Characterization of Pyridazine Bioisosteres and Their Effects

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This entry is adapted from the peer-reviewed paper 10.3390/pr11082306

Bioisosteres are substituents or groups (atoms, ions, or molecules) with similar chemical or physical properties, and which usually have similar biological properties. Pyridazine and its derivatives are invaluable scaffolds in medicinal chemistry, having a large variety of activities such as antibacterial, antifungal, antimalarial, anticancer, antituberculosis, antihypertensive, etc. Also, the pyridazine core is of high interest in agriculture, being used as a growth factor for plants, herbicides, etc.

pyridazine bioisosteres wheat germination seedling growth

1. Introduction

In drug design, bioisosterism ^[1]^[2]^[3]^[4] is used to enhance the desired biological or physical properties of a compound without making significant changes in its chemical structure. Also, bioisosterism is used to reduce toxicity, change bioavailability, or modify the activity of the lead compound and may alter the metabolism of the lead.

Pyridazine (1,2-diazine) and its derivatives have demonstrated interesting potential applications in different fields of science, being highly valuable materials in medicinal chemistry, opto-electronics, agriculture, etc. ^[4]^[5]^[6]^[7]^[8]^[9]^[10]^[11]^[12]^[13]. The compounds derivatives from pyridazine are invaluable scaffolds in medicinal chemistry, possessing a large range of biological activities: antibacterial, antifungal, antiplasmodial, antitubercular, antiviral, anticancer, antihypertensive, diuretic, antithrombic, anticoagulant, etc.

2. Characterization of Pyridazine Bioisosteres and Investigation of Their Effects

2.1. The Spectral Characterization of Pyridazine Bioisosteres

The structure of the obtained pyridazine-4-R-acetophenone classical bioisosteres 3a–c to 11a–c and trifloromethyl-pyrrolo-pyridazine nonclassical bioisosteres 12a–c to 14a–c was proven by elemental (C, H, N) and spectral analysis: FT-IR and NMR [1-H and 13-C NMR spectra and two-dimensional 2D-COSY, 2D-HETCOR (HMQC), and long range 2D-HETCOR (HMBC) experiments]. All the elemental and spectral data correspond with the proposed structures and could be found in the previously published papers of the team ^[14]^[15]^[16]^[17].

2.2. The Biological Activity of Pyridazine Bioisosteres

The in vitro antibacterial and antifungal activities of the pyridazine-4-R-acetophenone classical bioisosteres 3a–c to 11a–c and trifloromethyl-pyrrolo-pyridazine nonclassical bioisosteres 12a–c to 14a–c, were determined against five Gram-positive and Gram-negative bacterial strains (Staphylococcus aureus ATCC 25923, Sarcina lutea ATCC 9341, Bacillus subtillis, Pseudomonas aeruginosa, Escherichia coli ATCC 25922), and one fungus (Candida albicans ATCC 10231). Table 1 and Table 2 summarise the antibacterial and antifungal activity of the bioisosteres and control drugs, expressed as inhibition zone diameters (mm).

Table 1. The antibacterial and antifungal activity of pyridazine-4-R-acetophenone in classical bioisosteres 3a–c to 11a–c *.

Comp.	S. aureus ⁽¹⁾	S. Lutea ⁽²⁾	B. subtillis ⁽³⁾	P. aeruginosa ⁽⁴⁾	E. coli ⁽⁵⁾	C. albicans ⁽⁶⁾
Chloram phenicol 30 μg/disc	30	40	26	19	25	-
Nystatin, 100 μg/disc	-	-	-	-	-	29
3a.	38	61	31	20	31	19
3b.	36	57	32	20	36	29
3c.	47	81	40	20	25	27
5a.	26	50	27	14	20	23
5b.	30	57	29	14	28	35
5c.	46	67	39	19	23	30
7a.	27	48	22	20	23	22
7b.	25	48	25	20	33	30
7c.	40	56	37	18	25	28
8a.	27	52	23	15	21	21
8b.	30	57	26	18	31	24
8c.	46	65	26	19	25	29
9a.	27	63	28	16	25	25
9b.	28	54	28	18	28	34
9c.	31	73	37	18	24	29
10a.	29	60	37	18	35	24
10b.	33	56	39	18	32	25
10c.	41	62	39	19	37	30
11a.	29	51	35	17	35	27
11b.	23	54	36	15	31	27
11c.	47	59	38	17	37	29

⁽*⁾ the series ‘a’ of compound is related to F, the series ‘b’ of compound is connected to Cl and the series ‘c’ of compound involve CH₃. ⁽¹⁾ Staphylococcus aureus. ⁽²⁾ Sarcina lutea. ⁽³⁾ Bacillus subtillis. ⁽⁴⁾ Pseudomonas aeruginosa. ⁽⁵⁾ Escherichia coli. ⁽⁶⁾ Candida albicans; Bold and underline means very active compound.

Table 2. The antibacterial and antifungal activity for trifloromethyl -pyrrolo-pyridazine nonclassical bioisosteres 12a–c to 14a–c.

Comp.	S. aureus	S. lutea	B. subtillis	P. aeruginosa	E. coli	C. albicans
Chloram phenicol 30 μg/disc	25	30	25	19	29	-
Nystatin, 100 μg/disc	-	-	-	-	-	29
12a.	30	41	31	16	34	29
12b.	29	44	38	18	42	26
12c.	49	60	36	19	40	32
13a.	28	55	31	19	26	27
13b.	30	58	33	20	35	37
13c.	30	59	39	20	28	30
14a.	88	58	38	21	31	29
14b, b’	35	61	42	19	38	39
14c.	29	61	38	21	27	31

Bold and underline means very active compound.

2.3. Tables

The most active compounds are listed in bold and underlined.

In Table 3, the effect of the pyridazine-4-R-acetophenone classical bioisosteres on wheat germination is summarised.

Table 3. The effect of pyridazine-4-R-acetophenone classical bioisosteres 3a–c to 11a–c on wheat germination.

Compound	Germination Rate (GR, %)	Number of Plantlets in the Lot
3a.	64 ± 5	26 ± 1
3b.	38 ± 4	14 ± 5
3c.	69 ± 4	9 ± 2
5a.	61 ± 4	26 ± 4
5b.	54 ± 5	20 ± 3
7a.	81 ± 3	34 ± 4
7b.	54 ± 4	20 ± 4
8a.	73 ± 5	32 ± 2
8b.	80 ± 4	24 ± 3
9a.	72 ± 4	34 ± 3
9b.	72 ± 4	25 ± 1
10a.	73 ± 5	30 ± 3
10b.	61 ± 5	17 ± 2
10c.	59 ± 6	22 ± 1
11a.	0 ± 0	0 ± 0
11b.	79 ± 4	26 ± 6
11c.	40 ± 5	28 ± 5

In Table 4, the effect of the pyridazine-4-R-acetophenone classical bioisosteres on wheat germination and seedling growth is summarised. The main parameters used are the total height of plantlets in the lot, H, the mean height of plantlets in the lot, Hm, the weight of plantlets in the lot, W, and the mean weight of plantlets in the lot, Wm. The blank control was water, W.

Table 4. The effect of pyridazine-4-R-acetophenone classical bioisosteres 3a–c to 11a–c on wheat germination and seedling growth.

Compound	H, cm	Hm, cm	W, g	Wm, mg
3a.	121 ± 15	5 ± 1	0.89 ± 0.12	40 ± 5
3b.	52 ± 13	5 ± 0.4	0.47 ± 0.19	42 ± 17
3c.	52 ± 13	5 ± 0.9	0.47 ± 0.41	40 ± 3
5a.	178 ± 17	6 ± 0.6	1 ± 0.12	34 ± 2
5b.	120 ± 15	7 ± 0.8	0.8 ± 0.13	44 ± 0.07
7a.	239 ± 17	6 ± 0.4	1.38 ± 0.16	35 ± 4
7b.	117 ± 6	27 ± 0.4	0.75 ± 0.07	43 ± 4
8a.	233 ± 26	7 ± 0.7	1.37 ± 0.14	37 ± 4
8b.	133 ± 3	6 ± 0.1	0.87 ± 0.17	42 ± 8
9a.	198 ± 7	5 ± 0.6	1.11 ± 0.15	29 ± 13
9b.	149 ± 8	7 ± 0.3	0.95 ± 0.14	45 ± 4
10a.	186 ± 32	6 ± 0.9	1.11 ± 0.19	32 ± 5
10b.	77 ± 10	6 ± 0.7	0.64 ± 0.30	42 ± 2
10c.	11 ± 0.3	0.55 ± 0.01	0.08 ± 0.01	40 ± 0.01
11a.	0 ± 0	0 ± 0	0 ± 0	0 ± 0
11b.	185 ± 19	8 ± 0.8	1.06 ± 0.19	47 ± 8.48
11c.	136 ± 31	6 ± 1.3	0.98 ± 0.08	42 ± 3.36
W (water)	224 ± 23	7 ± 0.7	1.42 ± 0.19	42 ± 6

H—the total height of plantlets in the lot; Hm—the mean height of plantlets in the lot; W—the weight of plantlets in the lot; Wm—the mean weight of plantlets in the lot.

The data presented in Table 1, Table 2, Table 3 and Table 4, allow interesting correlations and conclusions related to the antibacterial, antifungal and biologic effect on wheat germination and seedling growth to be obtained.

2.4. Antibacterial Activity

Analysis of the data from Table 1 reveals some interesting structure-activity correlations in the series of pyridazine-4-R-acetophenone classical bioisosteres 3a–c to 11a–c. The authors notice a certain significative influence of the isosteres substituent R from the para(4)-position of the acetophenone moiety, with the bioisosteres compounds in which R is a methyl (-CH₃) moiety being far more active than those in which the substituent R is fluorine (-F) or chlorine (-Cl) atoms. The authors also notice that all bioisosteres, no matter to what class they belong, have excellent antibacterial activity against the Gram-positive strain Sarcina lutea, some results being spectacular, with an activity twice as high as that of the reference drug Chloramphenicol. The authors notice that the pyridazine-4-R-acetophenone salts 3a–c have excellent nonselective antibacterial activity against all Gram-positive and Gram-negative bacteria. A comparative analysis of the series of pyridazine-4-R-acetophenone bioisosteres 3a–c to 11a–c reveals that the bioisostere salts 3a–c are significantly more active than the bioisostere cycloadducts 5a–c to 11a–c (the authors explain this behaviour due to the complementary action of the bromine anion). In the series of bioisosteres cycloadducts 5a–c to 11a–c, the comparative analysis reveals that saturated structures (the tetrahydropyrrolo one) are more active compared with the others.

Analysis of the data from Table 2 reveals that trifloromethyl-pyrrolo-pyridazine nonclassical bioisosteres (12a–c to 14a–c) have an analogous behaviour with classical bioisosteres, with some particularities. All nonclassical bioisosteres, no matter the class to which they belong, have excellent antibacterial activity against two Gram-positive strains, Bacillus subtilis and Sarcina lutea. The authors notice that the trifloromethyl-pyrrolo-pyridazine nonclassical bioisosteres 13a–c and 14a–c have better activity compared with 12a–c, which leads them to the conclusion that a saturated tetrahydro-pyrrolo-pyridazine structure (bioisosteres 13a–c and 14a–c) is more favourable for antibacterial activity compared with an aromatized pyrrolo-pyridazine structure (bioisostere 12a–c).

2.5. Antifungal Activity

The data from Table 1 indicate that the synthesised pyridazine-4-R-acetophenone classical bioisosteres 3a–c to 11a–c have no significant antifungal activity. The data from Table 2 reveal that in the case of trifloromethyl-pyrrolo-pyridazine nonclassical bioisosteres 12a–c to 14a–c, there are two compounds (13b to 14b) that manifest a very good antifungal activity against the fungus Candida albicans; this fact led them to the conclusion that the combining presence of a trifloromethyl moiety (on the pyrrolo-pyridazine motif) and a chlorine atom (on the 4-R-acetophenone scaffold) is favourable for antifungal activity.

2.6. The Biologic Effect on Wheat Germination and Seedling Growth

Statistics. The data were validated by the Tukey test ^[18].

The data from Table 3 and Table 4 indicate that the pyridazine-4-R-acetophenone bioisosteres 3a–c to 11a–c have a significant influence on the germination process of the wheat seeds and also on the seedling growth process. From a bioisosterism point of view, the data from Table 3 indicate a certain influence of the substituent R from the para(4)-position of the acetophenone moiety, the bioisosteres having a chlorine (-Cl) atom having the most noxious effect on wheat germination. A comparative analysis of the series of pyridazine-4-R-acetophenone bioisosteres 3a–c to 11a–c reveals that the bioisostere salts 3a–c manifest a more toxic effect on wheat germination than the bioisostere cycloadducts 5a–c to 11a–c. Once again, the authors explain this behaviour as due to the complementary action of the bromine anion. The pyridazine-4-R-acetophenone bioisosteres also have an influence on the number of plantlets in the seedling process. The bioisostere compounds having a chlorine (-Cl) atom or a methyl (-CH₃) moiety have the most noxious effect, killing more than 50% of the seeds.

The data from Table 4 reveal that both the height and weight of the plantlets are significantly affected by pyridazine-4-R-acetophenone bioisosteres, with a significant decrease. Once again, the authors notice a certain influence of the isosteres substituent R from the para (4)-position of the acetophenone moiety, the bioisosteres having a chlorine (-Cl) atom have the most noxious effect, decreasing the significant height and weight of the plantlets; for instance, in the case of bioisostere salt 3c, the height is reduced to 52 cm (compared with 223 for blank) while the weight decreases to 0.47 g (compared with 1.42 g for blank). A comparative analysis of the series of pyridazine-4-R-acetophenone bioisosteres 3a–c to 11a–c revealed that the bioisostere salts 3a–c manifest a more toxic effect on the height and weight of the plantlets compared with the bioisostere cycloadducts 5a–c to 11a–c, roughly by about 50%.

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