Description:[0030] The following description describes various features and functions of the disclosed system with reference to the accompanying figures. In the figures, similar symbols identify similar components, unless context dictates otherwise. The illustrative aspects described herein are not meant to be limiting. It may be readily understood that certain aspects of the disclosed system can be arranged and combined in a wide variety of different configurations, all of which have not been contemplated herein.
[0031] Accordingly, those of ordinary skill in the art will recognize that various changes and modifications of the embodiments described herein can be made without departing from the scope of invention. In addition, descriptions of well-known functions and constructions are omitted for clarity and conciseness.
[0032] Features that are described and/or illustrated with respect to one embodiment may be used in the same way or in a similar way in one or more other embodiments and/or in combination with or instead of the features of the other embodiments.
[0033] The terms and words used in the following description are not limited to the bibliographical meanings but are merely used to enable a clear and consistent understanding of the invention. Accordingly, it should be apparent to those skilled in the art that the following description of exemplary embodiments of the present invention are provided for illustrative purpose only and not for the purpose of limiting the invention.
[0034] It is to be understood that the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise.
[0035] It should be emphasized that the term “comprises/comprising” when used in this specification is taken to specify the presence of stated features, integers, steps or components but does not preclude the presence or addition of one or more other features, steps, components or groups thereof.
[0036] Accordingly, the present invention relates to novel heterocyclic compounds and pharmaceutically acceptable salt or derivatives thereof. Particularly, the present invention relates to dihydroquinazoline derivatives as multi-targeting agents for the treatment of neurological disorders. More particularly, the present invention relates to dihydroquinazoline derivatives based multi-targeting agents for the treatment of neurological disorders and method for preparation thereof.
[0037] The present invention relates to a heterocyclic compound, preferably Dihydroquinazoline derivatives of formula 1 and pharmaceutically acceptable salt thereof (represented as formula 1). The formula 1 is represented a

Wherein
• R1 is the independently selected from a group of, not limiting to morpholine, piperidine, thiomorpholine, pyrrolidine, methyl piperazine, ethyl piperazine, benzyl piperazine, phenyl piperazine, -H, -NH2, -CH3, -Ph, -Ph-F, -Ph-Cl, -Ph-Br, -Ph-CH3.
• R2, R3, R4, R5, R6, R7, R8, R9, and R10 are independently selected from a group of, not limiting to, H, F, Cl, Br, I, NO2, CH3, OCH3, CN, NH2, CH2CH3, isopropyl, vinyl, allyl, phenyl and/or Y-(CH2)m-Z wherein,
o Y is selected from a group of, not limiting to, O or N;
o m is a value between 0 to 4; and
o Z is independently selected from a group of, not limited to, morpholine, piperidine, N, N-dimethyl, pyrrolidine, acetylene and the like.
[0038] In an embodiment, the present invention relates to dihydroquinazoline derivatives of formula 1 and pharmaceutically acceptable salt thereof (represented as formula 1). The formula 1 is represented as

wherein
• R1 is the independently selected from a group of, not limiting to morpholine, piperidine, thiomorpholine, pyrrolidine, methyl piperazine, ethyl piperazine, benzyl piperazine, phenyl piperazine, -H, -NH2, -CH3, -Ph, -Ph-F, -Ph-Cl, -Ph-Br, -Ph-CH3.
• R2, R3, R4, R5, R6, R7, R8, R9, and R10 are independently selected from a group of, not limiting to, H, F, Cl, Br, I, NO2, CH3, OCH3, CN, NH2, CH2CH3, isopropyl, vinyl, allyl, phenyl and/or Y-(CH2)m-Z wherein,
o Y is selected from a group of, not limiting to, O or N;
o m is a value between 0 to 4; and
o Z is independently selected from a group of, not limited to, morpholine, piperidine, N, N-dimethyl, pyrrolidine, acetylene and the like.
[0039] The present invention also provides a method of preparation of dihydroquinazoline derivatives of formula 1 or a pharmaceutically acceptable salt thereof.
[0040] In an exemplary embodiment, the present invention relates to dihydroquinazoline derivatives of formula 1 selected from the following compounds:
Compound IUPAC name Compounds of Formula 1
1 4-(4-phenyl-8-(prop-2-yn-1-yloxy)-5,6-dihydrobenzo[h]quinazolin-2-yl)thiomorpholine
2 4-phenyl-8-(prop-2-yn-1-yloxy)-2-(pyrrolidin-1-yl)-5,6-dihydrobenzo[h]quinazoline
3 4-(4-nitrophenyl)-2-(piperidin-1-yl)-5,6-dihydrobenzo[h]quinazoline

4 2-(4-fluorophenyl)-4-(3-(prop-2-yn-1-yloxy)phenyl)-5,6-dihydrobenzo[h]quinazoline (K2J-9)
5 4-(3-(prop-2-yn-1-yloxy)phenyl)-2-(p-tolyl)-5,6-dihydrobenzo[h]quinazoline (K2J-12)

6 2-methyl-4-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-5,6-dihydrobenzo[h]quinazoline
7 4-(4-(3-(dimethylamino)propoxy)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-amine

[0041] The method for preparation of dihydroquinazoline derivatives (formula 1) involve reaction between substituted aldehydes and substituted tetralone in the presence of an iodine, urea, BOP, base and a solvent.
[0042] In an embodiment, the method for synthesis of dihydroquinazoline derivatives comprises of the following schemes:
Scheme-I

Scheme-II

• In an exemplary embodiment, the alkylating agent used in the present invention is selected from a group consisting of such as, but not limited to, propargyl bromide, or allyl bromide or acetylene bromide, vinyl bromide, and Y-(CH2)m-Z wherein,
o Y is selected from a group of, not limiting to, O or N;
o m is a value between 0 to 4; and
o Z is independently selected from a group of, not limited to, morpholine, piperidine, N, N-dimethyl, pyrrolidine, acetylene and the like.
[0043] In an exemplary embodiment, the base used in the present invention is selected from a group consisting of such as, but not limited to, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) and the like.
[0044] In an exemplary embodiment, the cyclizing agent is selected from a group consisting of such as, but not limited to Urea and amidines.
[0045] In an exemplary embodiment, the solvent is selected from a group consisting of such as, but not limited to, ethanol, methanol, acetonitrile, dimethylformamide, acetone and the like.
[0046] In an exemplary embodiment, the catalyst used in the present invention is selected from a group consisting of, such as, but not limited to, iodine.
[0047] In an embodiment of the present invention, the process of preparation of dihydroquinazoline derivatives comprises the following steps:
i. Alkylation of substituted benzaldehydes & tetralones to prepare forming Intermediate I & II i.e. alkylated benzaldehydes/tetralones in Scheme I and alkylation of substituted benzaldehydes into Intermediate I i.e. alkylated benzaldehydes in Scheme II:
The substituted benzaldehydes/tetralones are reacted with an alkylating agent and a base in a solvent at a temperature in the range of 70-80 °C for 3 to 8 h. The ratio of substituted benzaldehyde or tetralone/base/alkylating agent is taken in the range of 1:1.1:1.1 to 1:2.5:2. The progress of the reaction is monitored through TLC. On the completion of reaction, the reaction mixture is poured on crushed ice to obtain precipitates of alkylated benzaldehydes or tetralones which are filtered and dried under vacuum. In a case, if precipitates are not formed the Intermediate I & II are extracted by workup with organic solvents (3x times) and organic layer washed with brine followed by passing from anhydrous sodium sulphate and dried under vacuum.

ii. Reacting alkylated benzaldehydes (Intermediate I) and alkylated tetralones (Intermediate II) prepared in step (i) as per Scheme I with urea to form cyclized Intermediate II i.e. substituted 4-phenyl-5,6-dihydrobenzo[h]quinazolin-2(1H)-one(s):
The substituted aldehydes prepared in step (i) is reacted with substituted tetralones (also prepared in step (i)) in the presence of a catalyst iodine and cyclizing agent urea in a ratio in the range of 0.1:1 to 0.5:3 in a solvent at 70-80ºC temperature for 8-10h in a reaction vial until completion. The progress of the reaction was monitored through TLC, and on completion of the reaction iodine was quenched with saturated solution of sodium thiosulfate and excess solvent was vaporized. Then the reaction mixture was extracted with organic solvent (3x times) and organic layer washed with brine followed by passing from sodium sulphate and dried to get Intermediate III as per scheme I.
iii. Substituting dihydroquinazolinone intermediate, a cyclized Intermediate III prepared in step (ii) as per scheme I with different secondary amines to form the final compound prescribed in formula 1;
The substituted 4-phenyl-5,6-dihydrobenzo[h]quinazolin-2(1H)-one(s) prepared in step (ii) dissolved in a solvent to add DBU and BOP in range of 1:1 to 2:1.5 to be stirred for 1-3 h. The TLC was performed to confirm the conversion of Intermediate III into a reactive intermediate which then reacted with nucleophiles i.e. different types of secondary amines (1 to 2) at room temperature for 12-14 h. The reaction’s progress was monitored through TLC. The reaction mixture was extracted with organic solvent (3x times) and organic layer washed with brine followed by passing from anhydrous sodium sulphate and dried to get the product. This crude product was purified with column chromatography to obtained pure substituted 4-phenyl-5,6-dihydrobenzo[h]quinazoline.
iv. In scheme II, reacting alkylated benzaldehydes obtained in step (i) and tetralone to form substituted 2-benzylidene-3,4-dihydronaphthalen-1(2H)-one
The substituted benzaldehydes prepared in step (i) are reacted with tetralone using a base in a solvent at room temperature for 6-8 h. The ratio of substituted benzaldehydes /base/ tetralone is taken in the range of 1:0.1:1 to 1:0.5:1; The progress of the reaction is monitored through TLC. On the completion of reaction, the reaction mixture is poured on crushed ice to obtain precipitates of substituted 2-benzylidene-3,4-dihydronaphthalen-1(2H)-one which are filtered, and dried. In a case, if precipitates are not formed the Intermediate II are extracted by workup with organic solvents (3x times) and organic layer washed with brine followed by passing from anhydrous sodium sulphate and dried under vacuum.
v. Cyclizing Intermediate II prepared in step (ii) as per Scheme II with different amidines to give final compound prescribed in formula 1:
The substituted 2-benzylidene-3,4-dihydronaphthalen-1(2H)-one prepared in step (ii) is reacted with different amidines in the presence of a base in a solvent at the temperature of 60-80ºC for 4-6 h in a ratio in the range of 1:0.7:1 to 1:2:4 until completion. The progress of the reaction was monitored through TLC, and on completion of the reaction, the reaction mixture was extracted with organic solvent (3x times) and organic layer washed with brine followed by passing from anhydrous sodium sulphate and dried to get crude product. Then, it was purified with gravity column chromatography to obtained pure substituted 4-phenyl-5,6-dihydrobenzo[h]quinazoline.
[0048] In an embodiment, dihydroquinazoline derivatives synthesized in the present invention serves as multi-targeting agents for the treatment of neurological disorders such as, but not limited to, Alzheimer’s disease, Parkinson’s disease, depression, Huntington chorea, amyotrophic lateral sclerosis, ageing, cerebral ischaemia, and substance-abuse risk. The multi-targeting agents formed in the present invention bind to the multiple targets and receptor activity can be modulated as per requirement.
EXPERIMENTAL APPROACH The following examples provide different products synthesized in the present invention and should not be construed to limit the scope of the present invention.
Methodology: Synthetic procedure for Examples 1 to 3
1. To a 50 ml round bottom flask (RBF), 6-hydroxy tetralone (1 eq.) was solubilized in a minimum volume of DMF as solvent, propargyl bromide (1.2 eq.) and potassium carbonate (2.2 eq.) were added. The resulting reaction mixture was heated in the oil bath at 70-80 ℃ for about 4-5 h with continuous stirring. Upon completion of the reaction, extraction was done with water-ethyl acetate (3x times). The organic layer was washed with brine, dried over anhydrous sodium sulphate, and concentrated using a rotary evaporator. The resulting crude product was used for the next step without any purification.
2. To a 50 ml round bottom flask (RBF), benzaldehyde (1 eq.), O-propargylated tetralone derivatives (1 eq.), Urea (3 eq.), and Iodine (1.5 eq.) were added, with ethanol as the solvent. The resulting reaction mixture was heated on the oil bath at 80 ℃ for about 7-8 h. Upon completion, the reaction mixture was poured on crushed ice in beaker and iodine was quenched using a saturated solution of sodium thiosulfate. Subsequent extraction was performed using chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and concentrated using a rotary evaporator. The resulting crude product, a dihydroquinazolinone derivative, was purified through multiple time washing and recrystallized with methanol and dried under vacuum oven for overnight and, used for the next step.
[0049] 3. In a 50 mL RBF, dihydroquinazolinone derivative (1 eq.) was dissolved in acetonitrile with stirring at room temperature (RT), DBU (2 eq.) was added to the mixture, followed by the addition of BOP (1.5 eq.). The reaction mixture was stirred at RT for 2-3 h, after which TLC was performed in methanol/chloroform to confirm the conversion of the intermediate. Subsequently, the nucleophile (2 eq.) was added to the reaction mixture, and stirring was continued at RT for 12–14 h. Upon completion of the reaction, water was added to it and the mixture was extracted with chloroform. The organic layer was separated, washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure using a rotary evaporator. The final crude product, a dihydroquinazoline compound, was subjected to purification via gravity column chromatography. Ethyl acetate in petroleum ether was used as the eluent to yield the desired product. NMR and HRMS analysis were done for the characterization of synthesized compounds.
[0050] Example 1: 4-(4-phenyl-8-(prop-2-yn-1-yloxy)-5,6-dihydrobenzo[h]quinazolin-2-yl)thiomorpholine

[0051] IC50 MAO-B: 1.17 µM, AChE: 0.93 µM. Aβ1-42 self-aggregation inhibition at 20 µM: 35.21 %; Yield: 62%, pale-yellowish coloured powder; 1H NMR (CDCl3, 600 MHz, δ with TMS=0) 8.27 (1H, d, J=6Hz), 7.60 (2H, d, J=6Hz), 7.48 (3H, m, J=6Hz), 6.93 (1H, d, J=12Hz), 6.79 (1H, s), 4.76 (2H, s), 4.28 (4H, t, J=6Hz), 2.90 (2H, t, J=6Hz), 2.81 (2H, t, J=6Hz), 2.72 (5H, m, J=6Hz); 13C NMR (CDCl3, 151 MHz): 164.5, 160.1, 159.0, 141.6, 139.0, 128.9, 128.8, 128.1, 127.7, 127.4, 114.2, 113.7, 113.4, 98.6, 82.3, 74.6, 46.3, 29.7, 28.7, 27.0, and 24.1; HRMS: m/z [M+H]+ for C25H23N3OS, calculated: 414.1635; observed: 414.1615.
[0052] Example 2: 4-phenyl-8-(prop-2-yn-1-yloxy)-2-(pyrrolidin-1-yl)-5,6-dihydrobenzo[h]quinazoline

[0053] IC50 MAO-B: 0.79 µM, AChE: 0.85 µM. Aβ1-42 self-aggregation inhibition at 20 µM: 40.34 %; Yield: 62%, light-brownish coloured powder; 1H NMR (CDCl3, 600 MHz, δ with TMS=0) 8.34 (1H, d, J=6Hz), 7.62 (2H, d, J=6Hz), 7.46 (3H, m, J=6Hz), 6.97 (1H, d, J=6Hz), 6.81 (1H, s), 4.75 (2H, s), 3.71 (4H, t, J=6Hz), 2.88 (2H, t, J=6Hz), 2.79 (2H, t, J=6Hz), 2.55 (1H, s), 2.01 (4H, t, J=6Hz); 13C NMR (CDCl3, 151 MHz): 164.5, 159.9, 159.6, 159.2, 141.6, 136.4, 129.0, 128.7, 128.1, 128.0, 127.4, 113.7, 113.3, 112.5, 78.5, 75.8, 55.8, 46.7, 28.9, 25.7, and 24.2; HRMS: m/z [M+H]+ for C25H23N3O, calculated: 382.1914; observed: 382.1894.
[0054] Example 3: 4-(4-nitrophenyl)-2-(piperidin-1-yl)-5,6-dihydrobenzo[h]quinazoline

[0055] IC50 MAO-B: 0.55 µM, AChE: 0.42 µM. Aβ1-42 self-aggregation inhibition at 20 µM: 40.6 %; Yield: 46%, intense yellow colored crystals; 1H NMR (CDCl3, 600 MHz, δ with TMS=0) 8.34 (1H, d, J=6Hz), 8.31 (2H, d, J=6Hz), 7.78 (2H, d, 6Hz), 7.38 (2H, dd, 6Hz), 7.22 (1H, d, 6Hz), 3.91 (4H, t, 6Hz), 2.83 (4H, t, 3Hz), 1.71 (2H, m), 1.66 (4H, m); 13C NMR (CDCl3, 151 MHz, δ with TMS=0): δ =162.2, 160.9, 160.7, 147.9, 145.6, 139.4, 133.7, 130.5, 130.0, 127.7, 127.0, 125.8, 123.4, 113.5, 44.9, 28.4, 25.9, 25.0, and 24.1; Calculated [M+H]+= 387.1819, Observed [M+H]+=387.1836.
[0056] Synthetic procedure for Examples 4 to 7
1. To a 50 ml RBF, 3-hydroxy-benzaldehyde (1 eq.) was dissolved in DMF and K2CO3 (2.2 eq.) was added along with propargyl bromide (1.1 eq.). The reaction mixture was heated at 80 °C for 6-8 h. On the completion of reaction, the reaction mixture was poured on crushed ice in beaker and precipitates of 3-(prop-2-yn-1-yloxy)benzaldehyde were filtered out and dried in vacuum oven. Further the precipitates were crystallized in ethanol and used for further reactions.
2. In a 50 ml of RBF, 3-(prop-2-yn-1-yloxy)benzaldehyde (1 eq.) was dissolved in minimum volume of methanol along with tetralone (1 eq.) and 1-2 ml of 20% NaOH. The reaction mixture was stirred at room temperature for 10-12 h and progress of the reaction was monitored through TLC. On the completion of reaction excess solvent was evaporated under vacuum using rotary evaporator. The reaction mixture was poured into the crushed ice and precipitates was form. The solid precipitates of 2-(3-(prop-2-yn-1-yloxy)benzylidene)-3,4-dihydronaphthalen-1(2H)-one was filtered under vacuum and dried in vacuum oven. The resultant intermediate was used for next step without purification.
3. In the final step 4-fluoro-benzamidine (1 eq.) was reacted with 2-(3-(prop-2-yn-1-yloxy)benzylidene)-3,4-dihydronaphthalen-1(2H)-one intermediate in the presence of NaOH (4 eq.) in ethanol as solvent. The reaction mixture was refluxed in the RBF with continuous stirring. On the completion of reaction excess solvent was evaporated under vacuum using rotary evaporator. followed by extraction with ethyl acetate (3x times). The combined organic layer was washed with brine and dried over anhydrous sodium sulphate. The organic layer was evaporated under vacuum using rotary evaporator to obtain the crude product. The crude product was purified with column chromatography (EA in PE) to obtained pure 2-(4-fluorophenyl)-4-(3-(prop-2-yn-1-yloxy)phenyl)-5,6-dihydrobenzo[h]quinazoline.
Example 4: 2-(4-fluorophenyl)-4-(3-(prop-2-yn-1-yloxy)phenyl)-5,6-dihydrobenzo[h]quinazoline

[0057] IC50 MAO-B: 0.950 µM, AChE: 1.72 µM. Aβ1-42 self-aggregation inhibition at 20 µM: 35.7 %; creamish coloured crystal; Yield 72%, 1H NMR (600 MHz, CDCl3) δ 8.65 (t, J = 7.3 Hz, 2H), 8.57 (d, J = 6.1 Hz, 1H), 7.45 (t, J = 6.9 Hz, 3H), 7.36 – 7.32 (m, 2H), 7.17 (t, J = 8.7 Hz, 2H), 7.13 (d, J = 8.3 Hz, 1H), 6.89 – 6.83 (m, 1H), 4.78 (s, 2H), 3.10 (t, J = 7.4 Hz, 2H), 2.91 (t, J = 7.4 Hz, 2H), 2.57 (s, 1H); 13C NMR (151 MHz, CDCl3) δ 163.9, 161.3, 160.3, 157.5, 139.7, 139.2, 134.3, 133.2, 130.9, 130.3, 130.2, 129.4, 127.8, 127.3, 126.0, 123.4, 122.5, 115.8, 115.3, 115.2, 78.5, 75.8, 56.0, 27.8, 24.8; HRMS: m/z [M+H]+ for C29H19FN2O, calculated: 407.1554; observed: 407.1567

Example 5: 4-(3-(prop-2-yn-1-yloxy)phenyl)-2-(p-tolyl)-5,6-dihydrobenzo[h]quinazoline

[0058] IC50 MAO-B: 1.68 µM, AChE: 1.10 µM. Aβ1-42 self-aggregation inhibition at 20 µM: 43.03 %; creamish coloured powder, Yield 64%, 1H NMR (600 MHz, CDCl3) δ 8.59 (d, J = 7.9 Hz, 1H), 8.54 (d, J = 7.9 Hz, 2H), 7.46 – 7.42 (m, 3H), 7.37 – 7.33 (m, 2H), 7.30 (d, J = 7.9 Hz, 2H), 7.25 (s, 1H), 7.11 (dd, J = 8.2, 2.6 Hz, 1H), 4.78 (d, J = 2.4 Hz, 2H), 3.09 (t, J = 7.2 Hz, 2H), 2.90 (t, J = 7.2 Hz, 2H), 2.56 (t, J = 2.5 Hz, 1H), 2.43 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 163.8, 162.2, 160.1, 157.5, 140.4, 139.9, 139.1, 135.5, 133.5, 130.8, 129.4, 129.1, 128.1, 127.7, 127.3, 126.1, 123.2, 122.5, 115.8, 78.5, 75.7, 56.0, 27.9, 24.8, 21.5; HRMS: m/z [M+H]+ for C28H22N2O, calculated: 403.1805; observed: 403.1818
[0059] Example 6: 2-methyl-4-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-5,6-dihydrobenzo[h]quinazoline

[0060] IC50 MAO-B: 0.12 µM, AChE: 0.79 µM. Aβ1-42 self-aggregation inhibition at 20 µM: 28.85 %; brown coloured liquid, Yield 74%, 1H NMR (600 MHz, CDCl3) δ 8.38 (dd, J = 5.6, 3.5 Hz, 1H), 7.56 (dd, J = 6.6, 2.4 Hz, 2H), 7.41 – 7.38 (m, 2H), 7.24 (t, J = 4.5 Hz, 1H), 7.01 (dd, J = 6.6, 2.4 Hz, 2H), 4.20 (t, J = 6.0 Hz, 2H), 3.00 (t, J = 7.2 Hz, 2H), 2.85 (p, J = 7.2 Hz, 4H), 2.80 (s, 3H), 2.57 (t, J = 7.8 Hz, 4H), 1.65 (p, J = 5.7 Hz, 6H); 13C NMR (151 MHz, CDCl3) δ 165.7, 163.9, 160.0, 159.6, 139.2, 133.2, 130.8, 130.6, 127.8, 127.3, 125.9, 122.3, 114.5, 65.9, 57.8, 55.0, 54.9, 29.8, 27.9, 26.2, 25.8, 24.7, 24.1.
[0061] Example 7: 4-(4-(3-(dimethylamino)propoxy)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-amine

[0062] IC50 MAO-B: 0.24 µM, AChE: 0.83 µM. Aβ1-42 self-aggregation inhibition at 20 µM: 31.30 %; Light brown coloured powder, Yield 69%, 1H NMR (600 MHz, CDCl3) δ 8.26 (dd, J = 7.0, 2.1 Hz, 1H), 7.52 (d, J = 8.7 Hz, 2H), 7.37 (t, J = 3.9 Hz, 2H), 7.22 (d, J = 5.9 Hz, 1H), 6.97 (d, J = 8.7 Hz, 2H), 5.10 (s, 2H), 4.12 (t, J = 6.0 Hz, 2H), 2.99 (t, J = 7.8 Hz, 2H), 2.87 (t, J = 6.6 Hz, 2H), 2.81 (t, J = 7.5 Hz, 2H), 2.66 (s, 6H), 2.26 (p, J = 13.8 Hz, 2H), 13C NMR (CDCl3, 151 MHZ, δ with TMS=0) 164.9, 161.6, 161.1, 159.1, 139.5, 133.3, 131.2, 130.5, 130.3, 127.7, 127.1, 125.6, 116.0, 114.2, 65.3, 56.0, 44.0, 28.4, 25.6, 24.3; HRMS: m/z [M+H]+ for C23H26N4O, calculated: 375.2179; observed: 375.2193
[0063] Biological Investigations
Biological investigations of dihydroquinazoline derivatives synthesized in the present invention was performed to evaluate the biological activity of the synthesized compound for the treatment of neurological disorders such as, but not limited to, Alzheimer’s disease, Parkinson’s disease, depression, Huntington chorea, amyotrophic lateral sclerosis, ageing, cerebral ischaemia, and substance-abuse risk. The potential of the synthesized compounds for monoamine oxidase enzyme, acetylcholinesterase enzyme, beta amyloid aggregation, reactive oxygen species inhibition, neurorescue and neuroprotective potential, metal chelating, and cytotoxic effects of the synthesized compound was assessed.

[0064] The MAO inhibition potential of the Dihydroquinazoline derivatives was evaluated on recombinant human MAO-A and MAO-B enzymes. All the tested compounds showed enhanced inhibition activities for the MAO-A and MAO-B isoform with IC50 values ranging from micro molar to sub nano molar range. Different compounds displayed selectivity for MAO-A and MAO-B isoform depending upon the substituents attached to the Dihydroquinazoline moiety. Presently, none of currently available dihydroquinazoline derivatives inhibit AChE, MAO and Amyloid beta simultaneously. The table hereinbelow provides IC50 values for AChE and MAO.

Name IC50 Values are in micromolar units
AChE (IC50) MAO-A (% inhibition) MAO-B (IC50)
4-(4-phenyl-8-(prop-2-yn-1-yloxy)-5,6-dihydrobenzo[h]quinazolin-2-yl)thiomorpholine 0.93 34.64 1.17
4-phenyl-8-(prop-2-yn-1-yloxy)-2-(pyrrolidin-1-yl)-5,6-dihydrobenzo[h]quinazoline 0.85 34.99 0.79
4-(4-nitrophenyl)-2-(piperidin-1-yl)-5,6-dihydrobenzo[h]quinazoline 0.42 34.96 0.55
2-(4-fluorophenyl)-4-(3-(prop-2-yn-1-yloxy)phenyl)-5,6-dihydrobenzo[h]quinazoline 1.72 29.47 0.95
4-(3-(prop-2-yn-1-yloxy)phenyl)-2-(p-tolyl)-5,6-dihydrobenzo[h]quinazoline 1.10 30.57 1.68
2-methyl-4-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-5,6-dihydrobenzo[h]quinazoline 0.79 28.28 0.12
4-(4-(3-(dimethylamino)propoxy)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-amine 0.83 39.54 0.24
Table 1
[0065] Method: The MAO inhibition assay was performed using an Amplex Red assay (as shown in Table 1) kit obtained from Thermo Fisher Scientific (Invitrogen) as reported in the literature. Recombinant MAO isoforms, MAO-A and MAO-B were sourced from Sigma Aldrich. Briefly, 40 µl of recombinant MAO enzyme (hMAO-A: 1.1 μg protein, specific activity: 150 nmol p-tyramine oxidized to p-hydroxyphenylacetaldehyde per minute per mg protein; hMAO-B: 7.5 μg protein, specific activity: 22 nmol p-tyramine transformed per minute per mg protein) was mixed with 10 µl of the test compounds in flat-black-bottom 96-well plate, were incubated at 37 ºC for 30 minutes in biological incubator. Further, working solution containing p-tyramine substrate, HRP (peroxidase from horseradish) and amplex red was added in each well after 30 min incubation, in which remaining enzyme reacted with tyramine substrate to produce the H2O2 following the oxidative deamination. Furthermore, in the presence of H2O2, non-fluorescent dye Amplex red convert into a fluorescent compound, resorufin. The production of the resorufin was quantified using a multi-mode microplate reader at 545 nm excitation and 590 nm emission wavelength.
[0066] The cholinesterase inhibition activities were determined using Ellman assay. The tested compounds displayed high potency with IC50 values varying from micro molar to low nano molar range.
[0067] Method: The AChE and BuChE inhibition assays of the synthesized compounds were performed using Modified Ellman's method. In brief, 40 µl of enzyme (AChE, 0.5 U/L and BuChE, 0.6 U/mL) and 20 µl of test compounds (three dilutions with final concentrations of 0.2 µM, 2 µM, and 20 µM) and donepezil (0.001-20µM) as reference standard were taken in triplicates in 96-well plates and incubated for 30 minutes in a CO2 incubator at 37 ºC. Following the incubation period, 20 µl of substrate (ATCI, acetylthiocholine iodide; BuTCI, butyryl thiocholine iodide; 20 mM) and 20 µl of Ellman’s reagent (DTNB, 0.01M) were added. The absorbance spectra of this system were recorded immediately on a TECAN multimode microplate reader at 415 nm for 30 min at an interval of 2 min. The percentage inhibition and IC50 of the test compounds was calculated by using Microsoft excel. The recorded absorbance was used to calculate IC50 values. (Table 1).
[0068] in vitro inhibition and disaggregation of self-induced Aβ1-42 (Amyloid β- peptide) aggregation was measured using a ThT-based assay (Table 2).
Method: Aβ1-42 was purchased from Adooq Biosciences and used as received for further studies. The Thioflavin-T (ThT) assay, a fluorimetry-based method, was employed to evaluate Aβ self-aggregation inhibition potential. Initially, Aβ was pretreated with HFIP (1,1,1,3,3,3-hexafluoro-2-propanol). Following HFIP evaporation under vacuum, a 50 μM Aβ solution was prepared in PBS buffer. A 20 μL solution of Aβ was incubated in a flat-black bottom 96-well plate without any test compound as the control. The test compounds were incubated with an equal volume of Aβ at 37 °C for 24 hours. After incubation, 180 μL of glycine-NaOH buffer (pH 8.0) containing 5 μM ThT was added to each well, and fluorescence was measured in the 440–485 nm range using a TECAN multimode microplate reader. The percentage inhibition of Aβ self-aggregation was calculated by subtracting the blank and considering the control as 0% inhibition (Table 2).
Name Aβ1-42 % inhibition (20 µM concentration)
4-(4-phenyl-8-(prop-2-yn-1-yloxy)-5,6-dihydrobenzo[h]quinazolin-2-yl)thiomorpholine 35.21
4-phenyl-8-(prop-2-yn-1-yloxy)-2-(pyrrolidin-1-yl)-5,6-dihydrobenzo[h]quinazoline 40.34
4-(4-nitrophenyl)-2-(piperidin-1-yl)-5,6-dihydrobenzo[h]quinazoline 40.56
2-(4-fluorophenyl)-4-(3-(prop-2-yn-1-yloxy)phenyl)-5,6-dihydrobenzo[h]quinazoline 35.70
4-(3-(prop-2-yn-1-yloxy)phenyl)-2-(p-tolyl)-5,6-dihydrobenzo[h]quinazoline 43.03
2-methyl-4-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-5,6-dihydrobenzo[h]quinazoline 28.85
4-(4-(3-(dimethylamino)propoxy)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-amine 31.30
Table 2: Aβ inhibition of examples
[0069] The neuroprotective potential of the tested compounds was evaluated using 6-OHDA exposed SH-SY5Y cells. The synthesized compounds were pre-treated at concentrations of 1.25, 2.5, and 5 µM for 1 hour prior to 6-hydroxydopamine (6-OHDA)/Aβ treatment. Afterward, the cells were incubated for 24 hours at 37 ºC in a humidified atmosphere containing 5% CO₂. Following this, a 10 µM solution of MTT reagent was added to each well, and the plates were incubated for an additional 3 hours. Subsequently, 100 µL of DMSO was used to dissolve the resulting formazan crystals with the help of an automatic shaker for 30 minutes. Absorbance was measured at 570 nm using a microplate reader (Infinite M200 Pro, TECAN, Switzerland), and the percentage of cell viability was calculated using Microsoft Excel. Synthesized compounds were evaluated for their neuroprotective potential against 6-OHDA/Aβ neurotoxin in SH-SY5Y cells. These compounds showed mild to moderate neuroprotective potential against 6-OHDA (Table 3).
S. No. Compounds Max. cell viability @ 5µM
1 4-(4-phenyl-8-(prop-2-yn-1-yloxy)-5,6-dihydrobenzo[h]quinazolin-2-yl)thiomorpholine 78.39
2 4-phenyl-8-(prop-2-yn-1-yloxy)-2-(pyrrolidin-1-yl)-5,6-dihydrobenzo[h]quinazoline 84.93
3 4-(4-nitrophenyl)-2-(piperidin-1-yl)-5,6-dihydrobenzo[h]quinazoline 86.06
4 2-(4-fluorophenyl)-4-(3-(prop-2-yn-1-yloxy)phenyl)-5,6-dihydrobenzo[h]quinazoline 65.43
5 4-(4-(3-(dimethylamino)propoxy)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-amine 96.08
Table 3 Neuroprotective study of examples
[0070] For reversibility studies the test inhibitors were incubated with the MAO and AChE enzymes at concentrations of 10 × IC50 and 100 × IC50 at 37 °C for of 30 min (negative control performed in the absence of inhibitor). All the compounds were found reversible with respect to MAO and AChE enzyme.
[0071] Method: For reversibility inhibition studies, the test inhibitors were incubated with MAO enzymes at concentrations of 10 × IC50 and 100 × IC50 at 37 °C for 30 minutes, with a negative control conducted in the absence of the inhibitor. Following incubation, the samples were diluted 100-fold with the addition of the tyramine substrate, resulting in final inhibitor concentrations of 0.1 × IC50 and 1 × IC50, respectively. As positive controls, MAO-A, MAO-B and AChE were incubated with the irreversible inhibitors clorgyline, pargyline and donepezil, respectively, at 10 × IC50 concentrations, then diluted 100-fold to achieve final inhibitor concentrations of 0.1 × IC50. The residual MAO and AChE activities after dilution were measured (n = 3), and the residual enzyme activities were expressed as mean ± SD.
[0072] Results for reversibility studies: The observed inhibition decreased as the concentrations increased to 10 × IC50 and 100 × IC50. Maximum inhibition was achieved at 100 × IC50 concentration, where the synthesized compounds retained 70% to 90% activity for both AChE and MAO-B isoforms. These findings indicate that the synthesized compounds act as reversible inhibitors of MAO and AChE enzymes ().
S. No Compounds % AChE activity at 0.1xIC50 % MAO-B activity at 0.1xIC50
1 4-(4-phenyl-8-(prop-2-yn-1-yloxy)-5,6-dihydrobenzo[h]quinazolin-2-yl)thiomorpholine 73.71 82.12
2 4-phenyl-8-(prop-2-yn-1-yloxy)-2-(pyrrolidin-1-yl)-5,6-dihydrobenzo[h]quinazoline 75.7 93.28
3 4-(4-nitrophenyl)-2-(piperidin-1-yl)-5,6-dihydrobenzo[h]quinazoline 81.2 86.23
4 2-(4-fluorophenyl)-4-(3-(prop-2-yn-1-yloxy)phenyl)-5,6-dihydrobenzo[h]quinazoline 82.39 62.11
5 4-(4-(3-(dimethylamino)propoxy)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-amine 72.13 68.03
Table 3 Reversibility study of examples

[0073] The intracellular ROS levels in SH-SY5Y cells were measured using the non-fluorescent compound 2,7-dichlorofluorescein diacetate (DCF-DA). This cell-permeable compound is oxidized by ROS to form the fluorescent 2,7-dichlorofluorescein (2,7-DCF). Most of the tested compounds demonstrated a reduction in ROS levels.
Method: To evaluate the inhibition of reactive oxygen species (ROS), test compounds were added at a concentration of 5 µM to the cell culture medium. A control group, without any test compounds, was included for comparison. Human neuroblastoma (SH-SY5Y) cells were maintained in DMEM medium and seeded at a density of approximately 10,000 cells per well in a flat-black-bottom 96-well plate. The cells were exposed to the test compounds and 6-OHDA and incubated for 24 hours at 37 ºC in a humidified environment with 5% CO2. Intracellular ROS levels were measured using 2,7-dichlorofluorescein diacetate (DCF-DA), a non-fluorescent probe, following a standardized protocol previously used by our research group. Fluorescence readings were taken at an excitation wavelength of 485 nm and an emission wavelength of 520 nm using a fluorescence detection system. Results were expressed as the mean ± standard deviation (SD) from at least three independent experiments conducted in triplicate.
Results: ROS levels were reduced to 168.35 ± 2.9 %, 138.68 ± 4.7 %, 156.31 ± 3.8 % and 147.83 ± 4.8 % at 5mM concentrations for 4-(4-phenyl-8-(prop-2-yn-1-yloxy)-5,6-dihydrobenzo[h]quinazolin-2-yl)thiomorpholine, 4-phenyl-8-(prop-2-yn-1-yloxy)-2-(pyrrolidin-1-yl)-5,6-dihydrobenzo[h]quinazoline, 4-(4-fluorophenyl)-2-(piperidin-1-yl)-5,6-dihydrobenzo[h]quinazoline, and 4-(4-nitrophenyl)-2-(piperidin-1-yl)-5,6-dihydrobenzo[h]quinazoline, respectively in the SH-SY5Y cells . Thus, from these observations, it is apparent that synthesized compounds may protect the neuronal cells from ROS.

[0074] The cytotoxic effects of the compounds were evaluated against human neuro-blastome cell line SH-SY5Y because of their similarity to dopaminergic neurons using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay protocol. The compounds were incubated at 0.625 μM to 5 μM concentrations and were analysed after 24h treatment time. The compounds were found non-toxic against the tested cells.
Results: The compounds were found to be non-toxic at lower concentrations. 4-(4-phenyl-8-(prop-2-yn-1-yloxy)-5,6-dihydrobenzo[h]quinazolin-2-yl)thiomorpholine, 4-phenyl-8-(prop-2-yn-1-yloxy)-2-(pyrrolidin-1-yl)-5,6-dihydrobenzo[h]quinazoline, 4-(4-fluorophenyl)-2-(piperidin-1-yl)-5,6-dihydrobenzo[h]quinazoline, and 4-(4-nitrophenyl)-2-(piperidin-1-yl)-5,6-dihydrobenzo[h]quinazoline, shows 74.63 ± 6.2 %, 81.37 ± 5.9 %, 74.88 ± 5.2 % and 82.00 ± 7.1 %, cell viability at 20 µM concentration respectively. Whereas it shows 95.32 ± 5.6 %, 96.83 ± 6.8 %, 98.74 ± 6.1 % and 98.10 ± 7.1 % cell viability at 0.625 µM concentration respectively. So, the lower micromolar range IC50 of the synthesized compounds confirms the non-toxic nature of the compounds to the cells.
[0075] Advantages of the Invention
The present invention exhibits following advantages:
1. The present invention provides a compound and pharmaceutical salts or derivatives thereof to which is effective in treating neurological disorders.
2. The product formed in the present invention possess potential for monoamine oxidase enzyme, acetylcholinesterase enzyme, beta amyloid self-aggregation, reactive oxygen species inhibition, neurorescue and neuroprotective potential, metal chelating, and cytotoxic effects.
3. The product formed in the present invention exhibits minimal or no side effects.
4. The product formed in the present invention is reversible in nature and receptor activity can be modulated as per requirement.
5. The present invention provides multi-targeting single drug molecule, thereby eliminating possibility of drug-drug interaction.
6. Activities displayed by the dihydroquinazoline derivatives of
formula I
1. acetylcholinesterase inhibition activities
2. monoamine oxidase inhibition activities
3. beta amyloid aggregation inhibition activities
4. reactive oxygen species inhibition activities
5. multipotent ligands for the treatment of neurological disorders wherein neurological disorder are Alzheimer’s disease, Parkinson’s disease and/or depression
6. multipotent ligands for the treatment of neurological disorders wherein neurological disorder are substance abuse
7. multipotent ligands for the treatment of neurological disorders Huntington chorea, amyotrophic lateral sclerosis, ageing, cerebral ischaemia and the like.

[0076] While this invention has been described in connection with what is presently considered to be the most practical and preferred embodiment, it is to be understood that the invention is not limited to the disclosed embodiments, but, on the contrary, is intended to cover various modifications and equivalent arrangements included within the scope of the appended claims.
, C , C , C , Claims:1. A dihydroquinazoline compound of Formula 1 for the treatment of neurological disorders:

wherein
• R1 is the independently selected from a group of, not limiting to morpholine, piperidine, thiomorpholine, pyrrolidine, methyl piperazine, ethyl piperazine, benzyl piperazine, phenyl piperazine, -H, -NH2, -CH3, -Ph, -Ph-F, -Ph-Cl, -Ph-Br, -Ph-CH3.
• R2, R3, R4, R5, R6, R7, R8, R9, and R10 are independently selected from a group of, not limiting to, H, F, Cl, Br, I, NO2, CH3, OCH3, CN, NH2, CH2CH3, isopropyl, vinyl, allyl, phenyl and/or Y-(CH2)m-Z wherein,
o Y is selected from a group of, not limiting to, O or N;
o m is a value between 0 to 4; and
• Z is independently selected from a group of, not limited to, morpholine, piperidine, N, N-dimethyl, pyrrolidine, acetylene and the like.
2. The compound as claimed in claim 1, wherein the compound of Formula 1 is selected from the group comprising of:
I. 4-(4-phenyl-8-(prop-2-yn-1-yloxy)-5,6-dihydrobenzo[h]quinazolin-2-yl)thiomorpholine
II. 4-phenyl-8-(prop-2-yn-1-yloxy)-2-(pyrrolidin-1-yl)-5,6-dihydrobenzo[h]quinazoline
III. 4-(4-nitrophenyl)-2-(piperidin-1-yl)-5,6-dihydrobenzo[h]quinazoline; and
IV. 2-(4-fluorophenyl)-4-(3-(prop-2-yn-1-yloxy)phenyl)-5,6-dihydrobenzo[h]quinazoline
V. 4-(3-(prop-2-yn-1-yloxy)phenyl)-2-(p-tolyl)-5,6-dihydrobenzo[h]quinazoline
VI. 2-methyl-4-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-5,6-dihydrobenzo[h]quinazoline
VII. 4-(4-(3-(dimethylamino)propoxy)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-amine
3. A method for preparation of dihydroquinazoline derivatives (formula 1) as claimed in claim 1, wherein the method comprising the steps of:
a) Alkylation of substituted benzaldehydes & tetralones to prepare forming Intermediate I & II i.e. alkylated benzaldehydes/tetralones in Scheme I and alkylation of substituted benzaldehydes into Intermediate I i.e. alkylated benzaldehydes in Scheme II: The substituted benzaldehydes/tetralones are reacted with an alkylating agent and a base in a solvent at a temperature in the range of 70-80 °C for 3 to 8 h. The ratio of substituted benzaldehyde or tetralone/base/alkylating agent is taken in the range of 1:1.1:1.1 to 1:2.5:2. The progress of the reaction is monitored through TLC. On the completion of reaction, the reaction mixture is poured on crushed ice to obtain precipitates of alkylated benzaldehydes or tetralones which are filtered and dried under vacuum. In a case, if precipitates are not formed the Intermediate I & II are extracted by workup with organic solvents (3x times) and organic layer washed with brine followed by passing from anhydrous sodium sulphate and dried under vacuum.
b) Reacting alkylated benzaldehydes (Intermediate I) and alkylated tetralones (Intermediate II) prepared in step (i) as per Scheme I with urea to form cyclized Intermediate II i.e. substituted 4-phenyl-5,6-dihydrobenzo[h]quinazolin-2(1H)-one(s): The substituted aldehydes prepared in step (i) is reacted with substituted tetralones (also prepared in step (i)) in the presence of a catalyst iodine and cyclizing agent urea in a ratio in the range of 0.1:1 to 0.5:3 in a solvent at 70-80ºC temperature for 8-10h in a reaction vial until completion. The progress of the reaction was monitored through TLC, and on completion of the reaction iodine was quenched with saturated solution of sodium thiosulfate and excess solvent was vaporized. Then the reaction mixture was extracted with organic solvent (3x times) and organic layer washed with brine followed by passing from sodium sulphate and dried to get Intermediate III as per scheme I.
c) Substituting dihydroquinazolinone intermediate, a cyclized Intermediate III prepared in step (ii) as per scheme I with different secondary amines to form the final compound prescribed in formula 1; The substituted 4-phenyl-5,6-dihydrobenzo[h]quinazolin-2(1H)-one(s) prepared in step (ii) dissolved in a solvent to add DBU and BOP in range of 1:1 to 2:1.5 to be stirred for 1-3 h. The TLC was performed to confirm the conversion of Intermediate III into a reactive intermediate which then reacted with nucleophiles i.e. different types of secondary amines (1 to 2) at room temperature for 12-14 h. The reaction’s progress was monitored through TLC. The reaction mixture was extracted with organic solvent (3x times) and organic layer washed with brine followed by passing from anhydrous sodium sulphate and dried to get the product. This crude product was purified with column chromatography to obtained pure substituted 4-phenyl-5,6-dihydrobenzo[h]quinazoline.
d) In scheme II, reacting alkylated benzaldehydes obtained in step (i) and tetralone to form substituted 2-benzylidene-3,4-dihydronaphthalen-1(2H)-one
The substituted benzaldehydes prepared in step (i) are reacted with tetralone using a base in a solvent at room temperature for 6-8 h. The ratio of substituted benzaldehydes /base/ tetralone is taken in the range of 1:0.1:1 to 1:0.5:1; The progress of the reaction is monitored through TLC. On the completion of reaction, the reaction mixture is poured on crushed ice to obtain precipitates of substituted 2-benzylidene-3,4-dihydronaphthalen-1(2H)-one which are filtered, and dried. In a case, if precipitates are not formed the Intermediate II are extracted by workup with organic solvents (3x times) and organic layer washed with brine followed by passing from anhydrous sodium sulphate and dried under vacuum.
e) Cyclizing Intermediate II prepared in step (ii) as per Scheme II with different amidines to give final compound prescribed in formula 1: The substituted 2-benzylidene-3,4-dihydronaphthalen-1(2H)-one prepared in step (ii) is reacted with different amidines in the presence of a base in a solvent at the temperature of 60-80ºC for 4-6 h in a ratio in the range of 1:0.7:1 to 1:2:4 until completion. The progress of the reaction was monitored through TLC, and on completion of the reaction, the reaction mixture was extracted with organic solvent (3x times) and organic layer washed with brine followed by passing from anhydrous sodium sulphate and dried to get crude product. Then, it was purified with gravity column chromatography to obtained pure substituted 4-phenyl-5,6-dihydrobenzo[h]quinazoline.
f) The method as claimed in claim 3, wherein the substituted benzaldehydes are selected from the group of hydroxy substituted benzaldehydes such as 3-hydroxy benzaldehyde, 4-hydroxy benzaldehyde, vanillin or substituted vanillin such as, isovanillin, 4-hydroxy vanillin or the like.
• The method as claimed in claim 3, wherein the alkylating agent used in the present invention is selected from a group consisting of such as, but not limited to, propargyl bromide, or allyl bromide or acetylene bromide, vinyl bromide, and Y-(CH2)m-Z and the like. wherein,
o Y is selected from a group of, not limiting to, O or N;
o m is a value between 0 to 4; and
o Z is independently selected from a group of, not limited to, morpholine, piperidine, N, N-dimethyl, pyrrolidine, acetylene and the like
4. The method as claimed in claim 3, wherein the base is selected from a group of sodium carbonate, potassium carbonate, caesium carbonate, sodium hydroxide, potassium hydroxide, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) and the like.
5. The method as claimed in claim 3, wherein the cyclizing agent is selected from a group of urea, amidines and the like.
6. The method as claimed in claim 3, wherein the solvent is selected from group of ethanol, methanol, acetonitrile, dimethylformamide, acetone and the like.
7. The dihydroquinazoline derivatives of formula I as claimed in claim 1, wherein the compounds display activities including monoamine oxidase inhibition activities, acetylcholinesterase inhibition activities, beta amyloid aggregation inhibition activities, and reactive oxygen species inhibition activities.
8. The dihydroquinazoline derivatives of formula I as claimed in claim 1, as multipotent ligands for the treatment of neurological disorders wherein neurological disorder are Alzheimer’s disease, Parkinson’s disease and/or depression, substance abuse, Huntington chorea, amyotrophic lateral sclerosis, ageing, cerebral ischemia and the like.