Discovery of Novel Thiophene-arylamide Derivatives as DprE1 Inhibitors with Potent Antimycobacterial Activities

Abstract

In this study, we report the design and synthesis of a series of novel thiophene-arylamide compounds derived from the noncovalent decaprenylphosphoryl-β- d -ribose 2′-epimerase (DprE1) inhibitor TCA1 through a structure-based scaffold hopping strategy. Systematic optimization of the two side chains flanking the thiophene core led to new lead compounds bearing a thiophene-arylamide scaffold with potent antimycobacterial activity and low cytotoxicity. Compounds 23j , 24f , 25a , and 25b exhibited potent in vitro activity against both drug-susceptible (minimum inhibitory concentration (MIC) = 0.02–0.12 μg/mL) and drug-resistant (MIC = 0.031–0.24 μg/mL) tuberculosis strains while retaining potent DprE1 inhibition (half maximal inhibitory concentration (IC 50 ) = 0.2–0.9 μg/mL) and good intracellular antimycobacterial activity. In addition, these compounds showed good hepatocyte stability and low inhibition of the human ether-à-go-go related gene (hERG) channel. The representative compound 25a with acceptable pharmacokinetic property demonstrated significant bactericidal activity in an acute mouse model of tuberculosis. Moreover, the molecular docking study of template compound 23j provides new insight into the discovery of novel antitubercular agents targeting DprE1.

Tuberculosis Drug Discovery: Challenges and New Horizons

“…A different group of investigators recently developed the 4substituted benzamide analogue 51 (Figure 5) through a systematic SAR study of the same hit (49). 173 This new molecule (51) also displayed strong cellular activity (relative to 49), with an MIC 90 value of 0.29 μM against Mtb H37Rv (a 4fold improvement). Additionally, 51 exhibited reduced cytotoxicity toward Vero cells (CC 50 > 154 μM vs 85 μM for 49), providing a superior SI value (>531 vs 66 for 49); it also showed slightly lower hERG inhibition (IC 50 23 The in vivo efficacy of both compounds was evaluated using the BALB/c mouse model of acute Mtb infection.…”

“…A different group of investigators recently developed the 4-substituted benzamide analogue 51 (Figure ) through a systematic SAR study of the same hit ( 49 ) . This new molecule ( 51 ) also displayed strong cellular activity (relative to 49 ), with an MIC 90 value of 0.29 μM against Mtb H37Rv (a 4-fold improvement).…”

Recent Advances of DprE1 Inhibitors against Mycobacterium tuberculosis: Computational Analysis of Physicochemical and ADMET Properties

“…Several of these inhibitors were investigated for cytotoxicity in various human cell lines, including A 5 4 9 , 6 4 , 6 7 , 7 7 , 8 2 , 8 3 H e L a , 3 7 , 3 9 HepG2, 28,56,66,69,72,74,87,88,[90][91][92]109,111 J-774, 111 THP-1, 60 and Vero cell lines. 9,[37][38][39][40][41][42]44,[47][48][49]51,52,54,98,108,113,119 A small negative correlation (r = −0.291, p = 0.011, Figure 4B) was found between the experimental cytotoxicity concentrations (CC 50 ) and MIC, for covalent binders. This observation suggests that even the most effective covalent binders appear to display a safe profile, encouraging the ongoing search for novel inhibitors.…”

“…Numerous scaffolds acting noncovalently also have been investigated for their activity against Mtb and are depicted in Table . These inhibitors include non-nitro BTZ analogues (NC BTZ), − benzothiazoles (BTO), , 1,2,3-triazole-2-mercaptobenzothiazoles (2-S-BTO), 1,4-azaindoles (AZA), − benzimidazoles (BI), pyrazolopyridones (PP), 4-aminoquinolone piperidine amides (4-AQ), 2-carboxyquinoxaline derivatives (2-CQ), pyrrolothiadiazoles (PTD), , morpholine-pyrimidines (MP), N -alkyl-5-hydroxypyrimidinone carboxamides (NAHPC), , hydantoins (HYD), , benzodioxanes (BD), 3,4-dihydrocarbostyril derivatives (CD), − thiophene-arylamide compounds (TPA), N -(4-hydroxy-3-mercaptonaphthalenyl) sulfonamides (NHMS), and avermectins (AVMT) …”

Development of Predictive Classification Models for Whole Cell Antimycobacterial Activity of Benzothiazinones

“…Very promising targets are the enzymes decaprenylphosphoryl-β- d -ribose oxidase (DprE1) and decaprenylphosphoryl-2-ketoribose reductase (DprE2), which are responsible for the biosynthesis of decaprenylphosphoryl- d -arabinofuranose (DPA), a key precursor of the mycobacterial cell wall arabinan. , Selective inhibition of DprE1 leads to the abolishment of DPA formation, resulting in cell lysis and killing. , The first class of highly active DprE1 inhibitors was disclosed in 2009, when its total inactivation by nitrobenzothiazinones (BTZs) through covalent binding was demonstrated . Inspired by this discovery, several covalent and non-covalent inhibitors, including dinitrobenzamides, nitroquinoxalines, nitrotriazoles, azaindoles, carbostyrils, and thiophenearylamides, have been identified. The outstanding activity of BTZ-043 ( 1 ; Figure A) against both drug-susceptible and multidrug-resistant strains of Mycobacterium tuberculosis ( Mtb ) made it the first lead compound. ,, At present, 1 is being studied within a phase IIa clinical trial and co-developed as a joined effort of academic groups.…”