Novel N-substituted indole hydrazones as potential antiplatelet agents: synthesis, biological evaluations, and molecular docking studies.

BACKGROUND AND PURPOSE: Antiplatelet agents can diminish the chance of coronary heart diseases due to the prevention of unusual clotting in the arteries by inhibiting platelet aggregation and avoiding the formation of a blood clot. This mechanism can help to prevent ischemic stroke likewise. To improve the activity of these drugs and reduce their side effects, further studies are required. EXPERIMENTAL APPROACH: Based on the previous studies representing the promising antiplatelet activity of indole hydrazones, a series of their homologs containing twenty-one compounds were prepared in two steps. First, alkylation reaction on the nitrogen of the indole ring, and second, chiff base formation by condensation of a primary amine and N-substituted indole-3 carbaldehyde. Consequently, their platelet anti-aggregation activity was evaluated based on the Born turbidimetric method. FINDINGS/RESULTS: Most of the compounds exhibited noticeable activity against platelet aggregation induced by arachidonic acid. Amongst them, two compounds 2e and 2f showed higher activity with IC50 values that made comparable to indomethacin and acetylsalicylic acid as standard drugs and had no toxicity on platelets. CONCLUSION AND IMPLICATIONS: The synthesized compounds exhibited promising activity against arachidonic acid-induced aggregation; however, none of them showed noticeable antiplatelet activity induced by adenosine di-phosphate. Chemical structure comparison of the prepared derivatives indicated the existence of a lipophilic medium-sized group on the phenyl ring increased their activity. In addition, the docking studies confirmed this hydrophobic interaction in the lipophilic pocket of cyclooxygenase-1 enzyme suggesting that hydrophobicity of this region plays a pivotal role in the anti-platelet activity of these compounds. To prove this finding, the enzymatic evaluation with the target enzyme is required.

Discovery of novel isatin-based thiosemicarbazones: synthesis, antibacterial, antifungal, and antimycobacterial screening.

BACKGROUND AND PURPOSE: A group of thiosemicarbazones were prepared and their structures were confirmed by spectroscopic methods such as IR and H-NMR, mass spectrometry and also analytical method like elemental analysis. The synthesized semicarbazones were then assessed for their inhibitory activity against bacterial strains including Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus epidermidis, Bacillus cereus, Salmonella species, Enterobacter faecalis, methicillin-resistant Staphylococcus aureus, and fungi such as Candida albicans and Aspergillus niger. EXPERIMENTAL APPROACH: The schiff bases of isatin (2a-j) were prepared by a condensation reaction between thiosemicarbazide and substituted N-aryl isatins leading to the desired thiosemicarbazones with exquisite purity. FINDINGS / RESULTS: The results disclosed that all compounds have noticeable inhibitory activity. Compounds 2a, 2b, 2c, 2g, and 2h were among the most potent derivatives against Gram negative bacteria and fungi. Besides, the activity of theses compounds were tested against Mycobacterium bovis bacillus Calmette-Guerin (M. bovis BCG). The antimycobacterial activity indicated compounds 2e and 2j are highly active against M. bovis BCG (minimum inhibitory concentration < 3.9 µg/mL). Among fluorinated structures, compounds 2a and 2j showed the best activities against M. bovis BCG. CONCLUSION AND IMPLICATIONS: To sum up, amongst the 10 synthesized compounds, fluorinated derivatives exhibited remarkable activities against both gram negative strains and candida albicans microorganism. Therefore, they should be considered as a clue for further modifications in next investigations. Furthermore, inserting a small/medium size halogen atom with electron-withdrawing and lipophilic properties increases anti- salmonella activity of these compounds and moreover 2-halogenated semithiocarbazones presented promising antimycobacterial activity.

Protective Effects of Cydonia oblonga Mill. Fruit on Carbon Tetrachloride-induced Hepatotoxicity Mediated through Mitochondria and Restoration of Cellular Energy Content.

Quince (Cydonia oblonga Mill.) is one of the medicinal plant with a broad range of pharmacological activities such as hepatoprotective effect. The present study was conducted to evaluate the effect of aqueous extract of Cydonia oblonga Mill. fruit (ACOF) against carbon tetrachloride (CCl4)-induced liver damage in rats. Hepatotoxicity was induced by CCl4 and all tested group animals were treated with the plant extract at a dose of 75, 150, and 300 mg/kg orally for 5 days. Blood was collected for the assessment of serum marker enzymes (alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH)). Adenosine triphosphate (ATP) of liver mitochondria was also measured using a validated high performance liquid chromatography (HPLC) method. The antioxidant capacity of the extract resulted in the reduction of MDA and the restoration of GSH in the liver (P < 0.05). Free radical scavenging activity of the extract was evaluated by DPPH method and the IC50 value was found to be 568 µg/mL. Our results indicated that bioenergetic depletion occurred in the intoxicated rats as a consequence of mitochondrial dysfunction and ATP production collapse. ACOF markedly restored ATP contents that is a key step in liver regeneration. It can be concluded that the role of ACOF to improve liver function on CCl4-hepatoxicity could be attributed, at least partially, to its action at mitochondira by preventing the loss of ATP content.

Synthesis, Antiplatelet Activity and Cytotoxicity Assessment of Indole-Based Hydrazone Derivatives.

A series of indole-based aryl(aroyl)hydrazone analogs of antiplatelet indole-3-carboxaldehyde phenylhydrazone were synthesized by the Schiff base formation reaction and their antiplatelet activity was assessed using human platelet rich plasma. The platelet concentrate was obtained using a two-step centrifugation protocol and ADP, arachidonic acid and collagen were used as inducers of platelet aggregation. Based on the results, substituted phenylhydrazones showed promising activity. Among them, compound 1i was the most potent derivative with an IC50 comparable to that of indomethacin as a standard drug. The hydrazone derivatives were also tested for their cytotoxicity using on platelet concentrates and fibroblast L929 cells. The majority of the derivatives showed an acceptable selectivity towards antiplatelet aggregation activity. Based on the activity data, phenylhydrazone derivatives (1a-i) exhibited considerable antiplatelet activity and minimal toxic effect on platelet cells. The results of the present study could provide a better understanding of the structure activity relationship of antiplatelet indolehydrazones.

Determination of Mebudipine in Human Plasma by Liquid Chromatography-tandem Mass Spectrometry.

In previous studies, mebudipine, a dihydropyridine calcium channel blocker, showed a considerable potential to be used in cardiovascular diseases. The aim of the current study was to develop a valid method using reversed-phase high performance liquid chromatography coupled with electrospray ionization mass spectrometry to assay mebudipine in the human plasma. Separation was achieved on a Zorbax Eclipse(®) C18 analytical column using a mobile phase consisted of methanol/water (90:10, v/v). The flow rate was 0.6 mL/min and carbamazepine was used as an internal standard (IS). This method involved the use of [M +Na](+) ions of mebudipine and IS at m/z 411 and 259, respectively with the selected ion monitoring (SIM) mode. There were no interfering peaks from endogenous components in blank plasma chromatograms. Standard curves were linear (r(2)>0.99) between 5 to 100 ng/mL. The mean extraction efficiency was about 84% and the limit of quantification for mebudipine was 5 ng/mL in plasma. The coefficient of variation and error at all of the intra-day and inter-day assessments were less than 11%. The results indicated that this method is a fast, accurate, sensitive, selective and reliable method for the determination of mebudipine in the human plasma. The assay method has been successfully used to estimate plasma concentration of mebudipine after the oral administration of 2.5 mg tablet in healthy adults.

Synthesis and Antiplatelet Aggregation Activity Evaluation of some 2-Aminopyrimidine and 2-Substituted-4,6-diaminopyrimidine Derivatives.

A series of novel 2-aminopyrimidine and 2-Substituted-4,6-diaminopyrimidine derivatives have been synthesized and their antiplatelet aggregation activities were assessed against ADP and arachidonic acid-induced platelet aggregation in human plasma using light transmission aggregometry. Among the tested derivatives, compounds Ia, Ib, IB and II16 exhibited the highest antiplatelet aggregation activity (36.75, 72.4, 62.5 and 80 µM). None of the compounds showed satisfactory activity against the aggregation induced by ADP but acceptable activities were observed against the aggregation induced by arachidonic acid. 2- aminopyrimidines were more active than 4,6- diaminopyrimidines in this respect.

Synthesis, dihydrofolate reductase inhibition, anti-proliferative testing, and saturation transfer difference ¹H-NMR study of some new 2-substituted-4,6-diaminopyrimidine derivatives.

A series of 2-substituted-4,6-diaminipyrimidine derivatives were synthesized and evaluated for their dihydrofolate reductase (DHFR) inhibitory activity. Saturation transfer difference (STD) (1)H-NMR experiments were used to probe the binding characteristics of the compounds with human DHFR enzyme. The most potent molecules, 12 and 15, in enzyme assay study showed the best results in STD experiments indicating their intimate interaction with the receptor. The docking studies were followed to explain the structural basis for the observed interaction between the ligands and DHFR. All the compounds were also assayed in vitro for their growth inhibitory activity on MCF-7, HepG2, SKHep1, and Hela tumor cell lines. Compounds 16, 17, and 22 demonstrated the most potent in vitro anti-proliferative activity among the others.

Design and synthesis of new 2-substituted-5-[2-(2-halobenzyloxy)phenyl]-1,3,4-oxadiazoles as anticonvulsant agents.

A new series of 2-substituted-5-[2-(2-halobenzyloxy)phenyl]-1,3,4-oxadiazoles was designed and synthesized as anticonvulsant agents. Electroshock and pentylenetetrazole-induced lethal convulsion tests showed that the introduction of an amino group at position 2 of 1,3,4-oxadiazole ring and a fluoro substituent at ortho position of benzyloxy moiety had the best anticonvulsant activity. Our results showed that this effect is mediated through benzodiazepine receptors mechanism.