N-Monocarbamoyl Derivatives of Symmetrical Diamines with Antiviral Activity

Abstract

The continuing search for antiviral compounds has identified N-monoacylated 2,6-diaminopyridines (A1-3) as a novel class of anti-herpes simplex virus (HSV)-1 agents (Chart 1).1) Some of the derivatives of urea, thiourea, and their related molecules are known to be important structural components in biological processes 2,3) such as antiviral activity.2,4-6) In connection with previous studies on the search for antiviral compounds, the recent focus has been on the symmetrical chiral diamines and some achiral diamine derivatives.This paper reports the synthesis and properties of the Nmonocarbamoyl derivatives obtained by the addition of diamines to isocyanates or isothiocyanates. In addition, this study documents the results of their antiviral [anti-herpes simplex virus (HSV)-1] activity. Results and Discussion Synthesis of N-Monocarbamoyl Derivatives of Symmetrical Diamines [(5a-c), (1R,2R)-6(a-c), cis-6c, (1R,2R)-7b-c] The above target compounds have been prepared by the reaction of the symmetrical diamines, and (1R,2R)-1,2-diphenylethylenediamine (3)] with the corresponding isocyanate (4a), or isothiocyanates (4b, c) (Chart 2). The reaction, which involved the simple refluxing of an equimolar amount of DAP (1) and 1-adamantyl isocyanate (4a) in dry tetrahydrofuran (THF) or dry pyridine required a long reaction time to generate the target compound (5a) and resulted in a low yield (entries 1, 2). Similarly, the reaction of DAP with an equimolar amount of 1-adamantyl isothiocyanate (4b) or 3,4-dimethoxyphenyl isothiocyanate (4c) in common organic solvents also gave the product 5b or 5c, in low yields (10-23%, see entries 5, 6, 8 in Table 1). In both reactions, for the preparation of 5a (entries 1, 2), there was a gradual disappearance of the starting materials (4a and DAP) and the formation of N,NЈ-disubstituted diaminopyridine could not be detected by monitoring with thin layer chromatography (TLC). The change of the ratio of diamine : isocyanate (1 : 2) resulted in the formation of N-monosubstituted diaminopyri- ; 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan: and b Faculty of Pharmaceutical Sciences, Sojo University; 4-22-1 Ikeda, Kumamoto 862-0082, Japan. Received May 15, 2007; accepted June 25, 2007 Some new N-monocarbamoyl symmetrical diamines have been prepared by the addition of symmetrical amines to isocyanates or isothiocyanates. 2,6-Diaminopyridine (1), (1R,2R)-1,2-diaminocyclohexane [(1R,2R)-2], meso-1,2-diaminocyclohexane (meso-2), or (1R,2R)-1,2-diphenylethylenediamine (3) were used as the starting symmetrical diamine frameworks. All of the newly synthesized compounds were subjected to an evaluation of antiviral activity with herpes simplex virus (HSV)-1. N-Monocarbamoyl 2,6-diaminopyridines (5a, b) showed significant antiviral activity (EC 50 ‫,0.71؍‬ 6.2 m mg/ml) comparable to that of N-monododecanoyl 2,6-diaminopyridine (A2). As a result, compound 5a showed a better selectivity index (CC 50 /EC 50 ‫؍‬ca. 10.0) than that of A2.

Synthesis and Antiviral Activities of N-Mono- and/or N,N'-Di- Carbamoyl and Acyl Derivatives of Symmetrical Diamines

“…1) Compound cis-7b, however, showed a greater cytotoxic property than (1R,2R)-7a and had a much lower selectivity index (CC 50 /EC 50 ϭ1.4). The compound 9b derived from 1,3-diaminocyclohexane (3) showed no significant antiviral activity at the concentration of 40 mg/ml.…”

“…11) Among these compounds, N-monocarbamoyl derivatives (cis-7b) from 1,2-diaminocyclohexane (1) showed more potent anti-HSV-1 activity (EC 50 ϭ27.0) than the original lead (1R,2R)-7a 1) (EC 50 ϭ42.0) reported previously. 1) Compound cis-7b, however, showed a greater cytotoxic property than (1R,2R)-7a and had a much lower selectivity index (CC 50 /EC 50 ϭ1.4).…”

“…1,2) We reported previously on the synthesis and properties of the Nmonocarbamoyl derivatives obtained by the addition of symmetrical 1,2-diamines (1, 3) to iso(thio)cyanates. By the introduction of an adamantyl group as a substitutent, we found that derivative B showed less cytotoxicity and comparable antiviral activity than that of compound A.…”

“…5) These reports led us to further study molecular modification and evaluation of synthesized derivatives, aiming at the discovery of new leads with antiviral activity via interference with sugar chains, as postulated in our previous hypothesis. 2) In this paper, we describe the preparation of N-carbamoyl and N-acyl derivatives from symmetrical 1,2-and 1,3-diamines (1)(2)(3) and show the results of plaque reduction assay conducted for their anti-HSV-1 activity.…”

Inhibition of DNA virus: Herpes-1 (HSV-1) in cellular culture replication, through an antioxidant treatment extracted from rosemary spice

“…Even with the regular dose recommended for parenteral or topical uses, collateral effects are mentioned, such as neurotoxicity and renal dysfunction. Drugs with activity against DNA viruses, present a mechanism of action dependent on viral thymidine kinase, which requires phosphorylation, cellular metabolism of the drug, and a certain grade of sensitivity to viral polymerase (Cotarelo et al, 1999;Mibu et al, 2007). Macrophages from mice infected with herpesvirus simplex type 2 (HSV-2) demonstrated extrinsic antiviral resistence.…”