Discovery of benzothiazole amides as potent antimycobacterial agents

Abstract

From a high throughput screening of commercially available libraries against nontuberculous mycobacteria and Mycobacterium tuberculosis, numerous hits were identified with moderate activity. Extensive medicinal chemistry optimization has led to a series of potent benzothiazole amide antimycobacterial agents. Replacement of the adamantyl group with cyclohexyl derivatives and further development of this series resulted in an advanced lead compound, CRS400393, which demonstrated excellent potency and a mycobacteria-specific spectrum of activity. MIC values ranged from 0.03 to 0.12 μg/mL against Mycobacterium abscessus and other rapid-grower NTM, and 1-2 μg/mL against Mycobacterium avium complex. The preliminary mechanism of action studies suggested these agents may target MmpL3, a mycobacterial mycolic acid transporter. The series has demonstrated in vivo efficacy in a proof of concept mouse model of M. abscessus infection.

Optimization and Lead Selection of Benzothiazole Amide Analogs Toward a Novel Antimycobacterial Agent

“…This led to the identification of scaffolds with broad antimycobacterial spectrum, such as the adamantyl amides. We applied an iterative process of design-synthesis-screen and increased potency by 1–2 orders of magnitude compared to the initial library hits (Graham et al, 2018 ). Optimization of the adamantyl amide series resulted in compound CRS400226, an adamantyl benzothiazole amide.…”

“…This potential limitation had been discovered through detailed SAR of the early lead compound CRS400153, by exploring hydrophilic substitutions at the 4-, 5-, 6-, and 7-position of the benzothiazole moiety, such as a hydroxyl, tertiary amine, and ether or ester groups. In all cases, these hydrophilic substitutions resulted in MIC > 64 μg/mL against M. abscessus compared to MIC = 0.5 μg/mL for the 4,6-diF-benzothiazole analog CRS400153, except for the 7-OH benzothiazole analog which retained some activity with an MIC range of 2–16 μg/mL against M. abscessus (compound #37) (Graham et al, 2018 ). Our lead compounds are very potent, but have very low solubility (≤3 μM), high protein binding (MIC ≥ 16 μg/mL in 50% serum) and low oral bioavailability due to their lipophilic nature, precluding their utility as oral agents.…”

“…The general synthetic route started from substituted 2-amino-benzothiazole intermediates and variably substituted cycloalkyl carboxylic acids under standard amide coupling conditions using 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro-phosphate (HATU) in the presence of N,N-diisopropylethylamine (DIEA) in dichloroethane (DCE). A detailed description of chemical synthesis, purification and SAR of substituted benzothiazole cyclohexyl amides is presented elsewhere (Graham et al, 2018 ). The products were purified by column chromatography using ethyl acetate and hexanes as eluents and fully characterized by NMR and LC-MS.…”

MmpL3 Inhibition: A New Approach to Treat Nontuberculous Mycobacterial Infections

“…It was suggested that the 1-methylated cycloaliphatic ring improves activity against RGM and SGM. The 1-methylcycloheptyl derivative shows >530-fold and >8-fold increase in activity against M. abscessus and M. avium compared to that of the unsubstituted cycloheptyl [ 70 ]. The ineffectiveness of the unsubstituted cycloheptyl against M. abscessus using CIP 104536 susceptible strain is reported in another study [ 62 ].…”

NEW ROUTE FOR THE SYNTHESES OF SOME NOVEL DERIVATIVES OF 3-ARYL BENZO[d] THIAZOLE-2(3H)-IMINE FROM HIGH SUBSTITUTED THIOUREAS

“…Benzothiazole is an organosulfur, as well as organonitrogen heterocyclic compound was a which benzene ring is fused with thiazole [4][5][6][7][8][9][10][11][12][13]. Benzothiazoles are an important class of heterocyclic compounds that act as core nucleus in various drugs such as anticancer [5,14], antileishmanial [15], antimicrobial [9,16], anti-asthmatic [11], antitumor [6], antibacterial [17,18], anti-tubercular, [19] anticonvulsant [4,20], anti-HIV [15,21], anti-inflammatory [5,7], antifungal [9,13], antiproliferative [6,14,21,22], antiviral [23], anti-Alzheimer [10,14], antimalarial [15], and antidiabetic [24][25][26] effects. The related research and developments in BTA-based medicinal chemistry have become a rapidly developing and increasingly active topic [6,19].…”