Synthesis and leishmanicidal activity of cinnamic acid esters: structure–activity relationship

Several cinnamic acid esters were obtained via Fischer esterification of cinnamic acids derivatives with aliphatic alcohols. Structures of the products were elucidated by spectroscopic analysis. The synthesized compounds were evaluated for antileishmanial activity against L. (V) panamensis amastigotes and cytotoxic activity was evaluated against mammalian U-937 cells. The compounds 11, 15–17, and 23, were active against Leishmania parasite and although toxic for mammalian cells, they still are potential candidates for antileishmanial drug development. A SAR analysis indicates that first, while smaller alkyl chains lead to higher selectivity indices (10, 11 vs. 12–17); second, the degree of oxygenation is essential for activity, primarily in positions 3 and 4 (17 vs. 18–20 and 22); and third, hydroxyl groups increase both activity and cytotoxicity (14 vs. 23). On the other hand, the presence of a double bond in the side chain is crucial for cytotoxicity and leishmanicidal activity (12 vs. 21). However, further studies are required to optimize the structure of the promising molecules and to validate the in vitro activity against Leishmania demonstrated here with in vivo studies.     

Structure–activity relationships of bumetanide derivatives: correlation between diuretic activity in dogs and inhibition of the human NKCC2A transporter

Background and Purpose

The N-K-Cl cotransporters (NKCCs) mediate the coupled, electroneutral movement of Na⁺, K⁺ and Cl⁻ ions across cell membranes. There are two isoforms of this cation co-transporter, NKCC1 and NKCC2. NKCC2 is expressed primarily in the kidney and is the target of diuretics such as bumetanide. Bumetanide was discovered by screening ∼5000 3-amino-5-sulfamoylbenzoic acid derivatives, long before NKCC2 was identified in the kidney. Therefore, structure–activity studies on effects of bumetanide derivatives on NKCC2 are not available.

Experimental Approach

In this study, the effect of a series of diuretically active bumetanide derivatives was investigated on human NKCC2 variant A (hNKCC2A) expressed in Xenopus laevis oocytes.

Key Results

Bumetanide blocked hNKCC2A transport with an IC₅₀ of 4 μM. There was good correlation between the diuretic potency of bumetanide and its derivatives in dogs and their inhibition of hNKCC2A (r² = 0.817; P < 0.01). Replacement of the carboxylic group of bumetanide by a non-ionic residue, for example, an anilinomethyl group, decreased inhibition of hNKCC2A, indicating that an acidic group was required for transporter inhibition. Exchange of the phenoxy group of bumetanide for a 4-chloroanilino group or the sulfamoyl group by a methylsulfonyl group resulted in compounds with higher potency to inhibit hNKCC2A than bumetanide.

Conclusions and Implications

The X. laevis oocyte expression system used in these experiments allowed analysis of the structural requirements that determine relative potency of loop diuretics on human NKCC2 splice variants, and may lead to the discovery of novel high-ceiling diuretics.     

Synthesis and structure–activity relationship of nuciferine derivatives as potential acetylcholinesterase inhibitors

Acetylcholinesterase inhibitors (AChEIs) are currently the best available pharmacotherapy for Alzheimer patients, but because of bioavailability issues, there is still great interest in discovering better AChEIs. The aporphine alkaloid is an important class of natural products, which shows diverse biological activity, such as acetylcholinesterase inhibitory activity. To find new lead AChEIs compounds, eight aporphine alkaloids were synthesized by O-dealkylation, N-dealkylation, and ring aromatization reactions using nuciferine as raw material. The anti-acetylcholinesterase activity of synthesized compounds was measured using modified Ellman’s method. The results showed that some synthesized compounds exhibited higher affinity to AChE than the parent compound nuciferine. Among these compounds, 1,2-dihydroxyaporphine (2) and dehydronuciferine (5) were the most active compounds (IC₅₀ = 28 and 25 μg/mL, respectively). Preliminary analysis of structure–activity relationships suggested that aromatization of the C ring, the presence of the alkoxyl group at C1 and the hydroxy group at C2 position as well as the alkyl substituent at the N atom were favorable to the acetylcholinesterase inhibition. Molecular docking was also applied to predict the binding modes of compounds 1, 2, and 9 into the huperzine A binding site of AChE.     

Structure–toxicity relationship and structure–activity relationship study of 2-phenylaminophenylacetic acid derived compounds

2-Phenylaminophenylacetic acid is a widely-exploited chemical scaffold whereby notable NSAIDs such as diclofenac and lumiracoxib were derived. Yet, their clinical usage has been associated with toxicities in the liver. While some studies have attributed toxicities to the bioactivation of both drugs to reactive intermediates, the structural predisposition for toxicity, as well as relationship between this toxicity and COX inhibitory activity has not been elucidated. In this study, we aimed to address their intricate link by synthesizing compounds that possess the 2-phenylaminophenylacetic acid backbone with varying alkyl and halogen substituents at three positions critical to the COX inhibitory pharmacophore. These compounds were subjected to cytotoxicity testing on two liver cell lines of contrasting metabolic competencies. We observed higher toxicity in the more metabolically competent cell line, supporting the role of bioactivation as a prerequisite for toxicity. We have also shown that structural changes on the chemical scaffold exerted pronounced effect on liver cytotoxicity. The most lipophilic and brominated compound (24) was identified as the most cytotoxic of all the compounds. A concurrent determination of their pharmacological activity using COX inhibition assays allowed us to derive a safety profile, which showed that selectivity towards COX-2 negatively affected activity and toxicity.     

Synthesis and analgesic activity of new α-truxillic acid derivatives with monoterpenoid fragments

Novel derivatives of α-truxillic acid with a camphor framework were synthesized and evaluated for their in vivo analgesic activity. α-Truxillic acid derivatives were prepared via solvent-free photocatalyzed [2+2] cyclodimerization of (E)-cinnamic acid. Target compounds were obtained through the substitution of –Cl or –OH groups in α-truxillic acid. The chemical structures of the synthesized compounds were elucidated by ¹H, ¹³C-NMR, and mass spectrometry. Their analgesic activities were evaluated by the acetic acid-induced writhing test and the hot plate method. Compounds 7b and 7f containing the cyclobutane unit and natural fragments at 10 mg/kg exhibited analgesic activity in the acetic acid-induced writhing test, while α-truxillic acid (10 mg/kg, per os) did not show analgesic activity in the test. Intermediate 2 caused a decrease in the writhing with pain inhibition of 28 %. In the hot plate test, borneol showed high analgesic activity with pain inhibition of 60 %.     

Synthesis and structure–activity relationships of serotonin derivatives effect on α-glucosidase inhibition

The α-glucosidase inhibitory activities of serotonin derivatives were evaluated. Two serotonin derivatives, N-p-coumaroyl serotonin (2) and N-caffeoyl serotonin (4) exhibited most potent inhibition on α-glucosidase, whereas, cinnamic acid derivatives were less efficient. Furthermore, we analyzed their structural importance for α-glucosidase inhibition. The linkage of cinnamic acid moiety and serotonin moiety and the olefin in cinnamic acid moiety of serotonin derivatives were crucial for α-glucosidase inhibition. This is the first report on structure–activity relationships (SAR) for the α-glucosidase inhibitory activity of serotonin derivatives.     

Structure–activity relationships and evaluation of esterified diterpenoid alkaloid derivatives as antiproliferative agents

Journal of Natural Medicines - Diterpenoid alkaloids with remarkable chemical properties and biological activities are frequently found in plants of the genera Aconitum, Delphinium, and Garrya....     

Synthesis of new phenylcarbamoylbenzoic acid derivatives and evaluation of their in?vitro antioxidant activity

In this study, new derivatives of phenylcarbamoylbenzoic acid were synthesized and evaluated for their in?vitro antioxidant activity. The target compounds were prepared by bonding pharmacophoric moieties possessing antioxidant activity, including hydrazones, acid hydrazides, imino, Schiff’s bases, and phthalimides with phenylcarbamoylbenzoic acid via simple and efficient synthetic strategies. The structures of the newly synthesized compounds were confirmed by physical and spectral data. The in?vitro antioxidant activity was carried out using ABTS antioxidant assay. All the tested compounds showed low antioxidant activity except compound 7, which showed moderate antioxidant activity compared with ascorbic acid.     

Synthesis,antibacterial and antifungal activities of naphthoquinone derivatives: a structure–activity relationship study

The synthesis of 1,4-naphthoquinone derivatives is of great interest since these compounds exhibit strong activity as antimalarial, antibacterial, antifungal and anticancer agents. A series of 50 naphthoquinone derivatives was synthesized and evaluated for antibacterial and antifungal activity against Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis, Staphylococcus aureus, Candida krusei, Candida parapsilosis and Cryptococcus neoformans using the broth microdilution method. The Candida species were the most susceptible microorganisms. Halogen derivatives of 1,4-naphthoquinone presented strong activity, e.g., 2-bromo-5-hydroxy-1,4-naphthoquinone, which exhibited inhibition at an MIC of 16 µg/mL in S. aureus, and 2-chloro-5,8-dihydroxy-1,4-naphthoquinone, with an MIC of 2 µg/mL in C. krusei. These compounds showed higher activity against fungi, but the antibacterial activities were very low. The study of structure–activity relationships is very important in the search for new antimicrobial drugs due to the limited therapeutic arsenal.     

Structure–property relationships in series of natural and synthetic inhibitors of catalytic activity of 15-lipoxygenase

Structural signatures characteristic of high-, medium-, and low-efficiency inhibitors of the catalytic activity of 15-lipoxygenase (15-LOG) have been revealed using the SARD-21 (Structure Activity Relationship & Design) computer system. The degree of their influence on the efficiency of the inhibiting activity was estimated. Based on these data, two models are constructed for predicting the interval of LOG-inhibiting activity of various sulfur-, nitrogen-, and oxygen-containing heterocyclic compounds with an 80% prediction accuracy level for the two recognition methods. The revealed structural features can be used to construct highly selective inhibitors of 15-LOG catalytic activity.     

Serotonin transporter activity of imidazolidine-2,4-dione and imidazo[2,1-f]purine-2,4-dione derivatives in aspect of their acid–base properties

Affinities of arylpiperazinylalkyl derivatives of imidazo[2,1-f]purine-2,4-dione and imidazolidine-2,4-dione for serotonin transporter and their acid–base properties were evaluated. The dissociation constant (pK _a) of compounds 1–22 were determinated by potentiometric titration and calculated using pKalc 3.1 module of the Pallas system. The data from experimental methods and computational calculations were compared and suitable conclusions were reached.     

Structure–activity relationships and the cytotoxic effects of novel diterpenoid alkaloid derivatives against A549 human lung carcinoma cells

The cytotoxicity of three alkaloids from the roots of Aconitum yesoense var. macroyesoense as well as 36 semi-synthetic C₂₀-diterpenoid atisine-type alkaloid derivatives against A549 human lung carcinoma cells was examined. Ten acylated alkaloid derivatives, pseudokobusine 11-veratroate (9), 11-anisoate (12), 6,11-dianisoate (14), 11-p-nitrobenzoate (18), 11,15-di-p-nitrobenzoate (22), 11-cinnamate (25) and 11-m-trifluoromethylbenzoate (27), and kobusine 11-p-trifluoromethylbenzoate (35), 11-m-trifluoromethylbenzoate (36) and 11,15-di-p-nitrobenzoate (39), exhibited cytotoxic activity, and 11,15-dianisoylpseudokobusine (16) was found to be the most potent cytotoxic agent. Their IC₅₀ values against A549 cells ranged from 1.72 to 5.44 μM. In the occurrence of cytotoxic effects of atisine-type alkaloids, replacement by an acyl group at both C-11 and C-15 resulted in the enhancement of activity of the parent alkaloids compared to that from having hydroxy groups at this position, and the presence of a hydroxy group at the C-6 position was required for the cytotoxic effects. These acylated alkaloid derivatives inhibit cell growth through G1 arrest.     

Structure–activity relationship studies of indolin-2-one derivatives as vascular endothelial growth factor receptor inhibitors and anticancer agents

Angiogenesis is a requirement for the growth of cancer cells. The family of vascular endothelial growth factor receptors (VEGFRs) is the main target in metastasis. Indolin-2-one is proved to be an essential scaffold of antiangiogenic drugs. Sunitinib is the first oral indolin-2-one derivative marketed as a VEGFR inhibitor in the treatment of renal cell carcinoma and gastrointestinal stromal tumors. Therefore, novel compounds possessing the scaffold of sunitinib were designed and synthesized by different researchers to improve the anticancer activity, bioavailability, and solubility, and to decrease the toxicity of sunitinib. In this comprehensive review, the structure–activity relationship of different indolin-2-one analogs as VEGFR inhibitors is discussed. It has been observed that the indolin-2-one core is necessary for the inhibition of VEGFRs. It was determined that substitutions at C-3 of the oxindole ring play an important role in their antiangiogenic and anticancer activities.     

Aqueous extract of Securidaca longipendunculata Oliv. and Olax subscropioidea inhibits key enzymes (acetylcholinesterase and butyrylcholinesterase) linked with Alzheimer’s disease in vitro

Context: Plants have historically been used to treat neurodegerative diseases which include Alzheimer’s disease.

Objective: This study investigated the antioxidant properties and inhibitory effect of aqueous extracts of Securidaca longipendunculata root and Olax subscropioidea leaf on the cholinergic system in rat brain in vitro.

Materials and methods: Aqueous extracts (1:20 w/v) of S. longipendunculata root and O. subscropioidea leaf was prepared and the ability of the extract to inhibit the activities of acetylcholinesterase and butyrylcholinesterase was evaluated as well as antioxidants as typified by 2,2-azino-bis-(3-ethylbenthiazoline-6-sulphonic acid (ABTS^?) radical scavenging ability and Fe chelation spectophotometrically.

Results: ABTS^? radical scavenging ability showed that S. longipendunculata (0.075?Mmol TEAC/100?g) had a higher scavenging ability than O. subscropioidea (0.07?Mmol TEAC/100?g). Also, the Fe^2+?chelating ability of both extracts revealed that S. longipendunculata (IC_50?=_?105.57?g/mL) had a significantly (p?2+?chelating ability than O. subscropioidea (IC_50?=_?255.84?g/mL). Extracts of S. longipendunculata and O. subscropioidea inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities. However, S. longipendunculata (IC_50?=_?108.02?g/mL) has the higher AChE inhibitory activity than O. subscropioidea (IC_50?=_?110.35?g/mL). Also, both extracts inhibit BChE activity in vitro but S. longipendunculata (IC_50?=_?82.55?g/mL) had a higher BChE inhibitory activity than O. subscropioidea (IC_50?=_?108.44?g/mL).

Discussion and conclusions: The mechanism by which S. longipendunculata root and O. subscropioidea leaf perform their anti-Alzheimer’s disease activity may be by their inhibition on the key enzymes linked to this disease.     

Association of hospital pharmacy–related knowledge and skills with occupational stress of clinical pharmacists in tertiary hospitals of China

ObjectiveOccupational stress of health care providers may lower the quality of care. Person-environment fit theory and practical evidence have indicated that various types of knowledge and skills of health care providers are differentially associated with occupational stress. Clinical pharmacists are an indispensable part of medical teams. Clinical pharmacists in China are generally under high occupational stress, but what kind of knowledge and skills can relieve their occupational stress remains unclear. This study aimed to assess the association between the specific knowledge and skills of clinical pharmacists and their occupational stress in China. This study aimed to assess the association between the specific knowledge and skills of clinical pharmacists and their occupational stress in China.MethodsA field questionnaire survey using a stratified sampling was conducted to gather data on occupational stress, knowledge and skills related to hospital pharmacy, and other factors of occupational stress using the Brief Job Stress Questionnaire and a self-developed instrument. Ordinary least squares regression was used to evaluate the association of the participants’ knowledge, skills, and other factors with their occupational stress.ResultsA total of 625 clinical pharmacists from 311 tertiary hospitals in China (response rate = 84%) participated. Knowledge of or skills related to pharmaceutical care service provision (P = 0.02), the use of computers and the Internet in pharmacy practice (P = 0.02), interpersonal communication (P = 0.10), or pharmacoepidemiology (P = 0.08) was associated with reduced occupational stress of the participants. Participants who had credentials of nation-level specialized (P = 0.09) and general training (P = 0.04) for clinical pharmacist had lower degrees of occupational stress than those without these credentials. The participants’ clinical professions, routine tasks, technical titles, and type of hospital they work in were also associated with their occupational stress.ConclusionEnhancing several aspects of knowledge or skills among clinical pharmacists in tertiary hospitals in China may help reduce their occupational stress. Efforts are needed to improve the education and training system of clinical pharmacists in China.     

Synthesis and biological activities of Schiff bases of gabapentin with different aldehydes and ketones: a structure–activity relationship study

A series of novel gabapentin derivatives 6a–k and 7a–f were synthesized, and their biological activities were determined. The chemical structures were confirmed by elemental analyses, UV–visible, FT-IR, and ¹H NMR spectral studies. The structure–activity relationships (SAR) for anticonvulsant and antioxidant activities were discussed. Compounds 7a–f were evaluated for their possible anticonvulsant activity by Maximal Electroshock Seizure (MES) test, and their neurotoxic effects were determined by rotorod test. Majority of the compounds were active in MES tests. Compounds 7b and 7e showed good protective effect from seizure when compared to standard drug, phenytoin (100 mg/kg). The same compounds showed no neurotoxicity at the maximum dose administered (100 mg/kg). Most of the novel compounds showed DPPH radical scavenging activity, where compounds 6f, 6j, and 7a were the best radical scavengers (IC₅₀ was about 60 μg/ml).