Phase II metabolic pathways of spectinamide antitubercular agents: a comparative study of the reactivity of 4-substituted pyridines to glutathione conjugation

Abstract

Spectinamides are promising new semisynthetic anti-tubercular agents that are modified with a pyridyl side chain, which blocks native efflux from the tuberculosis cell. This study, describes the stability of an advanced panel of spectinamide analogs, with varying substitutions to the pyridyl side chain, to Phase-II conjugative metabolism by glucuronosyl transferase, sulfotransferase and glutathione-S-transferase enzymes using both human and rat S9 enzyme fractions. All solely 5-substituted pyridyl spectinamides exhibited complete stability towards Phase II conjugative enzymes. However, 4-chloro substituted pyridyl spectinamides were susceptible to glutathione conjugation with rates dependent on other substitutions to the pyridine ring. Electron donating 5-substitutions increased the propensity for glutathione conjugation and conversely the introduction of an electron withdrawing 5-fluoro group blocked all observed glutathione conjugation. Based on these Phase II metabolism studies, lead spectinamides 1329, 1445, 1599, 1661 and 1810 were found to have favorable properties for potential lead compounds with no Phase II liabilities.

Structure–Activity Relationships of Spectinamide Antituberculosis Agents: A Dissection of Ribosomal Inhibition and Native Efflux Avoidance Contributions

“…As we have noted previously, 47 and 36 are subject to some phase II conjugative metabolism. 18 Protein serum binding was low for all compounds with the lowest levels for 39 (35%) and highest for 49 (56%), which is consistent with increasing lipophilicity of the pyridyl substitutions. The negligible toxicity towards mammalian cells, low propensity for phase I metabolism, low protein binding and high solubility are shown here to be a clear and desirable general properties of this antibiotic class.…”

“…The pharmacological implications in regard to safety and potential susceptibility to conjugative phase II metabolism with glutathione of 4-chloro substituted pyridines, is an issue we have recently evaluated in detail. 18 …”

“…However, we have demonstrated that introduction of an electron withdrawing 5-fluoro group ( 49 ) can stabilize the 4-chloro group, while compounds with electron donating groups, such as 47 and 48 are more electrophilic and subject to metabolism. 18 The final compound in this subset is 50 , a 4-methoxy and 5-fluoro substituted analog, essentially a hybrid of 34 and 42 . Unfortunately, only moderate MIC activity was achieved, consistent with the notion that an electron donating functional group in the 4-position is disfavored.…”

Anti-tubercular Potency and Computationallyassessed Drug-likeness and Toxicology of Diversely Substituted Indolizines

“…It is encouraging to note that numerous novel antitubercular agents are currently in the drug development pipeline (Figure 1). These drugs include, GSK 2556286 (D3); 13 TBAJ-587 (D4) from diarylquinoline; 13 TBI-223 (D5) from oxazolidinone; 14 spectinamide 1810 (D6) and spectinomycin analogues, 15 BTZ-043 (D7), 16 GSK 070 and GSK 3036656 (D8) from oxaborole; 13 contezolid (MRX-4/MRX-1) (D9) from oxazolidinone; 17 OPC-167832 (D10), a 3,4-dihyrdocarbostyril derivative; 18 Macozinone (PBTZ169) (D11), a piperazinobenzothiazinone derivative; [19][20] clofazimine (TBI-166) (D12) from riminophenazine; 21 TBA-7371 (D13) from azaindole; 13 and Sutezolid (D14) from oxazolidinone. [22][23][24][25] In continuation of our effort to investigate novel heterocyclic agents for multi-drug resistant anti-tubercular property [26][27][28][29] and in addition to the aforementioned chemical structures, the heterocyclic scaffold of indolizine ( Figure 2) has shown promising anti-tubercular activity in early experiments.…”

Facile Synthesis of New 6‐Alkylamino‐1H‐pyrazolo[3,4‐b]pyridine‐5‐carbonitrile Derivatives

“…Pyrazoles are also not only of interest as important intermediates for the synthesis of fused heterocycles but also as efficient analytical regents in the complexation of transition‐metal ions . On the other hand, the pyridine moiety is the base of many bioactive molecules having important biological properties such as anticancer , antioxidant , anti‐inflammatory , antimicrobial , antitubercular , antifungal , antileishmanial , antiproliferative , and anticonvulsant activities. Because of the importance of these heterocycles, we became interested in the synthesis of new compounds formed from a combination of both pyrazole and pyridine scaffolds.…”