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Angiotensin-converting enzyme 2 (ACE2) is a membrane-bound zinc metallopeptidase that generates the vasodilatory peptide angiotensin 1-7 and thus performs a protective role in heart disease. It is considered an important therapeutic target in controlling the COVID-19 outbreak, since SARS-CoV-2 enters permissive cells via an ACE2-mediated mechanism. The present in silico study attempted to repurpose existing drugs for use as prospective viral-entry inhibitors targeting human ACE2. Initially, a clinically approved drug library of 7,173 ligands was screened against the receptor using molecular docking, followed by energy minimization and rescoring of docked ligands. Finally, potential binders were inspected to ensure molecules with different scaffolds were engaged in favorable contacts with both the metal cofactor and the critical residues lining the receptor's active site. The results of the calculations suggest that lividomycin, burixafor, quisinostat, fluprofylline, pemetrexed, spirofylline, edotecarin, and diniprofylline emerge as promising repositionable drug candidates for stabilizing the closed (substrate/inhibitor-bound) conformation of ACE2, thereby shifting the relative positions of the receptor's critical exterior residues recognized by SARS-CoV-2. This study is among the rare ones in the relevant scientific literature to search for potential ACE2 inhibitors. In practical terms, the drugs, unmodified as they are, may be introduced into the therapeutic armamentarium of the ongoing fight against COVID-19 now, or their scaffolds may serve as rich skeletons for designing novel ACE2 inhibitors in the near future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Selective alkylation of dyphylline (1) with (2-acetoxyethoxy)methyl bromide (2a) or 4-acetoxybutyl bromide (2b) afforded 3'-O-[(acetoxyethoxy)methyl]dyphylline (3a) and 3'-O-(4-acetoxybutyl)-dyphylline (3b), respectively. A trans esterification process rather than alkylation of the dihydroxy-propyl side chain in 1 had taken place during the reaction with 2-p-toluoyloxy)ethyl chloride (5) to afford the respective 3'-toluoyloxy derivative 7 and not the anticipated 3'-O-[(p-toluoyloxy)ethyl]-dyphylline (6). Deacylation of 3a,b and 7 afforded 4a,b and 1, respectively. Viral screening of selected compounds against HBV has been investigated.

A new derivative of diprophylline--[2-hydroxy-3(theophylline-7-ol)] propyl ester 4-benzyloxybenzoic acid was shown to decrease the content of cholesterol and of atherogenic lipoproteins in blood serum of hyperlipidemic guinea pigs. In blood serum of rabbits the new substance studied decreased cholesterol, free fatty acids and malonic dialdehyde concentrations.

In order to determine the efficacy of new compounds--an amino acid derivative of clofibric acid (WKLB-5), and a theophylline monoester of nicotinic acid (ME1)--a high fat diet (HFD) was applied to rabbits for 3 months, with or without the above mentioned compounds. The HFO included coconut oil, cholesterol and cholic acid. A substantial hypolipemic activity of those compounds was demonstrated; however, the studied lipid fractions did not undergo normalization, except FFA whose level after ME1 administration was distinctly lower than in control animals. Sudanophilic changes were found on 83% of surface of the interior membrane of aorta in rabbits kept on the HFD only, on 35% of surface--in rabbits treated with the HFD + WKLB-5, and on 75% of surface--in rabbits treated with the HFD + ME1. Thus in those animals no parallelism between the hypolipemic and antiatherosclerotic activities was observed.

To assess the hypolipemic and antiatherosclerotic activity of diprophyllinyl-4-benzyloxybenzoate guinea-pigs were kept on a high-lipid diet alone or with the tested compound for 21 days, and rabbits--for 3 months. It was found that diprophyllinyl-4-benzyloxybenzoate displays a distinct hypolipemic activity, particularly with respect to cholesterol, both in guinea-pigs and rabbits. It also depresses the cholesterol and the trigliceride content in liver homogenates and shows a tendency to normalize the low-density-lipoprotein fraction in guinea-pigs, as well as cholesterol of the high-density lipoprotein fraction, and malon dialdehyde in rabbits. The area of intima covered with atheromatous plaques was smaller in rabbits receiving the high-lipid diet with diprophyllinyl-4-benzyloxybenzoate than in those receiving that diet alone.