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. 2021 Jun 1;26(11):3320.
doi: 10.3390/molecules26113320.

Synthesis and Neurotropic Activity of New Heterocyclic Systems: Pyridofuro[3,2- d]pyrrolo[1,2- a]pyrimidines, Pyridofuro[3,2- d]pyrido[1,2- a]pyrimidines and Pyridofuro[3',2':4,5]pyrimido[1,2- a]azepines

Samvel N Sirakanyan  1 , Domenico Spinelli  2 , Athina Geronikaki  3 , Victor Kartsev  4 , Elmira K Hakobyan  1 , Anthi Petrou  3 , Ruzanna G Paronikyan  1 , Ivetta M Nazaryan  1 , Hasmik H Akopyan  1 , Anush A Hovakimyan  1
Affiliations

Synthesis and Neurotropic Activity of New Heterocyclic Systems: Pyridofuro[3,2- d]pyrrolo[1,2- a]pyrimidines, Pyridofuro[3,2- d]pyrido[1,2- a]pyrimidines and Pyridofuro[3',2':4,5]pyrimido[1,2- a]azepines

Samvel N Sirakanyan et al. Molecules. .

Abstract

Background: Neurotic disturbances, anxiety, neurosis-like disorders, and stress situations are widespread. Benzodiazepine tranquillizers have been found to be among the most effective antianxiety drugs. The pharmacological action of benzodiazepines is due to their interaction with the supra-molecular membrane GABA-a-benzodiazepine receptor complex, linked to the Cl-ionophore. Benzodiazepines enhance GABA-ergic transmission and this has led to a study of the role of GABA in anxiety. The search for anxiolytics and anticonvulsive agents has involved glutamate-ergic, 5HT-ergic substances and neuropeptides. However, each of these well-known anxiolytics, anticonvulsants and cognition enhancers (nootropics) has repeatedly been reported to have many adverse side effects, therefore there is an urgent need to search for new drugs able to restore damaged cognitive functions without causing significant adverse reactions.

Objective: Considering the relevance of epilepsy diffusion in the world, we have addressed our attention to the discovery of new drugs in this field Thus our aim is the synthesis and study of new compounds with antiepileptic (anticonvulsant) and not only, activity.

Methods: For the synthesis of compounds classical organic methods were used and developed. For the evaluation of biological activity some anticonvulsant and psychotropic methods were used.

Results: As a result of multistep reactions 26 new, five-membered heterocyclic systems were obtained. PASS prediction of anticonvulsant activity was performed for the whole set of the designed molecules and probability to be active Pa values were ranging from 0.275 to 0.43. The studied compounds exhibit protection against pentylenetetrazole (PTZ) seizures, anti-thiosemicarbazides effect as well as some psychotropic effect. The biological assays evidenced that some of the studied compounds showed a high anticonvulsant activity by antagonism with pentylenetetrazole. The toxicity of compounds is low and they do not induce muscle relaxation in the studied doses. According to the study of psychotropic activity it was found that the selected compounds have an activating behavior and anxiolytic effects on the models of "open field" and "elevated plus maze" (EPM). The data obtained indicate the anxiolytic (anti-anxiety) activity of the derivatives of pyrimidines, especially pronounced in compounds 6n, 6b, and 7c. The studied compounds increase the latent time of first immobilization on the model of "forced swimming" (FST) and exhibit some antidepressant effect similarly to diazepam. Docking studies revealed that compound 6k bound tightly in the active site of GABAA receptor with a value of the scoring function that estimates free energy of binding (ΔG) at -7.95 kcal/mol, while compound 6n showed the best docking score and seems to be dual inhibitor of SERT transporter as well as 5-HT1A receptor.

Conclusions: Тhe selected compounds have an anticonvulsant, activating behavior and anxiolytic effects, at the same time exhibit some antidepressant effect.

Keywords: anticonvulsant action; furo[3,2-d]pyrido[1,2-a]pyrimidines; furo[3,2-d]pyrrolo[1,2-a]pyrimidines; furo[3′,2′:4,5] pyrimido [1,2-a]azepines; neurotropic activity.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
General I and lead structure II, III of compounds from our previous study. I. X = CH2, O; R = H, Me; n = 0, 1; R1 = alkyl, aryl; m = 1, 3.
Figure 2
Figure 2
The structure of starting cyclic ketones 1a–c. 1a: X = CH2, n = 0, R = H, b: X = CH2, n = 1, R = H, c: X = O, n = 1, R = Me.
Scheme 1
Scheme 1
Reagents and conditions: i (i’) morpholine, C6H6, TsOH, reflux 5 h, (i’’) RCOCl, Et3N, 35–40 °C, 6 h, (i’’’) NCCH2CONH2, NH(Et)2, reflux 10 h; ii ClCH2COOEt, K2CO3/DMF, 75–80 °C, 2 h; iii EtONa, reflux 20 min. 2–4. a–d: X = CH2, n = 0, R = H, a: R1 = i-Pr; b: R1 = n-Bu; c: R1 = C6H11; d: R1 = 2-furyl; e–h: X = CH2, n = 1, R = H, e: R1 = Me; f: R1 = Et; g: R1 = i-Pr; h: R1 = i-Bu; i–o: X = O, n = 1, R = Me, i: R1 = Me; j: R1 = Et; k: R1 = i-Pr; l: R1 = n-Bu; m: R1 = i-Bu; n: R1 = Ph; o: R1 = 2-furyl.
Scheme 2
Scheme 2
Reagents and conditions: i−2-pyrrolidone (a), 2-piperidone (b), 2-azepanone (c), POCl3, C2H4Cl2, reflux 25 h.
Figure 3
Figure 3
Single crystal X-ray structure of compound 6a.
Figure 4
Figure 4
Docked pose of compound 6k and GABAA receptor complex; Red lines show the hydrogen bonds, yellow and purple-colored spheres and lines represent hydrophobic and aromatic interactions, respectively.
Figure 5
Figure 5
Docked conformation of diazepam and GABAA receptor complex.
Figure 6
Figure 6
(A) Docked pose of compound 6n and SERT transporter complex; (B) 2D ligand interaction diagram for docked ligand.
Figure 7
Figure 7
(A) Docked pose of compound 6n (blue) and alprenolol (red) into 5-HT1A receptor (B) 2D ligand interaction diagram for docked compound 6n.
Figure 8
Figure 8
BOILED-Egg diagram of the tested compounds.
Figure 9
Figure 9
Bioavailability Radar of compounds 6b, 6j, 6k, 6n, 7c, and 7h. The pink area represents the optimal range for each property for oral bioavailability, (Lipophilicity (LIPO): XLOGP3 between −0.7 and +5.0, Molecular weight (SIZE): MW between 150 and 500 g/mol, Polarity (POLAR) TPSA between 20 and 130 Å2, Solubility (INSOLU): log S not higher than 6, Saturation (INSATU): fraction of carbons in the sp3 hybridization not less than 0.25, and Flexibility (FLEX): no more than 9 rotatable bonds.
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