X-ray structural analysis and antitumor activity of new salicylic acid derivatives (original) (raw)
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Structural Chemistry, 2010
New salicylic (2-hydroxybenzoic) acid derivatives 1-6 were prepared by conventional heating or microwave irradiation of a mixture consisting of methyl salicylate and the corresponding amino alcohol (2,2 0 -dihydroxydiethylamine, 2,2 0 ,2 00 -trihydroxytriethylamine or N-phenyl-2,2 0dihydroxydiethylamine) and metallic sodium as catalyst. For compounds 1, 3, and 5 X-ray structure analysis was performed, as well as molecular mechanics calculations (MMC), to define their conformation in terms of their energy minima. Comparison of crystal and MMC structures for these three compounds (1, 3, and 5) revealed that the intramolecular hydrogen bonds play an important role, stabilizing conformation of the most part of the molecule. The antioxidant activity and cytotoxicity of the synthesized derivatives were evaluated in a series of in vitro tests. The newly synthesized compounds exhibited strong activity against hydroxyl radical, as well as promising lipid peroxidation inhibition. The study showed that the electronic effects of the groups at the N atom are responsible for neutralization of the OH radical, i.e., antioxidant activity. Compounds 1-3 exhibited sub-micromolar cytotoxicity against HeLa S3, whereas compounds 1, 3 and 5 efficiently inhibited the growth of PC3 cells.
Medicinal Chemistry, 2012
A series of salicylic acid analogues of celecoxib where the phenylsulfonamide moiety in the structure of celecoxib is replaced by salicylic acid moiety was synthesized and tested for in vitro cyclooxygenase (COX)-1 and COX-2 enzyme inhibition. Among the series, 5-substituted-2-hydroxy-benzoic acid analogues (7a-7h) generally showed better inhibitory activities on both enzymes than 4-substituted-2-hydroxy-benzoic acid analogues (12a-12h). In particular, the chloro analogue 7f which had the highest inhibitory effect (IC 50 0.0057 µM) to COX-1 with excellent COX-1 selectivity (SI 768) can be classified as a new potent and selective COX-1 inhibitor. The high inhibitory potency of 7f was rationalized through the docking simulation of this analogue in the active site of COX-1 enzyme.
Antioxidant and cytotoxic activity of mono- and bissalicylic acid derivatives
Acta periodica technologica, 2014
A simple synthesis of mono- and bis-salicylic acid derivatives 1-10 by the transesterification of methyl salicylate (methyl 2-hydroxybenzoate) with 3-oxapentane-1,5-diol, 3,6- dioxaoctane-1,8-diol, 3,6,9-trioxaundecane-1,11-diol, propane-1,2-diol or 1-aminopropan- 2-ol in alkaline conditions is reported. All compounds were tested in vitro on three malignant cell lines (MCF-7, MDA-MB-231, PC-3) and one non-tumor cell line (MRC- 5). Strong cytotoxicity against prostate PC-3 cancer cells expressed compounds 3, 4, 6, 9 and 10, all with the IC50 less than 10 ?mol/L, which were 11-27 times higher than the cytotoxicity of antitumor drug doxorubicin. All tested compounds were not toxic against the non-tumor MRC-5 cell line. Antioxidant activity of the synthesized derivatives was also evaluated. Compounds 2, 5 and 8 were better OH radical scavengers than commercial antioxidants BHT and BHA. The synthesized compounds showed satisfactory scavenger activity, which was studied by QSAR modeling. ...
New estrane salicyloyloxy or D-homo derivatives were synthesized under microwave (MW) or conventional heating from estrane precursors and methyl salicylate. The MW technique provides advantages regarding product yield and reaction time, and represents a more environmentally friendly approach than conventional heating. Considering the biomedical potential of estrane compounds, we evaluated the antioxidant activity and cytotoxicity of synthesized estrane derivatives in a series of in vitro tests, as well as their 3b-hydroxysteroid dehydrogenase/D 5 ? D 4 isomerase (3bHSD) and 17b-hydroxysteroid dehydrogenase types 1, 2 and 3 (17bHSD1, 17bHSD2 and 17bHSD3) inhibition potentials. In DPPH tests, 3-methoxyestra-1,3,5(10)-trien-17b-yl salicylate displayed antioxidant potential, while all compounds exhibited OH radical neutralization activity. 3-Oxoestr-4-en-17b-yl salicylate showed strong cytotoxicity against MDA-MB-231 breast cancer cells, while 17-oxoestra-1,3,5(10)trien-3-yl salicylate, estra-1,3,5(10)-triene-3,17b-diyl 3-benzoate 17-salicylate and 3-benzyloxy-17-salicyloyloxy-16,17-secoestra-1,3,5(10)-triene-16-nitrile showed the strongest inhibition of PC-3 prostate cancer cell growth. 3-Hydroxyestra-1,3,5(10)-trien-17b-yl salicylate was the best inhibitor of 17bHSD2, suggesting potential use in treating pathological conditions associated with estrogen depletion. For 3-methoxyestra-1,3,5(10)-trien-17b-yl salicylate and 3-oxoestr-4-en-17b-yl salicylate, X-ray crystal structure analysis and molecular energy optimization were performed to define their conformations and energy minima. Very good overlap in the region of the steroidal nucleus was observed for the molecular structures of each analyzed molecule in the crystalline state and after energy optimization, while conformer analysis indicates conformational flexibility in the form of rotation around the C17ÁÁÁO2 bond. Structural geometry analysis for these compounds shows that the region of ring A in steroids, and especially the C3 atom functional group, is important structural features concerning antiproliferative activity against MDA-MB-231 cells.
Synthesis and biological evaluation of some new 2-oxazoline and salicylic acid derivatives
ARKIVOC, 2011
Starting from methyl salicylate and 2-amino-2-(hydroxymethyl)propane-1,3-diol 1a, or 2-amino-2-methylpropane-1-ol 1b, the 2-oxazoline derivatives 2a, 2b or 3, as well as mono-4a and 4b and bis-5a and 5b derivatives of salicylic acid were synthesized. Reactions were performed by microwave irradiation in the presence of tetrabutylammonium bromide or metallic sodium as catalyst, as well as by conventional heating. Microwave-induced reaction of some diols, diamines and amino alcohols with methyl salicylate gave mono-and/or bis-derivatives of salicylic acid 4c, 5c, 5d, 6c, 8c, 7a, 7b, 8a and 8b. The mono-and bis-salicyloyl derivatives 4c, 5c and 5d were transformed to the corresponding phenyl-azo derivatives 9, 10c and 10d. The structure of compound 3 was proved by the X-ray analysis and the R-configuration on its stereocenter was confirmed. The antioxidant and cytotoxic activities of the synthesized derivatives were evaluated in a series of in vitro tests. Compounds 5d, 8b and 8c exhibited very strong activity against hydroxyl radical. Six 4c, 5d, 8a-c, 10c of 16 tested compounds inhibited growth of MDA-MB-231 cells at a nanomolar concentration. Compounds 8c and 10c showed high cytotoxicity against MCF7 cells, whereas compounds 4c, 5d, 8a-c and 10d showed high activity against K562 cells.
Journal of Structural Chemistry, 2012
A systematic computational study was carried out to determine the structural stability of salicylic acid derivatives as well as the acidic properties of the protonation-deprotonation site and excitation parameters of the considered drugs at different temperatures using quantum chemical calculations. For further structural information, the dipole moment and differences in the energy of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) as (HOMO-LUMO) were compared. A high stability of the salicylic acid derivatives was referred to the large HOMO-LUMO band gap. The result of the current study may give useful information about the drug biochemical functionality based on the physical and chemical nature at different temperatures, and in this way the study on the structural features of analogous molecules of salicylic acid derivatives with higher drug functionality would be possible. K e y w o r d s: salicylamide (SAM), gentisamide (GAM), HOMO-LUMO band gap, excitation energies, ab initio.
Egyptian Journal of Basic and Applied Sciences, 2015
A series of azosalicylic acid analogs were newly synthesized by coupling various aryl and heteroarylamine functionalities with salicylic acid nucleus. All the synthesized compounds were structurally confirmed by various modern analytical methods. The said synthesized compounds were screened to investigate their antimicrobial, analgesic and antioxidant activities. The compounds 4e and 4h showed excellent significant antibacterial activity against most of the bacterial strains as no compounds showed significant antifungal activity against Cryptococcus neoformans. The bromine substituted molecule 4e (4-bromo-3-methyl phenyl azosalicylic acid analog) showed the highest significant analgesic activity with 46.10% of inhibition. The results of in vitro antibacterial and analgesic activity were justified with the outcome of in-silico investigation. The results of biological activities were statistically interpreted. The compounds substituted with antipyrinylazo and 4-carboxy phenylazo moiety exhibited potential antioxidant activity.
Chemical Papers, 2012
Since many estrane and androstane derivatives exhibit cytotoxic, anti-oxidant, or anti-hormone activity, new steroidal derivatives were synthesised from appropriate estrogen or androgen precursors in order to obtain potential therapeutics for the treatment of steroid-dependent diseases. Starting from estradiol (I ), 6-oxo derivatives V and VII were prepared. 17β-Salicyloyl-6-oxo derivatives VI and VIII were synthesised by the reaction of compounds V or VII with methyl salicylate in the presence of sodium. 17β-Salicyloyloxy estradiol IX was prepared from estradiol. Beckmann fragmentation of 16-oxyimino alcohols XII and XIII with methyl salicylate yielded corresponding Dseco derivatives XIV and XV. Simultaneous fragmentation and acylation of compound XII resulted in 3β-salicyloyl-D-seco derivative XVI which was also obtained from compound XIV. Anti-oxidant assays of the newly synthesised compounds V-IX, XIV, and XVI indicated a stronger capacity for hydroxyl radical scavenging, and a weaker capacity for DPPH radical scavenging, compared with the standard anti-oxidants BHA and BHT. Compounds V, XIV, and XVI showed higher or the same activity as BHT. The cytotoxicity of new compounds was evaluated against human breast and prostate carcinoma cells. Compound VI exhibited strong cytotoxicity against MDA-MB-231 cells; compound XIV exhibited strong cytotoxicity against PC-3 cell line, while compound VII moderately inhibited the growth of PC-3 cells.
Steroids, 2015
Steroidal salicylic acid derivatives Antioxidant activity Cytotoxicity D 5 -3b-Hydroxysteroid dehydrogenase (D 5 -3bHSD) inhibition 17b-Hydroxysteroid dehydrogenase type 2 and type 3 (17bHSD2 and 3) inhibition X-ray structural analysis a b s t r a c t A convenient microwave assisted solvent free synthesis as well as conventional synthesis of salicyloyloxy and 2-methoxybenzoyloxy androstane and stigmastane derivatives 7-19 from appropriate steroidal precursors 1-6 and methyl salicylate is reported. The microwave assisted synthesis in most cases was more successful regarding reaction time and product yields. It was more environmentally friendly too, compared to the conventional method. The antioxidant activity and cytotoxicity of the synthesized derivatives were evaluated in a series of in vitro tests, as well as their inhibition potency exerted on hydroxysteroid dehydrogenase enzymes (D 5 -3bHSD, 17bHSD2 and 17bHSD3). All of the tested compounds were effective in OH radical neutralization, particularly compounds 9, 11 and 14, which exhibited about 100-fold stronger activity than commercial antioxidants BHT and BHA. In DPPH radical scavenging new compounds were effective, but less than reference compounds.