Synthesis, anti-inflammatory activity, inverse molecular docking, and acid dissociation constants of new naphthoquinone-thiazole hybrids.

Chronic Inflammation is associated with various types of diseases that involves pro-inflammatory cytokines like IL-6 and TNF-α. High costs and serious side effects of available anti-inflammatory/immunomodulatory drugs led us to design new compounds with promising anti-inflammatory activities. Many drugs and biologically important compounds involve naphthoquinone and thiazole moieties in their core structures. Thereby, here we report the synthesis, characterization and anti-inflammatory activities of new naphthoquinone thiazole hybrids by reaction of naphthoquinone acyl thioureas with various α-bromoketone derivatives. The position of NO2 group in one of the phenyl rings of naphthoquinone thiazole hybrids was changed while different substituents were introduced at the para position of the second phenyl ring. All compounds were tested for potential immunomodulatory effect. No inflammatory cytokines were observed in the absence of LPS stimulant. On the other hand, they had promising anti-inflammatory immunomodulatory activities by being able to decrease the production of the pro-inflammatory cytokines (TNF-α and IL-6) in the LPS-stimulated cells. In an effort to find the possible mechanism of action, several enzymes involved in signalling pathways that play critical roles in inflammatory responses were screened in silico. Subsequent to inverse molecular docking approach, PI3K was predicted be the potential target. The docked complexes of the most potent compounds 5g and 5i were subjected to molecular dynamics simulation to assess the binding stability of the igands with the putative target. Acid dissociation constants (pKa) of the products were also determined potentiometrically.

Synthesis, biological properties, and acid dissociation constant of novel naphthoquinone-triazole hybrids.

A series of novel 1,4-naphthoquinone-triazole hybrids, N-(3-amino-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-2-(4-R-1H-1,2,3-triazol-1-yl)acetamide, was synthesized by click chemistry in the presence of sodium ascorbate and copper(II) sulfate pentahydrate in 81-94% yield. Various biological properties of the synthesized compounds including DNA binding/cleavage, antioxidant, antibacterial and antifungal properties were evaluated. The DNA binding study was performed using dsDNA and G-quadruplex DNA. All of the compounds showed fluorescence increase in the presence of DNA, regardless of the structure. Up to 2.9 and 2.5 times fluorescence increase upon incubation with double stranded or G-quadruplex DNA was detected for 5f and 5g, respectively. The docking studies performed on dsDNA and G-quadruplex structures suggested compounds' mode of interactions were populated around the grooves. All of the compounds showed excellent DNA cleavage activity and 5e was almost degraded the plasmid DNA. The highest radical scavenging activity was obtained as 89.9% at 200 mg/L with 5d. However, the highest ferrous chelating activity was obtained as 68.1% at 200 mg/L with 5g. The compounds exhibited antimicrobial activity against Bacillus cereus, Legionella pneumophila subsp. pneumophila, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and Enterococcus hirae as bacteria strains and Candida albicans and Candida tropicalis as microfungus strains. The compounds exhibited antibacterial and antifungal activity in the range of 4-128 µg/mL and 16-128 µg/mL, respectively. The best antimicrobial activity was obtained with 5d and 5e with a MIC value of 4 µg/mL against Enterococcus hirae. The acid dissociation constants (pKa) were determined potentiometrically in 20% (v/v) dimethyl sulfoxide-water hydro-organic solvent at an ionic background of 0.1 mol/L of NaCl, at 25 ± 0.1 °C. Five pKa values were obtained for each ligand.

Synthesis, antimicrobial activity and acid dissociation constants of methyl 5,5-diphenyl-1-(thiazol-2-yl)pyrrolidine-2-carboxylate derivatives.

In this study, a series of polysubstituted methyl 5,5-diphenyl-1-(thiazol-2-yl)pyrrolidine-2-carboxylate derivatives were designed and synthesized by the cyclization reaction of methyl 1-(benzoylcarbamothioyl)-5,5-diphenylpyrrolidine-2-carboxylates and 2-bromo-1-(4-substituted phenyl)ethanones in 70-96% yield. The starting pyrrolidine derivatives were synthesized via a 1,3-dipolar cycloaddition reaction in 83-88% yield. The stereochemistry of one of these methyl 5,5-diphenyl-1-(thiazol-2-yl)pyrrolidine-2-carboxylate derivatives was characterized by a single crystal X-ray diffraction study and the acid dissociation constants of these compounds were determined. An antimicrobial screening was performed against different bacterial and fungal strains and against the M. tuberculosis H37Rv strain. Interesting antibacterial activity was observed for two compounds against the A. baumannii strain with MIC values of 31.25 µg/mL (Ampicillin: 125 µg/mL) and against the M. tuberculosis H37Rv strain with MIC values of 0.98-1.96 µg/mL (Isoniazid: 0.98 µg/mL, Ethambutol: 1.96 µg/mL). Therefore, these structures can be considered as good starting points for the development of new powerful antimycobacterial agents.

Potentiometric Study of the Dissociation and the Metal Complex-formation Competence of 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (Dacarbazine).

A potentiometric investigation has been carried out to disclose the coordination properties of Dacarbazine, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (abbreviated DTIC) with particular transition metal ions (Zn2+, Cu2+, Ni2+ and Co2+). The coordination of DTIC with these metal ions results in several complexes emerging in solution. The aim of this work is to determine the protonation constants of the DTIC and to show the extent of its coordination with (Zn2+, Cu2+, Ni2+ and Co2+), in other words, establish the stability of the complexes formed between the DTIC and these metal ions by the determination of their stability constants. Experimental environments were organized to attain the coordination and measurements in aqueous solutions at 25±0.1 ºC and an ionic background of 0.1 mol.dm-3 NaCl. The HYPERQUAD computer program was used to determine both the protonation and stability constants for the ligand and metal-ligand complexes respectively. DTIC has five protonation constants that can be obtained under experimental conditions used; 10.54, 20.15, 26.99, 32.02 and 36.01. The results are interpreted in terms of the basicity of the donor atoms and structural composition of the ligand. All the complexes produced in the solution are exhibited in speciation diagrams.

Determination of Equilibrium Constants of Some Novel Antioxidant Compounds and Study on their Complexes with Some Divalent Metal ions in Ethanol-water Mixed.

This study aims to investigate the nature and type of complexes formed in solution, between novel antioxidant compounds [P1(4-(1-(3-hydroxy-4-methoxyphenyl)propyl)benzene-1,2-diol) and P2(4-(1-(3-hydroxy-4-methoxyphenyl)propyl)benzene-1,3-diol)] and the ions Cu2+, Ni2+, Zn2+ and Co2+. Potentiometric titration technique was used to follow the formation of complexes during the course of coordination. The stability of the complexes formed was controlled through the determination of stability constants in aqueous ethanol solution at 25 ± 0.1 C° and ionic strength of 0.1 M NaCl. Basicity of the ligand was also assessed by the determination of the dissociation constants of the ligand. All the constants were computed by computer refinement of pH-volume data using the SUPERQUAD program. The species distribution diagram of each type of complex has been obtained after computer calculation process.

Determination of Acid Dissociation Constants (pK a ) of Bicyclic Thiohydantoin-Pyrrolidine Compounds in 20% Ethanol-Water Hydroorganic Solvent.

The acid dissociation constants of potential bioactive fused ring thiohydantoin-pyrrolidine compounds were determined by potentiometric titration in 20% (v/v) ethanol-water mixed at 25 ± 0.1°C, at an ionic background of 0.1 mol/L of NaCl using the HYPERQUAD computer program. Proton affinities of potential donor atoms of the ligands were calculated by AM1 and PM3 semiempiric methods. We found, potentiometrically, three different acid dissociation constants for 1a-f. We suggest that these acid dissociation constants are related to the carboxyl, enol, and amino groups.