Synthesis and biological evaluation of new benzo-thieno[3,2-d]pyrimidin-4-one sulphonamide thio-derivatives as potential selective cyclooxygenase-2 inhibitors

Abstract

The aim of this work was to evaluate the potential anti-inflammatory activity of eleven (5-15) new synthesized derivatives of benzo-thieno[3,2-d]pyrimidine on two cell models, namely human keratinocytes NCTC 2544 and mouse monocyte-macrophages J774. For the synthesis of test compounds an efficient approach was developed: the key isothiocyanate was prepared through a simple and ecological method using di-2-pyridyl thionocarbonate (DPT) in substitution of thiophosgene, a highly toxic agent, and the cyclization reaction of benzo-thiosemicarbazide derivates was performed through Wamhoff methods. This procedure can be a new alternative method economically and environmentally advantageous by the simplicity of procedure, reduction of isolation and purification steps, time, costs, and waste production. The potential anti-inflammatory activity of 5-15 was evaluated by determining the expression of cyclooxygenase (COX)-2, inducible NO synthase (iNOS), and intercellular adhesion molecule-1 (ICAM-1), and the release of prostaglandins (PG)E[Formula: see text] and interleukin-8 (IL-8). Our results demonstrate that the compounds 7, 10, 12, 13, 14, and 15 act as a potent inhibitor of COX-2, iNOS, ICAM-1 expression while also suppressing the production of PGE[Formula: see text] and IL-8 in human keratinocytes NCTC 2544 exposed to interferon-gamma (IFN-[Formula: see text]) and histamine and monocyte-macrophages J774 cells treated with lipopolysaccharides (LPS). In conclusion, some derivatives of benzo-thieno[3,2-d]pyrimidine could be developed as a novel class of anti-inflammatory agents.

Molecular Docking and Fluorescence Characterization of Benzothieno[3,2-d]pyrimidin-4-one Sulphonamide Thio-Derivatives, a Novel Class of Selective Cyclooxygenase-2 Inhibitors

“…It is possible to observe that the derivative 4 containing the antipyrine group showed the best binding energy: Δ G = −9.4 kcal/mol. Thus, there is a good correlation between the results of binding energies of the benzothieno[3,2-d] pyrimidine derivatives to mCOX-2 and the biological assays published in our previous article [2].…”

“…Over the last few years, we have focused our research in the synthesis of condensed heterocyclic derivatives, with the goal of developing efficient molecules with interesting pharmacological properties [1]. In a recent work, we described a new alternative synthetic method to produce new benzothieno[3,2-d]pyrimidin-4-one sulphonamide thio-derivatives 1 – 11 with anti-inflammatory properties (Figure 1), which is economically and environmentally very advantageous and characterized by the simplicity of the procedures, reduction of isolation and purification steps, time, costs, and waste production [2]. The anti-inflammatory activity of these derivatives was evaluated in vitro on a human keratinocyte NCTC 2544 cell line exposed to interferon (IFN)-γ and histamine, as well as on a monocyte-macrophage J774 cell line stimulated with bacterial lipopolysaccharide (LPS).…”

“…At the same time, these compounds suppress the production of PGE 2 and IL-8 in human keratinocytes NCTC 2544 and monocyte-macrophages J774 [2]. Therefore, the efficacy of benzo-thieno[3,2-d] pyrimidine derivatives in inhibiting COX-2 activity in inflamed cells indicates that this novel compound class may serve as potential therapeutic agents in inflammatory and proliferative disorders.…”

Direct, Microwave‐Assisted Synthesis of Isothiocyanates

“…Over the past few decades, isothiocyanates (ITCs) have become the focus of medicinal chemistry and chemical biology gaining attention as many of these natural (e.g., BITC or SFN) and synthetic heteroanulenes have chemopreventive and antiproliferative as well as antibacterial, activity. In flow cytometry and in proteomics studies, ITCs are also exploited as probes (see Scheme for selected examples); they are also useful building blocks in the synthesis of sulfur‐containing heterocycles and thiourea‐derived organocatalysts There are two basic strategies for synthesizing ITCs: the first uses organic azides as reactants, which in the tandem Staudinger/aza‐Wittig reaction with triphenylphosphane and carbon disulfide are converted into target ITCs; the second, which is most exploited due to the large availability of starting materials, achieves the goal through the direct reaction of primary amines with highly toxic thiophosgene, or its more expensive surrogates such as di(2‐pyridyl) thionocarbamate,[10a] 1,1′‐thiocarbonyldiimidazole,[10b] and 1,1′‐thiocarbonyldi‐2‐( 1H )‐pyridone. [10c] In an alternative two‐step protocol, amines are converted by reactions with carbon disulfide into dithiocarbamates followed by their decomposition to the desired ITCs under the action of the desulfurating agent.…”

Synthesis, structure–activity relationships, and bioactivity evaluation of 6-bromo-quinazolinone derivatives

“…For the biological evaluation of the anti-inflammatory activity, 5-12 were evaluated on in vitro human keratinocyte cell line NCTC-2544 exposed to interferon (IFN-c) and histamine. This cell model, particularly useful for reproducing the mechanisms involved in inflammation, was successfully used in our lab as reported in previous published studies (Cardile et al, 2010;Barone et al, 2013).…”