Selective Inhibition of Carboxylesterases by Isatins, Indole-2,3-diones

Abstract

Carboxylesterases (CE) are ubiquitous enzymes thought to be responsible for the metabolism and detoxification of xenobiotics. Numerous clinically used drugs including Demerol, lidocaine, capecitabine, and CPT-11 are hydrolyzed by these enzymes. Hence, the identification and application of selective CE inhibitors may prove useful in modulating the metabolism of esterified drugs in vivo. Having recently identified benzil (diphenylethane-1,2-dione) as a potent selective inhibitor of CEs, we sought to evaluate the inhibitory activity of related 1,2-diones toward these enzymes. Biochemical assays and kinetic studies demonstrated that isatins (indole-2,3-diones), containing hydrophobic groups attached at a variety of positions within these molecules, could act as potent, specific CE inhibitors. Interestingly, the inhibitory potency of the isatin compounds was related to their hydrophobicity, such that compounds with clogP values of <1.25 were ineffective at enzyme inhibition. Conversely, analogs demonstrating clogP values>5 routinely yielded Ki values in the nM range. Furthermore, excellent 3D QSAR correlates were obtained for two human CEs, hCE1 and hiCE. While the isatin analogues were generally less effective at CE inhibition than the benzils, the former may represent valid lead compounds for the development of inhibitors for use in modulating drug metabolism in vivo.

Synthesis and biological evaluation of some new N4-substituted isatin-3-thiosemicarbazones

“…Isatin itself exhibited a range of actions such as CNS-MAO inhibition, sedative, anticonvulsant and anxiogenic activities [1]. Similarly, isatin derivatives are known to possess a wide spectrum of pharmacological properties including anthelmintic, antibacterial, anticonvulsant, antifungal, antineoplastic, antiviral, cysticidal, herbicidal, hypotensive and enzymatic inhibition [1][2][3][4]. Among these, isatins-derived thiosemicarbazones have raised considerable interest [5 -12].…”

“…Among these, isatins-derived thiosemicarbazones have raised considerable interest [5 -12]. Stimulated by this and in continuation of our drug discovery programme [13 -18], we have introduced very recently a number of N 4 -substituted isatin-3-thiosemicarbazones as urease inhibitors [19,20]. Urease, a nickel-dependent metalloenzyme, catalyzes the hydrolysis of urea in plants, algae, fungi and several microorganisms in the final step of organic nitrogen mineralization to produce ammonia and carbamate [21].…”

Improved superaugmented eccentric connectivity indices

“…These superaugmented eccentric connectivity topochemical indices can be easily calculated from the chemical distance matrix and augmented chemical adjacency matrix obtained by modifying adjacency matrix (Dureja et al, 2008a) Model development A data set (Hyatt et al, 2007a) comprising of 65 analogs belonging to isatins, indole-2,3-ones as inhibitors of CEs was selected for this study. The basic structure of these analogs is depicted in Fig.…”

“…These includes sulfonamides (Wadkins et al, 2004), aromatic ethane-1,2 diones (Wadkins et al, 2005;Wadkins et al, 2007;Hyatt et al, 2007b), indole-2,3-diones (Hyatt et al, 2007a), and flurobenzils (Hicks et al, 2007). As CEs are responsible for the metabolism and activation of a host of diverse clinically useful agents, therefore, the development of specific CEs inhibitors may be beneficial in modulating the bioactivity of the agents inactivated by CEs or, conversely, may reduce the toxicity of compounds that are activated by these enzymes (Hyatt et al, 2007a). Consequently, specific CEs inhibitors may have both therapeutic as well as commercial utility .…”

Absorption enhancement of adefovir dipivoxil by incorporating MCT and ethyl oleate complex oil phase in emulsion

“…To further improve the absorption of prodrugs, esterase inhibitors were developed to interfere with enterocyte metabolism. In the past, various esterase inhibitors have been described, including bis(pnitrophenyl) phosphate [10] , benzil or benzene sulfonamide [11] , isatins, indole-2,3-diones [12] , trifluoromethyl ketone (TFK) [13] , fruit extracts [14,15] , and mixed esters [16] . However, the toxicity, pharmacological activity, and complexity of these inhibitors limited their incorporation into pharmaceutical formulations.…”