Discovery of pyrimidine-tethered benzothiazole derivatives as novel anti-tubercular agents towards multi- and extensively drug resistant Mycobacterium tuberculosis

Figures & data

Figure 1. Scaffolds of some reported benzothiazole with potent anti-mycobacterial activity (I–VI).

Figure 2. Structures of some reported pyrimidine or thiouracil-based derivatives (VII, VIII, and IXa–b) as potent anti-mycobacterial agents.

Figure 3. Examples of some benzothiazole derivatives (X and XIa–b) incorporating pyrimidine moiety as potent anti-mycobacterial agents.

Figure 4. Design of the lead compound 4 and the target hybrids.

Scheme 1. Synthesis of compounds 2–4; conditions and reagents: (a) dry benzene, anhydrous K₂CO₃, reflux for 12 h; (b) absolute ethyl alcohol, anhydrous K₂CO₃, reflux for 10–12 h; (c) dry acetone, anhydrous K₂CO₃, reflux for 8–10 h.

Scheme 2. Synthesis of 5a–c and 6; conditions and reagents: (a) dry DMF, CH₃I/C₆H₅CH₂Cl/ClCH₂COOC₂H₅, anhydrous K₂CO₃, reflux for 12 h; (b) POCl₃, reflux for 3 h.

Scheme 3. Synthesis of compounds 7a–f and 8–13; conditions and reagents: (a) absolute ethyl alcohol, primary or secondary amine, TEA, room temperature for 24 h, then the heating under reflux for 6–12 h; (b) hydrazine hydrate, abs. ethanol, reflux, 6 h; (c) thiourea, abs. ethanol, reflux, 6 h; (d) n-butanol, glycine, reflux for 3 h; (e) reflux for 2 h with acetic anhydride; (f) fusion with the anthranilic acid in the oil bath at 190 °C, for 2 h; (g) glacial acetic acid, sodium azide, reflux for 3 h.

Scheme 4. Synthesis of 14 and 15; conditions and reagents: (a) glacial acetic acid and acetyl acetone, reflux for 6 h. (b) Reflux with the ethyl acetoacetate in NaOC₂H₅, for 4 h.

Table 1. MIC in µg/mL for 4, 5a–c, 6, 7a–f, and 8–15, as well as INH against the sensitive M. tuberculosis (ATCC 25177).

Comp.	MIC (µg/mL)
	M. tuberculosis (ATCC 25177)
4	3.9
5a	1.95
5b	0.98
5c	0.24
6	1.95
7a	15.63
7b	125
7c	125
7d	31.25
7e	7.81
7f	7.81
8	3.9
9	3.9
10	15.63
11	31.25
12	0.98
13	62.5
14	7.81
15	0.48
St. Isoniazid	0.24

Table 2. MIC in µg/mL of 4, 5a–c, 6, 7e, 7f, 8, 9, 12, 14, and 15 against the MDR TB (ATCC 35822) and XDR TB (RCMB 2674) strains.

Comp.	MIC (µg/mL)
	M. tuberculosis (MDR) (ATCC 35822)	M. tuberculosis (XDR) (RCMB 2674)
4	125	<125
5a	7.81	31.25
5b	7.81	31.25
5c	0.98	3.9
6	31.25	62.5
7e	62.5	NA
7f	125	NA
8	62.5	<125
9	62.5	125
12	7.81	31.25
14	NA	NA
15	1.95	7.81
St. Isoniazid	>125	>125

Table 3. Binding energy results in kcal/mol for the tested hybrids versus the co-crystallised ligands.

Compound	DprE1 (pdb: 4KW5) Energy score (kcal/mol)	TMPKmt (pdb: 1W2H) Energy score (kcal/mol)
5c	−21.5	−19.7
15	−19.8	−18.4
The co-crystallised ligand	−20.3	−17.9

Figure 5. 2D and 3D interactions of compound 5c with the binding position of DprE1 enzyme.

Figure 6. 2D and 3D interactions of compound 15 with the binding position of DprE1 enzyme.

Figure 7. The 2D and 3D interactions of compound 5c with the binding position of TMPKmt enzyme.

Figure 8. The 2D and 3D interactions for the compound 15 with the binding position of TMPKmt enzyme.