Selective cyclooxygenase inhibition and ulcerogenic liability of some newly prepared anti-inflammatory agents having thiazolo[4,5-d]pyrimidine scaffold

doi:10.1016/j.bioorg.2019.102964

Bioorganic Chemistry

Volume 88, July 2019, 102964

https://doi.org/10.1016/j.bioorg.2019.102964 Get rights and content

Highlights

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Novel candidates of thiazolo[4,5-d]pyrimidines (9a-l) were synthesized.
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The target compound 9g was the most active derivative.
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The target derivatives 9a-l demonstrated moderate to high potent inhibitory action towards COX-2.
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The target compound (9e) recorded the lowest ulcerogenic effect (Ulcer index = 5).

Abstract

Novel candidates of thiazolo[4,5-d]pyrimidines (9a-l) were synthesized and their structures were elucidated by spectral and elemental analyses. All the novel derivatives were screened for their cyclooxygenase inhibitory effect, anti-inflammatory activity and ulcerogenic liability. All the new compounds exhibited anti-inflammatory activity, especially 1-(4-[7-(4-nitrophenyl)-5-thioxo-5,6-dihydro-3H-thiazolo[4,5-d]pyrimidin-2-ylideneamino]phenyl)ethanone (9g) was the most active derivative with 57%, 88% and 88% inhibition of inflammation after 1, 3 and 5h, respectively. Furthermore, this derivative 9g recorded higher anti-inflammatory activity than celecoxib which showed 43%, 43% and 54% inhibition after 1, 3 and 5h, sequentially. Moreover, the target derivatives 9a-l demonstrated moderate to high potent inhibitory action towards COX-2 (IC₅₀ = 0.87–3.78 µM), in particular, the derivatives 9e (IC₅₀ = 0.92 µM), 9g (IC₅₀ = 0.87 µM) and 9k (IC₅₀ = 1.02 µM) recorded higher COX-2 inhibitory effect than the selective COX-2 inhibitor drug celecoxib (IC₅₀ = 1.11 µM). The in vivo potent compounds (9e, 9g and 9k) caused variable ulceration effect (ulcer index = 5–12.25) in comparison to that of celecoxib (ulcer index = 3). Molecular docking was performed to the most potent COX-2 inhibitors (9e, 9g and 9k) to explore the binding mode of these derivatives with Cyclooxygenase-2 enzyme.

Graphical abstract

New thiazolo[4,5-d]pyrimidines (9a-l) were prepared and screened for their cyclooxygenase inhibitory effect, anti-inflammatory activity and ulcerogenic liability. All the new compounds exhibited anti-inflammatory activity; especially 9g was the most active derivative with 57%, 88% and 88% inhibition of inflammation after 1, 3 and 5h, respectively.

Introduction

Cyclooxygenase enzyme (COX) is responsible for the formation of prostaglandins (PGs), and thromboxanes (TXA2) from arachidonic acid [1], [2]. Cyclooxygenase enzyme exists in two distinct isoforms, (i) a constitutive form (COX-1) which is essential for the physiological production of (PGs) and maintenance functions such as cytoprotection in the stomach, and ii) an inducible form (COX-2) which is induced in inflammatory cells [3], [4]. Traditional non-steroidal anti-inflammatory drugs (NSAIDs) were recorded to suppress both COX-1 and COX-2 producing adverse side effects as ulceration, and gastrointestinal bleeding [5], [6], [7]. Coxibs were introduced in market as selective COX-2 inhibitors that inhibit COX-2 isoform achieving the same anti-inflammatory effect as traditional NSAIDs with minimized risk of ulcers [8], [9]. But some selective COX-2 inhibitors as valdecoxib exhibited cardiovascular side effects as myocardial infarction and hypertension leading to their withdrawal from markets [10], [11]. Thiazolidine derivatives revealed great attention due to their biological activity as anticancer [12], [13], antimicrobial [14], [15], hypoglycemic [16], [17] and anti-inflammatory [18], [19]. Zarghi et al. [20] designed new derivatives of 2,3-diaryl-1,3-thiazolidin-4-ones which recorded COX-2 inhibitory activity, in particular thiazolidino derivative 1 (Fig. 1) which was the most active derivative (IC₅₀ = 0.12 µM), and selective COX-2 inhibitor (SI > 833). Moreover, this compound 1 was more COX-2 selective than the standard drug celecoxib (SI > 403). In addition, (Z)-N-(3-chlorophenyl)-2-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)-2,6-dimethoxyphenoxy)acetamide (2) (Fig. 1) was detected to suppress the iNOS activity (IC₅₀ = 25.2 µM) and LPS-induced NO production (IC₅₀ = 45.6 µM) in RAW264.7 [21]. Furthermore, pyrimidine ring was recorded in literature as an important scaffold for anti-inflammatory activity [22], [23], [24]. For example, compound 3 was prepared and evaluated for its anti-inflammatory activity using carrageenan-induced paw oedema method in rats [25]. Results of this study showed that this compound 3 exhibited percentage inhibition of oedema = 52.9% after 5 h. Also,

7-amino-5-(3,4,5-trimethoxyphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile (4) (Fig. 1) demonstrated better COX-2 inhibitory activity in a range (IC₅₀ = 0.25 µM) than the standard drug celecoxib (IC₅₀ = 1.11 µM) [26].

In the view of the aforesaid studies and in continuation of our previous researches on the design of anti-inflammatory agents [26], [27], [28], [29], we have carried out synthesis of thiazolo[4,5-d]pyrimidine ring system having both pyrimidine ring and thiazolidine moiety in one hybrid structure attempting to obtain more potent and COX-2 selective anti-inflammatory agents with fewer gastric side effects.

Section snippets

Chemistry

A set of thiazolo[4,5-d]pyrimidine derivatives (9a-l) were synthesized using the reaction sequence illustrated in Scheme 1. Accordingly, stirring 4-aminoacetophenone, 3-aminoacetophenone and/or benzocaine (5a-c) with chloroacetyl chloride in dimethylformamide at room temperature yielded the corresponding chloroacetamide derivatives 6a-c in high yields (54–78%), which upon cyclization with ammonium thiocyanate in ethanol provided thiazolidinone derivatives 7a-c in 60–82% yield. Condensation of

Conclusion

Novel derivatives of thiazolo[4,5-d]pyrimidines (9a-l) were synthesized and screened for their Cyclooxygenase inhibitory effect, ulcerogenic and anti-inflammatory activities. The results of this study showed that the thiazolo[4,5-d]pyrimidine having a nitrophenyl moiety in position 7 and p-acetylphenyl ring in position 2 (9 g) was the most active candidate with edema inhibitory percent = 88% after three and five hours, while the derivative having a fluorophenyl moiety in position 7 (9e) was the

Chemistry

Melting points had been measured on a Thomas-Hoover capillary apparatus and are uncorrected. Infrared (IR) spectra were measured on NaCl plates using a Nicolet 550 Series II Magna FT-IR spectrometer. ¹H NMR and ¹³C NMR spectra were recorded on a Bruker III 400 MHz for ¹H and 100 MHz for ¹³C (Bruker AG, Switzerland) with BBFO Smart Probe and Bruker 400 AEON Nitrogen-Free Magnet, Faculty of Pharmacy, Mansoura University, Egypt in DMSO-d₆ with TMS as the internal standard, where J (coupling

Acknowledgement

The authors appreciate Jouf University, KSA, for funding this work through a research grant (Project no. 39/222).

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In this study, a series of new Schiff bases, based on a pyrimidine core, were synthesized by the condensation reactions of 1-amino-5-(4-methylbenzoyl)-4-p-tolylpyrimidin-2(1H)-one (1a) and 1-amino-5-(4-methylbenzoyl)-4-p-tolylpyrimidine-2(1H)-thione (1b) with different aromatic aldehyde derivatives using p-toluene sulfonic acid as a catalyst at refluxing in ethyl alcohol. The structures of these newly synthesized Schiff bases (2-11) were verified by ¹H NMR, ¹³C NMR, IR, LC-MS (only for 2, 3, 5, 6, 8, 9, 11), and elemental analysis. The presence of characteristic peaks proving the formation of imine supports the molecules' structures. The cytotoxic effects of molecules 2-11 on the viability of breast (MDA-MB-231) and colon (DLD-1) cancer cells were investigated using the MTT method. The molecules (2-11) demonstrated in vitro antiproliferative activity in the MDA-MB-231 cell line with IC₅₀ values ranging from 58.59 µM to ˃200 µM. A compound 3 was particularly found to be the most potent anticancer drug candidate in this series with an IC₅₀ value of 58.59 µM in MDA-MB-231. Unfortunately, neither the activity of this compound nor the others are high enough to be compared with the positive control drug cisplatin against MDA-MB-231 and DLD-1. In addition, Density Functional Theory (DFT) calculations of compounds 3, 4 and 8 were performed and the molecular docking studies of these compounds with breast cancer protein, PDB ID: 1JNX were presented to compare with experimental and theoretical results.
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Selective cyclooxygenase inhibition and ulcerogenic liability of some newly prepared anti-inflammatory agents having thiazolo[4,5-d]pyrimidine scaffold

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Chemistry

Conclusion

Chemistry

Acknowledgement

J. Biol. Chem.

Trends Mol. Med.

J. Therm. Biol

Kidney Int.

Eur. J. Med. Chem.

Eur. J. Med. Chem.

Eur. J. Med. Chem.

Eur. J. Med. Chem.

Bioorg. Med. Chem. Lett.

Eur. J. Med. Chem.

Bioorg. Med. Chem.

Bioorg. Med. Chem. Lett.

Biomed. Pharmacother.

Bioorg. Chem.

An evidence-based update on nonsteroidal anti-inflammatory drugs

Clin. Med. Res.

S.M.H.S. Group Upper gastrointestinal bleeding in haemophiliacs: incidence and relation to use of non-steroidal anti-inflammatory drugs

Haemophilia