Synthesis, comparative docking, and pharmacological activity of naproxen amino acid derivatives as possible anti-inflammatory and analgesic agents.

Background and aim: Naproxen is a member of the Nonsteroidal anti-inflammatory drugs (NSAIDs). This work aimed to synthesize a safe NSAID agent based on a peptide derivative. Methods: The structure of compounds 5-20 was established on the basis of spectral data. Frontier molecular orbitals and chemical reactivity were discussed to clarify inter- and intramolecular interactions among tested compounds. We applied competitive molecular docking using polynomial logarithms to identify the most accurate algorithm for pharmacological activity prediction for the tested compounds. The docking protocol with the lowest RMSD was selected for analyzing binding affinity. Results: Docking results illustrated that the binding interaction increased after introduction of an acidic fragment to the parent compound. These compounds were selected for additional study against adsorption, distribution, metabolism, excretion, and toxicity (ADMET) in silico. The compounds tested had good oral bioavailability without any carcinogenesis effect; no marked health effects were observed via rodent toxicity. Compounds passed through docking and ADMET profiles for them (5-16) were examined as anti-inflammatory and analgesic agents. Compounds 8 and 16 showed higher anti-inflammatory potency than the reference drug and tested compounds. Compounds 8, 10, and 14 exhibited the highest analgesic potency compared to the other tested compounds. Conclusion: The tested compounds have shown negligible ulcerogenic effects, and may be considered safer drugs than naproxen for treating inflammatory conditions.

Naproxenylamino acid derivatives: Design, synthesis, docking, QSAR and anti-inflammatory and analgesic activity.

This work aimed to design and synthesize a safe nonsteroidal anti-inflammatory drug NSAIDs agent based on Naproxen scaffold. The structure of compounds 6-21 established on the basis of different spectral data. Anti-inflammatory and analgesic profile were examined for synthesizing compounds. The compounds 6 and 17 have shown a higher anti-inflammatory potency than Naproxen. The compounds 16, 19 and 21 have exhibited the highest analgesic potency compared to other tested compounds. The synthesized compounds have shown negligible ulcerogenic effect and may be considered as safer drugs than naproxen for treating inflammatory conditions. The molecular docking against COX-2 was performed, it verified that compound 6, 17 show stronger interactions with COX-2. This may result in a better inhibitory effect on COX-2. The best generated QSAR model shows correlation between BCUT_SMR_3 and vsurf_Wp6 with biological activity. ADMET in silico showed that these compounds are a good oral bioavailability without observed carcinogenesis affect.

Synthesis, molecular properties and comparative docking and QSAR of new 2-(7-hydroxy-2-oxo-2H-chromen-4-yl)acetic acid derivatives as possible anticancer agents.

Novel coumarin amino acid derivatives were synthesized. The structure of synthesized compounds has established on basis of different spectral data. The optimization geometry, frontier molecular orbitals (FMOs), thermodynamic parameters and chemical reactivity, were discussed using DFT\B3LYP by 6-311G* basis set, to identify a clear view for inter and intramolecular interaction of tested compounds. The molecular electrostatic potential (MEP) has plotted to investigate a recognition manner of synthesized compounds upon COX-2 receptor. All tested compounds showed a promising (NLOs) nonlinear optical properties. Bond dissociation energy (BDE) has studied to investigate a potency of these molecules against autoxidation mechanism Polynomial molecular docking logarithms have performed into the COX-2 active site for tested compounds. The docking protocol that has low RMSD has selected for discussion the binding affinity. The compounds with a high docking score 3,4,6-8,10 and 11 were selected for additional study against ADMET insilico, which showed that these compounds are a good oral bioavailability without observed carcinogenesis affect. The compounds (3,4,6-8,10 and 11) which that passed through docking and ADMET profile have examined their potency against (MCF-7) breast cancer cell in vitro. The compound 7 showed a highest potency against MCF-7 with IC50 value 0.39 µM. The QSAR model has created to discover the structural necessity inhibition of MCF-7. The derived QSAR model has a statistically significant with a good predictive power.

Thymoquinone suppressses in vitro production of IL-5 and IL-13 by mast cells in response to lipopolysaccharide stimulation.

OBJECTIVE: Activated mast cells produce Th2 cytokines that regulate allergic inflammation. We have previously shown that thymoquinone (TQ) attenuated airway inflammation in a mouse model of allergic airway inflammation. The present study investigated whether TQ affects Th2 cytokine response in vitro in lipopolysaccharide (LPS)-activated rat mast cells, RBL-2H3. MATERIALS AND METHODS: RBL-2H3 cells were stimulated for 12 h with 0.1 microg/ml LPS in the presence or absence of 10 microM TQ. Th2 cytokine production was measured in the culture supernatants by ELISA. The mRNA expression of IL-5, IL- 13 and GATA transcription factors was determined by RT-PCR. The expression of the transcription proteins c-Fos, c- Jun and phospho-c-Jun were determined by western blotting. The in vivo binding of GATA, AP-1 and NF-AT transcription factors to IL-5 promoter was assessed by chromatin immunoprecipitation analysis. RESULTS: TQ significantly (p <0.05) inhibited LPS-induced IL-5 and IL-13 mRNA expression and protein production. However, TQ did not affect IL-10 production. GATA transcription factors are involved in the transcription of IL-5 and IL-13. TQ had no effect on the expression of AP-1 protein subunits, c-Jun and c-Fos, but markedly reduced the transcription of GATA-1 and -2 genes. Chromatin immunoprecipitation revealed that GATA, AP-1 and NF-AT binding to IL-5 promoter was induced by LPS stimulation and that TQ inhibited GATA binding at the IL-5 promoter but did not affect AP-1 and NF-AT binding. CONCLUSIONS: These results suggest that TQ inhibits LPS-induced proinflammatory cytokine production in RBL-2H3 cells by blocking GATA transcription factor expression and promoter binding which demonstrates the anti-inflammatory effect of TQ.

PU.1 is involved in the regulation of B lineage-associated and developmental stage-dependent expression of the germinal center-associated DNA primase GANP.

Germinal center-associated DNA primase (GANP) associated with MCM3 of the DNA replication complex is up-regulated selectively in germinal center B cells. We studied promoter activity of the 5' region involved in the developmental stage-dependent expression in B lineage cells by luciferase reporter assay. Selective regulation of ganp expression was observed in the -737-bp promoter region in B and plasma cell lines but was significantly low in pre-B and T cell lines. The deletion constructs displayed a gap decrease after shortening the region from -134 to -108 bp. Further narrowing suggested the involvement of the PU.1 consensus sequence at -126 bp by electrophoretic mobility shift assay. The protein component PU.1 complex is not inhibited with mutated probes at the consensus site but is inhibited with the known PU.1 probe of CD72 and with anti-PU.1 antibody. Moreover, introduction of PU.1 cDNA enhanced the reporter gene activity in a dose-dependent manner in B cells, whereas the reporter construct with the mutated PU.1 site did not respond. Anti-CD40 stimulation induced the reporter activity with a 100% increase, which is not observed with the PU.1-mutated reporter construct. These results demonstrate that the germinal center-associated DNA primase expression is partly regulated by the transcription factor PU.1 expressed in B lineage cells.

Synthesis and antimicrobial activity of some new 2-chloro-4-nitrobenzoylamino acid and dipeptide derivatives.

The synthesis of a series of 2-chloro-4-nitrobenzoylamino acid methyl esters (II-VIII), corresponding hydrazides (IX-XV), dipeptide methyl esters (XVI-XXII) and dipeptide hydrazides (XXIII-XXIX) was achieved employing the carbodiimide and azide methods. The derivatives containing the residues of Phe and Tyr were found to be active against several microorganisms.

Synthesis and biological activity of some new substituted aminoacyl-carbazole derivatives. Part II.

3-Nitro-9-(N-phthalyl- and N-tosylaminoacyl)carbazoles (II-XI) have been synthesized by the action of 3-nitro-9H-carbazole (I) on N-phthalyl- or N-tosylamino acid in THF-Et3N medium using the DCC method. Treatment of the 3-nitro derivatives (II-XI) with Sn/HCl gave the corresponding 3-amino-9-(N-phthalyl- or N-tosylaminoacyl)carbazoles (XII-XIX). Hydrazinolysis of the N-phthalylcarbazoles derivatives (III-VII) in ethanol gave the corresponding 3-nitro-9-(aminoacyl) carbazoles (XX-XXIII). Compounds (II-XI and XXI, XXII) were found to be active against some microorganisms.