Design, synthesis, and characterization of (1-(4-aryl)- 1H-1,2,3-triazol-4-yl)methyl, substituted phenyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates against Mycobacterium tuberculosis

Figures & data

Figure 1 Synthesis of 1,2,3-triazole hybrid with dihydropyrimidinone scaffolds 7a-l.

Table 1 Physicochemical constants of (1-(4-aryl)-1H-1,2,3-triazol-4-yl)methyl, substituted phenyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates 7a-l

Compound code	Molecular formula (molecular mass)	R	R^Citation1	Yield (%)a,b	mp (°C)	cLogPc
7a	C22H17F4N5O3 (475)	4-F	CF	85	194–196	4.6456
7b	C22H17F4N5O3 (475)	3-F	CF	87	178–180	4.6456
7c	C22H17ClF3N5O3 (491)	3-Cl	CF	82	204–206	5.2156
7d	C23H17F6N5O3 (525)	4-CF3	CF	89	188–190	5.3856
7e	C22H17ClF3N5O3 (491)	4-Cl	CF	90	194–196	5.2156
7f	C23H20F3N5O4 (487)	4-OCH3	CF3	92	196–198	4.4216
7g	C23H20F3N5O4(487)	3-OCH3	CF3	87	198–200	4.4216
7h	C23H20F3N5O3 (471)	4-CH3	CF3	89	202–204	5.0016
7i	C24H22F3N5O4 (501)	4-OC2H5	CF3	88	214–216	4.9506
7j	C21H17ClFN5O3 (441)	4-Cl	F	77	144–146	4.3467
7k	C22H17F4N0O3 (475)	CF3	F	89	184–186	4.5167
7l	C21H17F2N5O3 (425)	3-F	F	86	164–166	3.7767

Notes:

a All of the products were characterized by spectral and physical data.

b Yields after purification by column chromatography method.

c cLogP was calculated using ChemBioDraw Ultra 13.0 v.

Table 2 Single crystal data collection and refinement for compound 7g

Data	Compound code 7g
Formula	C23H20F3N5O4
Formula weight	487.3
Temperature (K)	110 (2)
Wavelength (Å)	0.71073
Solvent system, temperature	Benzene, 25°C
CCDC number	1465175
Crystal system	Monoclinic
Space group	P21/c
a (Å)	17.193 (6)
b (Å)	7.745 (3)
c (Å)	17.544 (7)
α (°)	90
β (°)	116.800 (12)
γ (°)	90
V (Å^3)	2,085.2 (14)
Z′, Z	1, 4
Density (g cm^−3)	1.553
μ (mm^−1)	0.126
F (000)	1,008
θ (min, max)	2.327, 29.571
hmin, max, kmin, max, lmin, max	−23 23, −10 10, −24 23
No of reflections	32,355
No of unique reflections/obs reflections	5,826/4,341
No of parameters	326
Rall, Robs	0.0693, 0.0444
wR2all, wR2obs	0.1100, 0.0995
∆ρmin, max (eÅ^−3)	−0.356, 0.378
GOF	1.028

Abbreviations: CCDC, Cambridge Crystallographic Data Center; GOF, goodness of fit.

Table 3 In vitro antitubercular activity of title compounds 7a-l against Mycobacterium tuberculosis

Compound	R	R^Citation1	MIC (µg/mL) code
			H37Rv	MDR-MTB*
7a	4-F	CF3	10	20
7b	3-F	CF3	20	20
7c	3-Cl	CF3	20	NA
7d	4-CF3	CF3	10	15
7e	4-Cl	CF3	NA	NA
7f	4-OCH3	CF3	10	NA
7g	3-OCH3	CF3	20	20
7h	4-CH	CF3	10	NA
7i	4-C2H5	CF3	NA	NA
7j	4-Cl	F	NA	NA
7k	CF3	F	15	NA
7l	3-F	F	20	20

Note:

* These isolates were found to be resistant to the first line antibiotics, rifampicin (1 μg/mL), and isoniazid (0.2 μg/mL).

Abbreviations: MDR-MTB, multidrug-resistant strains of Mycobacterium tuberculosis; MIC, minimum inhibitory concentration; NA, not active.

Figure 2 ORTEP (Oak Ridge Thermal Ellipsoid Plot) of the compound 7g drawn with 50% ellipsoidal probability.

Figure 3 Packing network of compound 7g (A) down the ac plane associated with N-H…O and CH…O dimers (noninteracting H-atoms have been removed for clarity); (B) molecules forming centrosymmetric dimers via N-H…N, C-H…N, C-H…π (Cg1) hydrogen bonds and π…π stacking connected down the ab plane through weak C-H…F hydrogen bond and F…F interactions.

Table 4 Intermolecular interactions in 7g

Motifs	D–H…A	Symmetry	Geometry
			D…A/Å	H…A/Å	∠D–H…A/°
I	N4-H4N…O3	−x+1, −y+1, −z+2	2.829 (2)	1.80	177
II	C9-H9B…N3	−x, y−1/2, −z+3/2	3.857 (2)	2.79	168
III	C18-H18…O1	x, −y+1/2, z−1/2	3.478 (2)	2.54	145
IV	C21-H21A…Cg1	−x, y−1/2, −z+3/2	3.415 (2)	2.60	132
V	C8 (π)…(π) C16	−x, y−1/2,−z+3/2	3.292 (2)	–	–
VI	C6-H6…(π) C13	−x, −y+1, −z+2	3.741 (3)	2.81	145
VII	C22-H22C…O3	x, y−1, z	3.460 (2)	2.50	147
VIII	C22-H22B…O3	−x+1, −y+1, −z+2	3.606 (2)	2.70	141
IX	C20-H20…F2	x+1, y, z	3.510 (2)	2.68	134
X	C5-H5…O2	−x, −y, −z+2	3.425 (2)	2.57	136
XI	N5-H5N…O2	x, y+1, z	3.667 (2)	2.86	136
XII	N5-H5N…N2	−x, y+1/2, −z+3/2	3.069 (2)	2.25	134
XIII	C19-H19…F3	x+1, y, z	3.572 (2)	2.78	130
XIV	C22-H22A…F3	x+1, −y+1/2, z+1/2	3.445 (2)	2.66	129
XV	C7-H7…O4	x, −y+1/2, z+1/2	3.353 (2)	2.66	121
XVI	C21-H21B…O4	−x, −y, −z+1	3.370 (2)	2.66	122
XVII	C21-H21A…N1	−x, y−1/2, −z+3/2	3.601 (2)	2.92	121
XVIII	F1…F3	−x−1, y+1/2, −z+3/2	3.026 (2)	–	–

Note: Cg1 refers to the center of gravity of ring formed by C7-C8-N3-N2-N1.

MayerTUKapoorTMHaggartySJKingRWSchreiberSLMitchisonTJSmall molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screenScience1999286544197197410542155

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