Antithrombotic and antiplatelet activity of an organometallic rhodium(I) complex incorporating a substituted thieno‐[2,3‐d]‐pyrimidine ligand: Synthesis, structural characterization, and molecular docking calculations

Abstract

The antiplatelet and antithrombotic activity of a novel organometallic rhodium(I) complex of the formula [Rh(cod)Cl(tpc)] (1) (cod = cis‐1,5‐cyclooctadiene; tpc = methyl 2‐amino‐4‐(diethylamino)‐thieno‐[2,3‐d]‐pyrimidine‐6‐carboxylate) was investigated. Complex 1 was easily synthesized by a one‐pot, high‐yield reaction and was fully characterized by standard spectroscopic techniques including FT‐IR, UV–Vis, and NMR spectroscopy and by elemental analysis. The molecular structures of tpc and 1 were determined by single‐crystal X‐ray crystallography. Complex 1 displayed a slightly distorted square planar geometry and is the first crystallographically characterized example of a coordination compound bearing the ligand precursor tpc. Biological studies demonstrate that 1 displays strong antiplatelet and antithrombotic properties in vitro, by inhibiting both the aggregation of human and washed rabbit platelets induced by the potent inflammatory and thrombotic mediator, platelet‐activating factor (PAF) in the micromolar range. This is an approach of continuous interest in the field. Molecular docking calculations suggest that 1 can fit at the ligand‐binding site of the PAF receptor (PAFR) and thus block PAF thrombotic activities, through an antagonistic effect on the PAF/PAFR‐related pathway, which is in accord with the experimental findings. Complex 1 constitutes an interesting example of a metal‐based PAF inhibitor with promising antiplatelet, antithrombotic, and anti‐inflammatory activity, because PAF is the most potent inflammatory lipid mediator. This is also supported by the fact that 1 is an inhibitor of other inflammatory and thrombotic mediators like thrombin, along with well‐established platelet agonists like ADP and collagen.

Tin(II) and Tin(IV) Complexes Incorporating the Oxygen Tripodal Ligands [(η5-C5R5)Co{P(OEt)2O}3]−, (R = H, Me; Et = -C2H5) as Potent Inflammatory Mediator Inhibitors: Cytotoxic Properties and Biological Activities against the Platelet-Activating Factor (PAF) and Thrombin

“…It is also evident that in conditions close to the real ones, the anti-PAF bioactivity of 2b , upon ligand coordination to the metal precursors, is enhanced ( synergetic effect ). This behaviour corroborates with the anti-PAF activities of other known Rh(III)- and Ru(II, III)-based inhibitors reported in the literature [ 25 , 27 , 29 , 49 ].…”

“…Cautiously, and ignoring the presence of plasma proteins and other biomolecules that potentially interact with the incoming substances, the observed IC 50 values of the organotin(II) and organotin(IV) complexes against the PAF-induced aggregation in rPRPs, could be compared with those of known metal complexes, tested in human PRPs [ 27 , 34 ]. Interestingly, the potency of 2b (IC 50 = 4.5 μM) is in the same range with that of a series of gold(I) N-heterocycle carbene (NHC) complexes (IC 50 ∼1–3 μM) [ 34 ], and significantly lower (almost two orders of magnitude) than that of the Rh(I) analog [Rh(cod)Cl(tpc)] (IC 50 = 122.6 μM; tpc is a substituted thieno-pyrimidine ligand) [ 27 ]. In particular, the activity of 2b is also higher compared to that of the [Ru(η 6 -cymene)(L)Cl] complex (L is chrysin, a natural flavonoid), exerting a non-concentration-dependent inhibition in the range of 100–500 μΜ [ 50 ].…”

“…That is the potency to inhibit the action of the PAF-induced aggregation in washed rabbit platelets (WRPs). As a result, we have presented a series of metal complexes with potent antiplatelet activities that inhibit the PAF-induced aggregation in the nanomolar and sub-micromolar level [ 25 , 26 , 27 ]. Consequently, preliminary structure–activity relationships have been established that are summarized in a review article, a patent, and a book chapter contribution [ 28 , 29 , 30 ].…”

Synthesis, antimicrobial activity, and molecular docking studies of new fused pyrimidinethiones

“…Its 1 HNMR spectrum exhibited new signals corresponding to methine (N CH ) and N (CH 3 ) 2 protons at δ 8.86 and 3.26 ppm, respectively. Acidification of compound 2 gave 2-cyano-N-phenylpropane bis-(thioamide) (5) [24], which reacted with DMF-DMA, unexpected closed compound, namely, 1-phenyl-4,-6-dithioxo-1,4,5,6-tetrahydro-pyrimidine-5-carbonitrile (6), was given. Its IR spectrum showed the disappearance of imino and amino groups' absorption bands, where its 1 HNMR spectrum appeared a new singlet signal at δ H 2.68 ppm corresponding for sp 3 -methine group (Scheme 1).…”

“…Polyfunctional reagent cyanothioacetamide (1) is broadly utilized in synthetic organic chemistry [1][2][3] as sulfur and nitrogen heterocyclic compounds, which often have biological activities [4]. Pyrimidines have received attention in medicinal chemistry due to their wide-spread pharmacological properties including antimicrobial [5], antithrombotic [6], antiplatelet [7], antitrypanosom [8], antiproliferative [9], anticancer [10], antifungal [11], antidepressant [12], antiparasitic [12], and herbicidal activity [13]. Inspired from the above observation and in continuation our previous work [14][15][16][17][18][19][20][21][22], we decided to explore the possibility of synthesizing new fused pyrimidines via the reaction of compounds 3 [23] and 4 with some nucleophile reagents.…”