Synthesis and structure activity study of N‐1 substituted (S)‐(+)‐5‐n‐propyl‐2‐iminohydantoins as potential anticonvulsant agents

Abstract

A series of (S)-(+)-5-n-propyl-2-iminohydantoins with various N-1 substituents were synthesized and tested for anticonvulsant activity to better understand the structure-activity relationship (SAR) of 2-iminohydantoins. Compounds with N-1 phenoxycarbonyl (2), ethoxycarbonyl (6), t-butoxycarbonyl (7), propoxycarbonyl (12), and p-methyl phenoxycarbonyl (14) groups provided the most substantial anticonvulsant activity against the maximal electroshock seizure (MES) test with ED 50 values in the range of 72-124 mg/kg. All of the above compounds except 7 also showed activity against the pentylenetetrazol (PTZ) test with ED 50 values in the range of 65-178 mg/kg. Compound 6 provided the highest protective index (PI) value against the PTZ test, while 7 provided the highest PI value against the MES test. All significantly active compounds against the MES test (1, 2, 6, 7, 12, and 14) possessed aliphatic hydrocarbon chains of relatively small carbon length or aryl/arylalkyl groups not greater than benzyl in the carbamate moiety. Longer or larger than a benzyl group (3, 5, 8, 9, 10, and 11) or a saturated six-member ring (4) destroyed the activity. In addition, N-1 methoxycarbonyl substituted compound (13) was also devoid of significant activity. These results suggest that steric size of the substituent at N-1 oxycarbonyl sidechain in the 2iminohydantoin molecule plays an important role in providing anticonvulsant activity, and that an alkyl substituent with a proper size further enhances PTZ anticonvulsant activity while maintaining MES activity. Drug Dev. Res. 47:17-26, 1999.

Peptide−Heterocycle Hybrid Molecules: Solid-Phase Synthesis of a 400-Member Library of N-Terminal 2-Iminohydantoin Peptides

“…2-Iminohydantoins or 2-iminoimidazolin-4-ones contain amide and guanidine functionalities within a five-membered ring structure, and they can exist in different tautomeric forms, such as 1 , 2 , and 3 (Figure ). They are known bioactive compounds and are similar to imidazoles and hydantoins, which have a range of biological activities. One simple natural product that contains the 2-iminoimidazolin-4-one ring is creatine.…”

Activation of Benzyl Aryl Carbonates: The Role of Cation−π Interactions

“…These fractions were concentrated and dried under high vacuum to give 2.88 g of product (yield: 73%). The 1 H NMR, data of the product was in agreement with the literature …”

“…The 1 H NMR, data of the product was in agreement with the literature. 21 Naphthalen-1-ylmethyl phenyl carbonate (1h). Method B was employed with the following quantities: naphthalene-1-ylmethanol (1.73 g, 10.9 mmol), phenyl chloroformate (1.7 mL, 13.5 mmol), pyridine (1 mL, 12.4 mmol), and DCM (10 mL).…”

Designed Synthesis of Diversely Substituted Hydantoins and Hydantoin-Based Hybrid Molecules: A Personal Account

“…6 Synthesis of Diversely Substituted Iminohydantoins 2-Iminohydantoin is a nitrogenous analog of hydantoin, and along with hydantoin and thiohydantoin, it forms a widespread and closely-knit group of derivatives that exhibit varied chemical and biological activities. [96][97][98] This analog contains amide and guanidine moieties within a 5-membered ring and exists in different tautomeric forms (Figure 9). Additionally, aminoimidazoles, 99 as well as creatine, 100 are two heterocycles that are well-known to possess this ring system (Figure 9).…”