Structure‐Activity Relationship, Cytotoxicity and Mode of Action of 2‐Ester‐substituted 1,5‐Benzothiazepines as Potent Antifungal Agents

Abstract

Our studies examined the structural features responsible for the antifungal activity of 2-ethoxycarbonyl-1,5-benzothiazepine (7a). Three series of 1,5-benzothiazepine derivatives were synthesized and screened for their antifungal activity. The results suggested that the ethoxycarbonyl group at the 2 position and the imine moiety on the seven-membered ring are essential for activity. The most potent of the synthesized analogues (7a, 7b) were further studied by evaluating their cytotoxicity and mode of action (for 7a). The results showed that compounds 7a and 7b were relatively safe for BV 2 cells, but compound 7a interfered with Cryptococcus neoformans cell wall integrity by increasing the chitinase activity. Therefore, compound 7a was considered safe as an antifungal agent for animal cells.

Synthesis of the 1,5‐Benzothiazepane Scaffold – Established Methods and New Developments

“…[ 12 , 18 , 34 , 37 , 38 ] In some cases, however, the reaction mixture is concentrated and subsequently recrystallized or purified by column chromatography. [ 33 , 35 ] Drawbacks of this method are that it requires high temperature and often takes multiple hours to complete, which is not in line with the principles of green chemistry. [18] …”

“…This method is widely used as it is simple, does not require expensive catalysts or solvents, and the product 34 is generally easily purified as it tends to precipitate from the reaction mixture and can be obtained in pure form after filtration and recrystallization [12,18,34,37,38] . In some cases, however, the reaction mixture is concentrated and subsequently recrystallized or purified by column chromatography [33,35] . Drawbacks of this method are that it requires high temperature and often takes multiple hours to complete, which is not in line with the principles of green chemistry [18] …”

“…All the benzothiazepane derivatives 102 were as good as inactive, while the phenyl‐substituted benzothiazepine 101 a and the fluorophenyl‐substituted benzothiazepine 101 b both showed good antifungal activity, although the chloro‐ and bromophenyl‐substituted benzothiazepines 101 c , d did not exhibit improved activity. [33] …”

“…The reaction is most commonly performed in (anhydrous) methanol or ethanol at reflux temperature with the addition of acetic acid [11,12,[33][34][35][36] or hydrochloric acid [37,38] to aid the condensation of the amino group. Bases, such as pyridine [39] and piperidine, [40,41] have also been used.…”

“…[12,18,34,37,38] In some cases, however, the reaction mixture is concentrated and subsequently recrystallized or purified by column chromatography. [33,35] Drawbacks of this method are that it requires high temperature and often takes multiple hours to complete, which is not in line with the principles of green chemistry. [18] The reaction can also be performed using cyclic α,βunsaturated carbonyl compounds, as demonstrated by the group of Urbanski et al 5,6-Dihydropyran-2-one 35 was added to 2-aminothiophenol 21 a in a solvent mixture and was then heated under reflux to encourage cyclization (Figure 10).…”