Activity of Quinazoline Derivatives: A Review
Dr D. D. Rishipathak*, A. B. Kokate, K. S. Madhawai
Department of Pharmaceutical Chemistry, MET’S Institute of Pharmacy, Bhujbal Knowledge City, Adgaon, Nashik-422 003. Savitribai Phule Pune University, Maharashtra. India.
A number of substituted quinazoline are known for their pharmacological importance, Literature indicate that derivatives consist of variety of pharmacological activity activities like anti-inflammatory, analgesic, anti-microbial, CNS depressant and anti-tubercular, anti-hypertensive anti-tumor activities have reported also. Current review is focusing on specific pharmacological activity anticonvulsant, anti-inflammatory, anti-hypertensive, anti- proliferative.
In medicinal chemistry quinazolinone derivative have been very well known for their potential therapeutic activity, In presence of heterocycle its binding affinity increases, Quinazoline is a bicyclic compound consisting of a pyrimidine system fused at 5, 6 with benzene As result of remarkable pharmacological activity intensive research has been focus on anti- inflammatory, ani-cancer, anti-bacterial, anti-viral, CNS depressant and antihypertensive activity.
1) Mohamed F. et al1Reported an synthesis of eight compounds of fluorinated quinazolinone derivatives. Their anticonvulsant activity was evaluated from maximal electro-shock-induced seizures in eight groups of six Swiss mice given the test compounds (100 mg/kg intra-peritoneal) one control group given 10% DMSO (10 ml/kg) and one given the reference compound phenytoin (100 mg/kg).
Neurotoxicity was evaluated by the rotarod test in eight groups of four Swiss mice given the test compounds (100 mg/kg), one given saline (10 ml/kg) and one given phenytoin (100 mg/kg). Among the synthesized compound 1, 2, 3, 4 show better anticonvulsant
R= -4-Cl (1) -4-F (2),-4-Br (3), -4-I (4)
2). Saleh. K. et aI2, havereported SOME novel fluorinated quinazolines (5a–j) were designed and synthesized to be evaluatedfor their anticonvulsant activity and their neurotoxicity. Structures of all newly synthesized compounds were confirmed by their infrared (IR), mass spectrometry (MS) spectra, 1H nuclear magnetic resonance (NMR), 13C-NMR, and elemental analysis (CHN). The anticonvulsant activity was evaluated by a subcutaneous pentylenetetrazole (scPTZ) test and maximal electroshock (MES)-induced seizure test, while neurotoxicity was evaluated by a rotorod test. The molecular docking was performed for all newly-synthesized compounds to assess their binding affinities to the GABA-A receptor in order to rationalize their anticonvulsant activities in a qualitative way. The data obtained from the molecular modeling was correlated with that obtained from the biological screening. These data showed considerable anticonvulsant activity for all newly-synthesized compounds. Compounds 5b, 5c, and 5d showed the highest binding affinities toward the GABA-A receptor, along with the highest anticonvulsant activities in experimental mice. These compounds also showed low neurotoxicity and low toxicity in the median lethal dose test compared to the reference drugs. A GABA enzymatic assay was performed for these highly active compounds to confirm the obtained results and explain the possible mechanism for anticonvulsant action. The most active compounds might be used as leads for future modification and optimization.
R= -4-Cl (5b) -4-F(5c), -4-Br (5d)
3)Niraj .S. et aI3.Synthesize3Quinazoline derivatives by three steps. Purity of compound is checked by TLC monitoring. All synthesized compounds are confirmed by UV, IR, Mass and H1NMR. All synthesized compound were screened for α1-adrenergic receptor blocking activity. Amongst all synthesized compounds A&B showed Better activity
R=C6H8ClN (A), C6H6NO2 (B)
4). et aI4.A series of ten new 6',8'-Disubstituted-5-methyl-3'substitutedphenyl2,4dihydro1'Hspiro[pyrazole-3,2'-quinazolin]-4'(3'H)-one derivatives have been synthesized by cyclization of substituted anthranilic acid and 5-Methyl-2,4-dihydro-3H-pyrazol-3-one giving corresponding 5'-methyl-2',4'-dihydrospiro [3,1-benzoxazine-2,3'-pyrazol]-4(1H)-one followed by amination. The structure of synthesized compounds were established by spectral (FTIR, NMR, and MS) and elemental (C, H, N) analysis. These synthesized compounds were screened for analgesic and anti-inflammatory activities by hot plate method and carrageenan induced rat paw method respectively. Compound 1, 3, 5, 6, 8 and 9 showed good anti-inflammatory whereas compound 2, 3, 7, and 10 exhibits promising analgesic activity when compared with Indomethacin and Tramadol respectively as a standard.
R= 6-Br, R1=H (1), R=6,8- Br, R1=H (2), R= 6-Br, R1= -Cl (3) , R= 6,8-Br, R1= -Cl (4)
R= 6-Br, R1= -NO2 (5), R=6,8-Br, R1= -NO2 (6), R= 6-Br,R1= -Br (7),
R= 6,8-Br, R1= -Br (8), R= 6-Br , R1= -CH3 (9), R=6,8-Br , R1= -CH3 (10)
5) Kumaraswami et al5.reported synthesis of substituted 6-bromoquinazolinones are known for their pharmacological importance like anti-inflammatory, analgesic and anti-bacterial activity. In the present investigation carried out for the synthesis of 2-(6-bromo-2-phenyl-4-oxoquinazolin-3(4H)-yl)-N-substituted acetamides and 1-Amino-5-(6-bromo-3,4-dihydro-2-phenyl-4-oxo quinazolin -3yl) methyl-1, 3, 4-triazin-2-thiol to carry out their pharmacological activities. A number of oxoquinazoline derivatives have been synthesized, purified and characterized with the help of their anal ytical and spectral data (IR, NMR & Mass).The required ethyl [6-bromo- 2-phenyl-4-oxoquinazolin-3(4H)-yl] acetate has been synthesized from 6-bromo-2-phenyl-1,3,4-benzoxazinone and ethyl glycinate. By the use of corresponding primary amines the N-substituted acetamides and by the use of hydrazine hydrate the 1-amino-5-[6-bromo-2-phenyl-4oxoquinazolin -3(4H)-yl] methyl 1, 3, 4-triazin-2-thiol were prepared. The synthesized compounds were screened for their anti-bacterial activity, anti-inflammatory activity and analgesic activity by standard methods. The compound A, B, C, D and E shows better Pharmacological activities in comparison with the standard.
R = -H (A), - Cl (B), - CH3 (C), - OCH3 (D)
6) Fadil et al6.have synthesized and characterized .quinazoline Schiff bases 3-[(5-Bromo-2-hydroxy-benzylidene)-amino]-2-(5-bromo-2-hydroxy-phenyl)-2,3-dihydro-1H-quinoline-4-one and 3-[(5-Bromo-2-hydroxy-3-methoxy-benzylidene)-amino]-2-(5-bromo-2-hydroxy-3-methoxy-phenyl)-2,3-dihydro-1H-quinoline-4-one were investigated for anticancer activity against MCF-7 human breast cancer cell line. Compounds 1 and 2 demonstrated a remarkable anti-proliferative effect, with an IC50 value of 6.246 × 10−6 mol/L and 5.910 × 10−6 mol/L, respectively, after 72 hours of treatment. Most apoptosis morphological features in treated MCF-7 cells were observed by AO/PI staining. The results of cell cycle analysis indicate that compounds did not induces and M phase arrest in cell after 24 hours of treatment.Furthermore,MCF-7 -cells treated with 1 and 2 subjected to apoptosis death, as exhibited by perturbation of mitochondrial membrane potential and cytochrome c release as well as increase in ROS formation. We also found activation of caspases-3/7, -8, and -9 in compounds 1 and 2.Moreover, inhibition of NF-B translocation in MCF-7 cells treated by compound 1 significantly exhibited the association of extrinsic apoptosis pathway. Acute toxicity results demonstrated the nontoxic nature of the compounds in mice. Our results showed significant activity towards MCF-7 cells via either intrinsic or extrinsic mitochondrial pathway and are potential candidate for further in vivo and clinical breast cancer studies. The nontoxic nature of the compounds in mice. Our results showed significant activity towards MCF-7 cells via either intrinsic or extrinsic mitochondrial pathway and are potential candidate for further in vivo and clinical breast cancer studies.(Compound 1 and 2 shown below)
Although Quinazolin and its derivative are reported to have diverse pharmacological activity. There is still scope for more research work to be done on anti-cancer activity, anti-inflammatory activity, anti-viral.
1. Mohamed F. Zayed, PhD, New fluorinated quinazolinone derivatives as anticonvulsant agents, Journal of Taibah University Medical Sciences 2014, 9(2), 104-109
2. Saleh K. Ihmaid .1, Hany E. A. Ahmed Synthesis, Modelling, and Anticonvulsant Studies of New Quinazolines Showing Three Highly Active Compounds with Low Toxicity and High Affinity to the GABA-A Receptor,Molecule, January 2017
3. Niraj Kumar S, Alpana J. Asnani, Bhushan R. Synthesis and pharmacological evaluation of spiroquinazolinone as anti-inflammatory and Analgesic Agents. International Journal of Advanced Research (2013), Volume 1, Issue 6, 445-450
4. Niraj Kumar S, Alpana J. Asnani, Bhushan R. Synthesis and pharmacological evaluation of spiroquinazolinone as anti-inflammatory and Analgesic Agents. International Journal of Advanced Research (2013), Volume 1, Issue 6, 445-450
5. Hurmath. S, Gayam. R, Aravazhi T. Synthesis and in vitro anti-tumor activity of some novel 2, 3- Disubstituted quinazoline 4(3H)-one derivatives. Journal of Applied Pharmaceutical Science Vol. 3 (10), pp. 136-140, October, 2013.
6. Fadhil Lafta Faraj, Synthesis, Characterization, and Anticancer Activity of New Quinazoline Derivatives against MCF-7 Cells. The Scientific World Journal Volume 2014, 15 pages( review 212096) 2014
Received on 17.07.2017 Accepted on 18.09.2017
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