Abstract
Objective: This study aimed to describe the synthesis and biological/pharmacokinetic potential of the 1,3-diisobutoxypropan-2-yl nitrate (NDIBP) using in silico and ex vivo approaches.
 Methods: The compound was characterized by Fourier-transform infrared spectroscopy and 1H and 13C- nuclear magnetic resonance spectra. NDIBP biological activity spectrum was obtained by Prediction of Activity Spectra for Substances (PASS). The pharmacological effect was validated in ex vivo studies using mesenteric artery. Drug-like properties and Absorption Distribution Metabolism Excretion and Toxicity (ADMET) studies were carried out by pkCSM (Predicting Small-Molecule Pharmacokinetic Properties Using Graph-Based Signatures) software.
 Results: PASS prediction indicated NDIBP as nitric oxide (NO) donor with vasodilator effect. Ex vivo studies validated PASS analysis and showed the NDIBP vasorelaxant activity in mesenteric arteries. Physicochemical parameters and ADMET prediction suggested that NDIBP is a drug-like molecule with a good theoretical oral bioavailability, good absorption in the gastrointestinal tract, and a low distribution in the tissues.
 Conclusion: All the data indicated that NDIBP possesses biological activities and drug-like properties to be considered as a vasorelaxant agent and a good candidate for further investigation in the treatment of arterial hypertension and drug development studies.
Highlights
Arterial hypertension (AH) has become the most prevalent chronic disease in the world [1] and is considered the main risk factor for the development of a range of other cardiovascular diseases, such as coronary diseases, stroke, and renal failure [2]
This process is mainly attributed to impairment on nitric oxide (NO) production and bioavailability in the vascular wall and increased NO degradation due to the rise in oxidative stress leading to increase in vascular resistance [5,6,7]
This result was similar to the obtained by Zhuge et al [50] who synthesized the organic nitrate 1,3-bis(hexyloxy) propan-2-yl (NDHP) confirming that this synthetic route is suitable for obtaining organic nitrates
Summary
Arterial hypertension (AH) has become the most prevalent chronic disease in the world [1] and is considered the main risk factor for the development of a range of other cardiovascular diseases, such as coronary diseases, stroke, and renal failure [2]. The endotheliumdependent vasorelaxation is normally reduced in hypertension due to alterations in the homeostatic regulation of vascular tone known as endothelial dysfunction [3,4]. Therapy with organic nitrates such as nitroglycerine (GTN) and isosorbide dinitrate (ISDN) has been used for many years in the treatment of cardiovascular disorders including AH [8] These drugs release NO from its structures and replace the NO deficiency leading to improvement of the endothelial function and modulation of the vascular tone, reducing AH, and its comorbidities [2,9,10,11,12]. Once this molecule is a novel organic nitrate and its biological and pharmacokinetics characteristics are unknown, a virtual screening of NDIBP is a good approach to determine its initial profile and verify the chance to be used in cardiovascular field
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