Novel Pyrimidine-1,3,4-Oxadiazole Hybrids and Their Precursors As Potential Antimycobacterial Agents

Figures & data

Figure 1. Design of new pyrimidine-1,3,4-oxadiazole-alkylamine hybrids.

Figure 2. Synthesis of hydrazine-1-carboxamides 3 and oxadiazoles 4.

Table 1. Structure and antimycobacterial activity of pyrimidine derivatives 3 and 4.

Code	R	MIC [μM]							ClogP
		Mycobacterium tuberculosis 331/88		Mycobacterium avium 330/88		Mycobacterium kansasii 6509/96
		14 days	21 days	14 days	21 days	7 days	14 days	21 days
3a	Methyl	10^3	10^3	10^3	>10^3	10^3	10^3	10^3	-1.62
4a		500	10^3	10^3	10^3	250	500	10^3	-0.59
3b	Ethyl	10^3	10^3	10^3	>10^3	10^3	10^3	10^3	-1.28
4b		500	10^3	10^3	10^3	250	500	10^3	-0.06
3c	Propyl	10^3	10^3	10^3	>10^3	10^3	10^3	10^3	-0.80
4c		500	10^3	10^3	10^3	250	500	10^3	0.47
3d	Butyl	10^3	10^3	10^3	>10^3	10^3	10^3	10^3	-0.38
4d		500	10^3	10^3	10^3	250	500	10^3	1.00
3e	Pentyl	10^3	10^3	10^3	>10^3	10^3	10^3	10^3	0.04
4e		250	500	500	500	250	250	500	1.53
3f	Hexyl	250	250	500	>500	125	250	500	0.45
4f		32	64	>500	>500	>500	>500	250	2.06
3g	Heptyl	125	250	500	500	125	125	500	0.87
4g		16	32	>500	>500	>500	>500	250	2.59
3h	Octyl	64	64	250	250	64	64	125	1.29
4h		32	32	250^†	250^†	250^†	250^†	250^†	3.12
3i	Nonyl	64	64	125	125	64	64	125	1.70
4i		8	16	250^†	250^†	250^†	250^†	250^†	3.65
3j	Decyl	64	64	125	125	64	64	125	2.21
4j		32	32	250^†	250^†	250^†	250^†	250^†	4.18
3k	Undecyl	64	64	125	125	64	64	125	2.54
4k		32	32	250^†	250^†	250^†	250^†	250^†	4.70
3l	Dodecyl	32	64	250^†	250^†	125	125	125	2.96
4l		2	4	64	125	250^†	250^†	250^†	5.23
3m	Tridecyl	250^†	250^†	250^†	250^†	250^†	250^†	250^†	3.37
4m		250^†	250^†	250^†	250^†	250^†	250^†	250^†	5.76
3n	Tetradecyl	250^†	250^†	250^†	250^†	250^†	250^†	250^†	3.79
4n		250^†	250^†	250^†	250^†	250^†	250^†	250^†	6.29
3o	Pentadecyl	250^†	250^†	250^†	250^†	250^†	250^†	250^†	4.21
4o		250	500	>10^3	>10^3	250	500	500	6.82
3p	Hexadecyl	250^†	250^†	250^†	250^†	250^†	250^†	250^†	4.63
4p		>10^3	>10^3	>10^3	>10^3	>10^3	>10^3	>10^3	7.35
3q	Heptadecyl	250^†	250^†	250^†	250^†	250^†	250^†	250^†	5.04
4q		250^†	250^†	250^†	250^†	250^†	250^†	250^†	7.88
3r	Octadecyl	250^†	250^†	250^†	250^†	250^†	250^†	250^†	5.46
4r		>10^3	>10^3	>10^3	>10^3	>10^3	>10^3	>10^3	8.41
3s	CH3	250^†	250^†	250^†	250^†	250^†	250^†	250^†	3.87
4s		250^†	250^†	250^†	250^†	250^†	250^†	250^†	5.73
3t	CF3	64	125	250^†	250^†	250^†	250^†	250^†	4.77
4t		64	125	250^†	250^†	250^†	250^†	250^†	6.15
3u	Ph	250^†	250^†	500^†	500^†	500^†	500^†	500^†	5.52
4u		250^†	250^†	500^†	500^†	500^†	500^†	500^†	7.33
3v	Cl	250	250	500^†	500^†	500^†	500^†500*	500*	4.09
4v		250	250	500*		500^†	500^†	500^†	5.95
3w	2–yl isomer	32	64	64	125	64	125	125	3.85
4w		4	8	125	250^†	125	250^†	250^†	5.44
3x	4–yl isomer	125	125	125	125	125	125	125	3.38
4x		250^†	250^†	250^†	250^†	250^†	250^†	250^†	4.76
INH	-	0.5	0.5	>250	>250	8	8	16	-0.64
EMB	-	1	2	16	16	1	2	2	0.06

The lowest MIC value(s) for each strain are given in bold.

† At this concentration, strain growth was observed; at twice the concentration, precipitate and/or turbidity was present, i.e. determination of the exact MIC was not possible.

EMB: Ethambutol; INH: Isoniazid; MIC: Minimum inhibitory concentration.

Figure 3. Antimycobacterial structure–activity relationships for pyrimidine derivatives.

Table 2. Activity of 3l and 4l against drug-resistant tuberculous strains.

Code	MIC [μM]
	Mycobacterium tuberculosis Praha 1		Mycobacterium tuberculosis Praha 4		Mycobacterium tuberculosis Praha 131		Mycobacterium tuberculosis 234/2005		Mycobacterium tuberculosis 9449/2007		Mycobacterium tuberculosis 7357/1998		Mycobacterium tuberculosis 8666/2010		Mycobacterium tuberculosis H37Rv
	14 days	21 days	14 days	21 days	14 days	21 days	14 days	21 days	14 days	21 days	14 days	21 days	14 days	21 days	14 days	21 days
3l	≥32	≥32	≥32	≥32	≥32	≥32	≥32	≥32	≥32	≥32	≥32	≥32	≥32	≥32	32	64
4l	2	4	2	4	2	4	2	4	2	4	2	4	4	4	2	4

The lowest MIC values for each strain are given in bold.

M. tuberculosis Praha 1; resistant to STM, INH, EMB, rifamycins, CFZ. M. tuberculosis Praha 4; resistant to STM, INH, EMB, rifamycins, OFX, CFZ. M. tuberculosis Praha 131; resistant to STM, INH, EMB, rifamycins, OFX, GEN, AMK (i.e., XDR-TB strain). M. tuberculosis 9449/2007; resistant to STM, INH, rifamycins. M. tuberculosis 234/2005; resistant to STM, INH, EMB, rifamycins. M. tuberculosis 7357/1998; resistant to STM, INH, rifamycins, EMB, OFX. M. tuberculosis 8666/2010; resistant to STM, INH, EMB, rifamycins, OFX, CFZ.

AMK: Amikacin; CFZ: Clofazimine; EMB: Ethambutol; GEN: Gentamicin; INH: Isoniazid; MIC: Minimum inhibitory concentration; OFX: Ofloxacin; STM: Streptomycin.