the development of more promising antihypertensive alternative.

Orthogonal Stimulus-Response as a Tool to Formulate Traditional Chinese Medicinal Herbal Combination: - New Scientific-Based TCM Herbal Formulating Method.

OBJECTIVES: There is an increasing number of complex diseases that are progressively more difficult to be controlled using the conventional "single compound, single target" approach as demonstrated in our current modern drug development. TCM might be the new cornerstone of treatment alternative when the current treatment option is no longer as effective or that we have exhausted it as an option. Orthogonal stimulus-response compatibility group study is one of the most frequently employed formulas to produce optimal herbal combination for treatment of multi-syndromic diseases. This approach could solve the relatively low efficacy single drug therapy usage and chronic adverse effects caused by long terms administration of drugs that has been reported in the field of pharmacology and medicine. METHODS: The present review was based on the Science Direct database search for those related to the TCM and the development of antihypertensive TCM herbal combination using orthogonal stimulus-response compatibility group studies approach. RESULTS: Recent studies have demonstrated that the orthogonal stimulus-response compatibility group study approach was most frequently used to formulate TCM herbal combination based on the TCM principles upon the selection of herbs, and the resulting formulated TCM formula exhibited desired outcomes in treating one of global concerned complex multi-syndromic diseases, the hypertension. These promising therapeutic effects were claimed to have been attributed by the holistic signaling mechanism pathways employed by the crude combination of herbs. CONCLUSION: The present review could serve as a guide and prove the feasibility of TCM principles to be used for future pharmacological drug research development.

Synthesis and discovery of new bisadducts derived from heterocyclic aldehydes and active methylene compounds as potent antitubercular agents.

A series of some new bisadducts possessing five, six membered and coumarin subunits were synthesized by the condensation of heterocyclic aldehydes with active methylene compounds and characterized by IR, NMR and X-ray crystallographic studies and were assayed as antitubercular agents. Among the bisadducts, 4-hydroxy-3-[(4-hydroxy-2-oxo-2H-3-chromenyl)(3-thienyl)methyl]-2H-2-chromenone 3a was found to be the most promising compound, active against Mycobacterium tuberculosis (Mtb) H37Rv and isoniazid resistant Mycobacterium tuberculosis (INHR-Mtb) with minimum inhibitory concentration 5.22 and 8.34 microM, respectively.

9-(7-Fluoro-4-oxo-4H-chromen-3-yl)-3,3,6,6-tetra-methyl-2,3,4,5,6,7,8,9-octa-hydro-1H-xanthene-1,8-dione.

In the title compound, C(26)H(25)FO(5), the terminal cyclo-hexane rings of the xanthene ring system adopt half-boat conformations. The 4H-chromene ring make a dihedral angle of 87.94 (5)° with the xanthene ring system and its carbonyl O atom lies above the xanthene O atom. In the crystal, mol-ecules are linked into ribbons propagating along the a-axis direction by C-H⋯O hydrogen bonds. Aromatic π-π stacking inter-actions [centroid-centroid distance = 3.7367 (12) Å] also occur.

2-[(E)-(2,4-Dichloro-benzyl-idene)amino]-isoindoline-1,3-dione.

In the title compound, C(15)H(8)Cl(2)N(2)O(2), the mol-ecule adopts an E configuration about the central C=N double bond. The isoindoline ring is essentially planar, with a maximum deviation of 0.019 (2) Å. The dihedral angle between the isoindoline ring and the dichloro-substituted benzene ring is 6.54 (9)°. An intra-molecular C-H⋯O hydrogen bond occurs. A short Cl⋯Cl contact of 3.4027 (9) Šis present in the crystal structure. The crystal packing is further stabilized by weak C-H⋯π inter-actions.

3-Hydroxy-2-[(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)(thiophen-3-yl)methyl]-5,5-dimethylcyclohex-2-en-1-one.

The asymmetric unit of the title compound, C(21)H(26)O(4)S, consists of two independent mol-ecules. In both mol-ecules, intra-molecular O-H⋯O hydrogen bonds stabilize the mol-ecular structure. In the crystal, each mol-ecule and its symmetry-related mol-ecule by twofold rotation form a dimer through a pair of inter-molecular C-H⋯O hydrogen bonds. In one of the mol-ecules, the thio-phene group is disordered over two sets of sites with occupancies of 0.735 (3) and 0.265 (3).

7-Fluoro-4-oxochromene-3-carbaldehyde.

In the title compound, C(10)H(5)FO(3), the chromenone ring is essentially planar, with a maximum deviation of 0.039 (1) Å. The dihedral angle between the fluoro-subsituted benzene ring and the pyran ring is 1.92 (4)°. In the crystal, mol-ecules are connected via weak inter-molecular C-H⋯O hydrogen bonds, forming supra-molecular ribbons along the b axis. These ribbons are stacked down the a axis.

4-Hy-droxy-3-[(4-hy-droxy-2-oxo-2H-3-chromen-yl)(3-thien-yl)meth-yl]-2H-chromen-2-one.

The whole mol-ecule of the title compound, C(23)H(14)O(6)S, is disordered over two sets of sites with refined occupancies of 0.8733 (12):0.1267 (12). The dihedral angle between the mean planes through the chromene ring systems is 56.31 (5) and 55.2 (3)° for the major and minor components, respectively. In both components, a pair of intra-molecular O-H⋯O inter-actions generate rings of S(8) graph-set motif. In the crystal, the mol-ecules are linked by inter-molecular C-H⋯O inter-actions, forming chains along the b axis. The structure is further stabilized by π-π inter-actions with centroid-centroid distances of 3.594 (2) and 3.608 (5) Å.

3-[5-(2,4-Dichloro-phen-yl)-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl]-4-hy-droxy-2H-chromen-2-one.

In the title compound, C(24)H(16)Cl(2)N(2)O(3), the chromene ring system is almost planar, with a maximum deviation of 0.042 (1) Å. It makes dihedral angles of 3.72 (6), 73.37 (5) and 12.00 (5)° with the dihydro-pyrazole, benzene and phenyl rings, respectively. An intra-molecular O-H⋯N hydrogen bond forms an S(6) ring motif. In the crystal, mol-ecules are linked via C-H⋯O inter-actions, forming an infinite chain along the a axis. The crystal packing is further stabilized by a π-π stacking inter-action [centroid-centroid distance = 3.5471 (7) Å] and a Cl⋯Cl short contact [Cl⋯Cl = 3.214 (1) Å].

4-Hy-droxy-3-[(4-hy-droxy-6-methyl-2-oxo-3,6-dihydro-2H-pyran-3-yl)(3-thien-yl)meth-yl]-6-methyl-3,6-dihydro-2H-pyran-2-one.

The asymmetric unit of the title compound, C(17)H(14)O(6)S, contains four crystallographically independent mol-ecules in which the pyran-one units are essentially planar, with maximum deviations of 0.016 (2), 0.019 (2), 0.025 (2), 0.014 (2), 0.020 (2), 0.010 (2), 0.003 (2) and 0.012 (2) Å. One of the thio-phene rings is disordered over two positions, with an occupancy ratio of 0.739 (4):0.261 (4). The dihedral angles between the two pyran-one rings in the independent mol-ecules are 59.42 (8), 48.67 (8), 60.62 (9) and 51.60 (8)°. In the crystal, mol-ecules are linked through inter-molecular O-H⋯O and C-H⋯O hydrogen bonds, forming a three-dimensional network.

4-[(E)-(4-Hy-droxy-2-oxo-2H-chromen-3-yl)methyl-idene-amino]-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one monohydrate.

In the title compound, C(21)H(17)N(3)O(4)·H(2)O, the coumarin ring system is almost planar (r.m.s. deviation = 0.002 Å) and makes dihedral angles of 1.50 (7) and 57.75 (7)° with the pyrazole and phenyl rings, respectively. The dihedral angle between the pyrazole and phenyl rings is 56.60 (9)°. The pyrazole ring adopts a twisted comformation. The mol-ecular conformation is stabilized by intra-molecular N-H⋯O and C-H⋯O hydrogen bonds, both of which form S(6) ring motifs. In the crystal, each water mol-ecule is linked to its adjacent organic mol-ecule via pairs of O-H⋯O hydrogen bonds. The packing is further consolidated by pairs of inter-molecular C-H⋯O hydrogen bonds, which link the mol-ecules into dimers; the dimers are stacked along the b axis.

4-Hy-droxy-3-[(4-hy-droxy-6,7-dimethyl-2-oxo-2H-chromen-3-yl)(4-oxo-4H-chromen-3-yl)meth-yl]-6,7-dimethyl-2H-chromen-2-one.

In the title compound, C(32)H(24)O(8), the mol-ecular structure is disordered over two positions with refined site occupancies of 0.8746 (10) and 0.1254 (10). The mean plane of the three chromeno rings make dihedral angles with each other of 65.12 (4), 62.91 (4) and 59.70 (4)° in the major occupancy component and 59.1 (3), 66.1 (3) and 58.8 (3)° in the minor component. Intra-molecular O-H⋯O hydrogen bonds stabil-ize the mol-ecular structure and the crystal structure is stabilized by weak C-H⋯π and π-π inter-actions [centroid-centroid distances 3.496 (6)-3.672 (7) Å].