The new quinazoline derivative (N2-methyl-N4-[(thiophen-2-yl)methyl]quinazoline-2,4-diamine) vasodilates isolated mesenteric arteries through endothelium-independent mechanisms and has acute hypotensive effects in Wistar rats.

During the screening of new N2,N4-disubstituted quinazoline 2,4-diamines as phosphodiesterase-5 inhibitors and pulmonary artery vasodilators, one N2-methyl-N4-[(thiophen-2-yl)methyl]quinazoline-2,4-diamine (compound 8) presented a greater selectivity for systemic than pulmonary vasculature. The present study aimed to characterize its vasorelaxant and hypotensive effects in Wistar rats. Vasorelaxant effects of compound 8 and underlying mechanisms were evaluated on isolated mesenteric arteries. Acute hypotensive effect was evaluated in anesthetized rats. Additionally, cell viability and cytochrome P450 (CYP) activities were studied in rat isolated hepatocytes. Nifedipine was used as a comparator. Compound 8 induced a strong vasorelaxant effect, similar to nifedipine. This was unaffected by endothelium removal but was decreased by inhibitors of guanylate cyclase (ODQ) and KCa channel (iberiotoxin). Compound 8 enhanced sodium nitroprusside-induced relaxation, but inhibited vasoconstriction evoked by α1-adrenergic receptor activation and extracellular Ca2+ influx via receptor-operated Ca2+ channels. Acute intravenous infusion of compound 8 (0.05 and 0.1 mg/kg) produced hypotension. It showed similar potency to nifedipine for lowering diastolic and mean arterial blood pressure, but less so for the effect on systolic blood pressure. Compound 8 had no effect on hepatocyte viability and CYP activities except at high concentration (10 µM) at which a weak inhibitory effect on CYP1A and 3A was observed. In conclusion, this study identified a N2-methyl-N4-[(thiophen-2-yl)methyl]quinazoline-2,4-diamine with a potent vasodilator effect on resistance vessels, leading to an acute hypotensive effect and a low risk of liver toxicity or drug-drug interactions. These vascular effects were mediated mainly through sGC/cGMP pathway, opening of KCa channels, and inhibition of calcium entry.

Quinazoline-based human phosphodiesterase 5 inhibitors exhibited a selective vasorelaxant effect on rat isolated pulmonary arteries involving NO-sGC-cGMP pathway and calcium inhibitory effects.

Phosphodiesterase 5 (PDE5) inhibitors are an attractive option among the currently available therapies in the management of pulmonary arterial hypertension (PAH). Good selectivity for PDE5 is associated with reduced side effects and greater vasorelaxant effect on pulmonary arteries (PA). This study investigated the vasorelaxant effects of a series of quinazoline-based PDE5 inhibitors and their precise mechanisms action using rat isolated PA and aorta, as compared to sildenafil. Their effects on rat hepatocytes (viability and CYP activities) were also evaluated. Compounds 5 and 11 displayed lower human PDE5 IC50 of the analogs studied here and induced a greater relaxant effect on PA (EC50 0.94 ± 0.30 and 1.03 ± 0.23 µM, respectively). As compared to sildenafil (EC50 = 0.05 ± 0.02 µM on PA), the relaxant effect of 5 and 11 on PA was lower but their selectivity for PA compared to aorta was higher. The effects of 5 and 11 were reduced by NG-nitro-L-arginine methyl ester, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one, but not by indomethacin or potassium channels blockers. They also enhanced the relaxant effect of sodium nitroprusside, and inhibited extracellular Ca2+ influx and intracellular Ca2+release. Compounds 5 and 11 did not reduce hepatocyte viability except at concentration > 10 µM, inhibited CYP3A at 10 µM, like sildenafil, but did not induce CYP1A. In conclusion, this study identified 2 quinazoline analogues with good PDE5 inhibitory activity and good selectivity for the pulmonary vasculature. Their relaxant effect involves both the potentiation of nitric oxide-sGC-cGMP pathway and calcium inhibition. These compounds are potential leads for developing new drugs for PAH.

Preparation, biological & cheminformatics-based assessment of N2,N4-diphenylpyrimidine-2,4-diamine as potential Kinase-targeted antimalarials.

Twenty eight new N2,N4-diphenylpyrimidine-2,4-diamines have been prepared in order to expand our understanding of the anti-malarial SAR of the scaffold. The aim of the study was to make structural modifications to improve the overall potency, selectivity and solubility of the series by varying the anilino groups attached to the 2- and 4-position. We evaluated the activity of the compounds against Plasmodium falciparum (Pf) 3D7, cytotoxicity against HepG2, % inhibition at a panel of 10 human kinases, solubility, permeability and lipophilicity, and human and rat in vitro clearance. 11 was identified as a potent anti-malarial with an IC50 of 0.66 µM at the 3D7 strain and a selectivity (SI) of ~ 40 in terms of cytotoxicity against the HepG2 cell line. It also displayed low experimental logD7.4 (2.27), reasonable solubility (124 µg/ml), good metabolic stability, but low permeability. A proteo-chemometric workflow was employed to identify putative Pf targets of the most promising compounds. Ligand-based similarity searching of the ChEMBL database led to the identification of most probable human targets. These were then used as input for sequence-based searching of the Pf proteome. Homology modelling and molecular docking were used to evaluate whether compounds could indeed bind to these targets with valid binding modes. In vitro biological testing against close human analogs of these targets was subsequently undertaken. This allowed us to identify potential Pf targets and human anti-targets that could be exploited in future development.