Design, synthesis, and biological evaluation of novel arylcarboxamide derivatives as anti-tubercular agents

Abstract

Our group has previously reported several indolecarboxamides exhibiting potent antitubercular activity. Herein, we rationally designed several arylcarboxamides based on our previously reported homology model and the recently published crystal structure of the mycobacterial membrane protein large 3 (MmpL3). Many analogues showed considerable anti-TB activity against drug-sensitive (DS) Mycobacterium tuberculosis (M. tb) strain. Naphthamide derivatives 13c and 13d were the most active compounds in our study (MIC: 6.55, 7.11 μM, respectively), showing comparable potency to the first line anti-tuberculosis (anti-TB) drug ethambutol (MIC: 4.89 μM). In addition to the naphthamide derivatives, we also identified the quinolone-2-carboxamides and 4-arylthiazole-2-carboxamides as potential MmpL3 inhibitors in which compounds 8i and 18b had MIC values of 9.97 and 9.82 μM, respectively. All four compounds retained their high activity against multidrug-resistant (MDR) and extensively drug-resistant (XDR) M. tb strains. It is worth noting that the two most active compounds 13c and 13d also exhibited the highest selective activity towards DS, MDR and XDR M. tb strains over mammalian cells [IC₅₀ (Vero cells) ≥ 227 μM], indicating their potential lack of cytotoxicity. The four compounds were docked into the MmpL3 active site and were studied for their drug-likeness using Lipinski's rule of five.

Fig. 1. Hit compound 1, lead compounds 2, 3 and 4.

Fig. 2. A diagram indicating the main subpockets of MmpL3 in which the indole-2-carboxamide scaffold is stabilised through hydrophobic interactions and hydrogen bonding, and the strategies adopted for the replacement of the indole ring in lead compound 3.

Scheme 1. General synthetic procedure for compounds 8a–k.

Scheme 2. General synthetic procedure for compounds 11a–g.

Scheme 3. General synthetic procedure for compounds 13a–g, 15a–d and 18a,b.

Scheme 4. General synthetic procedure for compounds 21, 23, 24 and 27.

Fig. 3. Lead compound 3 and compound 8i adopt a similar binding mode, overlaid onto the active site of MmpL3 together with ICA38. (A) Superposition of lead compound 3 (dark cyan), and ICA38 (light brown) in the MmpL3 binding pocket. (B) Superposition of 8i (dark cyan) onto ICA38 (light brown) in the MmpL3 binding pocket.

Fig. 4. Superposition of 13c (A), 13d (B) (dark cyan), and ICA38 (light brown) in the MmpL3 binding pocket, showing the inhibitors all have similar binding positions.

Fig. 5. 18b binding mode and overlay of 8i, 13d and 18b in the MmpL3 binding pocket. (A) Superimposition of 18b (dark cyan), and ICA38 (light brown) in the MmpL3 active site, oriented in a similar way and having a similar binding mode as ICA38. (B) Superimposition of new classes of inhibitors in the MmpL3 active site with similar binding positions as ICA38. ICA38 (light brown), 8i (dark red), 13d (dark grey), and 18b (magenta).