INTRODUCTION:

Heterocycles are among the most frequently encountered scaffolds in drugs and pharmaceutically relevant substances¹. The remarkable potential of heterocyclic nuclei to serve both as biomimetics and reactive pharmacophores has in large part contributed to their precise cost as conventional key elements of numerous drugs. The development of heterocycles as scaffolds, containing a high degree of diversity has become a leading focus on modern drug discovery². In this research program, the derivatives of various diverse classes of heterocycles e.g., imidazole, benzimidazole, benzoxazole, tetrazole, and quinazolinone were developed. Certain possible modifications on the heterocyclic ring with the addition of diverse substituents may lead to new products with better biological profiles. As a result of the biological activity exhibited by the heterocyclic molecules, the development of new chemical entities (NCEs) is the focus of intense activity in the pharmaceutical industry.

Heterocycles are organic compounds containing at least one atom of carbon, and at least one element other than carbon, such as sulfur, oxygen, or nitrogen within a ring structure. Heterocyclic chemistry is the branch of chemistry dealing with the synthesis, properties, and applications of Heterocycles. The various special nitrogen-containing heterocycles, quinazolinone plays an essential role in medicinal chemistry and ultimately have emerged as a pharmacophore³. Quinazolinone is a building block of approximately one hundred fifty going on alkaloids isolated from numerous households of the plant kingdom, from animals and microorganisms consisting of Bacillus cereus, Bouchardatianeurococca, Dichroafebrifuga, and Peganumnigellastrum⁴.

Chemistry:

Quinazoline is a compound made up of two fused six-membered aromatic rings, a benzene ring and a pyrimidine ring. Quinazoline is a fused bicyclic compound earlier known as benzo-1,3-diazine was firstPrepared in the laboratory by Gabrie. Quinazolinones are the oxidized form of quinazoline and are also part of the alkaloid form of quinazoline.Both naturally occurring and synthetic quinazolines and quinazolinones have attracted widespread attention due to the diverse range of pharmacological activities. These structures are defined by the location of the oxygen and the hydrogen on the nitrogen (NH)⁵. Of the many derivatives of the quinazoline system known so far, ketoquinazolines also called quinazolinones are the most important compounds. Quinazolinones will be classified into five categories, based on the substitution patterns of the ring system⁶ such as 2-Substituted-4(3H)-quinazolinones, 3-Substituted-4(3H)-quinazolinones, 4-Substituted-quinazolines, 2,3-Disubstituted-4(3H)-quinazolinones, and 2,4-Disubstituted-4(3H)-quinazolinones.

Biological Importance of Quinazolinone Derivatives:

1. Quinazolinone as anticancer activity:

A new series of 3-ethyl-2-sulfanylquinazolin-4(3H)-one and derivatives were synthesized and evaluated for their ability to inhibit⁷ the growth of human tumor cells. The antiproliferative effect of synthesized compounds was examined in three human tumor cell lines, namely, hepatocellular carcinoma (HepG-2), colorectal carcinoma (HCT-116), and breast cancer (MCF-7). A series of novel 3-methyl-quinazolinone derivatives were designed, synthesized, and evaluatedfor antitumor activity in vitro on wild type epidermal growth factor receptor tyrosine kinase (EGFR^wt-TK)and three human cancer cell lines including A549 (Human non-small cell lung cancer cell line), PC-3(Human prostate cancer cell line), and SMMC-7721(Human liver cancer cell line) along withnormal rat kidney cells (NRK 52E) was determined by MTT assay⁸. A new series of 2,3-Dihydroquinazolin-4(1H)-one derivatives were synthesized and evaluated antiproliferative activity against lung carcinoma (A549 cells) by Vybrant MTT Cell ProliferationAssay Kit (Life technologies Inc. USA).The study found few potent compounds 1a, 1b, 1c was found to be more effective antiproliferative against lung carcinoma, A549 cells.Doxorubicin was used as a standard reference drug⁹.

Compound 1: 2,3-Dihydroquinazolin-4(1H)-one derivatives (1a= R1, R2, R3= H, 1b= R1, R3= H, R2= OH, and 1c= R₁, R₂= Cl, R₃= H)

2. Quinazolinone as anti-inflammatory, analgesic activity:

A new sequence of 2,3-disubstituted quinazolin-4(1H)-one derivatives have been investigated for in vivo and in vitro anti-inflammatory activity in models of acute inflammation such as egg albumin protein denaturation, Cotton-pellet induced granuloma,carrageenan-induced paw edema in Wistar rats. The result revealed that Diclofenac sodium (50–250 μg/ml) was used as a reference drug with concentration-dependent protein denaturation inhibition; however, the effect of Diclofenac was found to be more significant (70% at 250 μg/ml) compared to synthesized compounds. A newly synthesized compound of 2,3-disubstitutedquinazolin-4(1H)-one derivatives may possessprominent anti-inflammatory action with minimumside effect over conventional quinazolinone derivative¹⁰.

A sequence of Spiro [(2H,3H) quinazoline-2,10-cyclohexan]-4(1H)-one derivatives were synthesized in which some novel derivatives of quinazolinone showed considerable potent anti-inflammatory and analgesic activity in experimental rats compared with Indomethacin (10mg /kg) and Tramadol (20mg /kg) as reference drugs¹¹.In addition to the various biological activities attributed to the derivatives of quinazolinone and the enzyme inhibitory effect of several 6-bromoquinazolinones and based on the continuation of our drug research program on the development of safe anti-inflammatory quinazolinone. Quinazolinone derivatives showed considerable potent analgesic activity of superior GIT safety profile in experimental mice compared with indomethacin (10mg /kg) asa reference drug¹². A series of 2-(2,4-disubstituted-thiazole-5-yl)-3-aryl-3H-quinazoline-4-one derivatives were designed and synthesized. The compounds were further evaluated for their inhibitory activity towards transcription factors NF-κB and AP-1 mediated transcriptional activation in a cell line based in vitro assay as well as for their anti-inflammatory activity in in vivo model of acute inflammation. This series provides us with selective and dual inhibitors of NF-κB and AP-1 mediated transcriptional activation which also exhibits significant efficacy in a model of inflammation (in vivo)¹³. A series of novel 2,3-disubstituted quinazolinone derivatives by condensing 2-methyl/2-phenyl/6-bromo-2-methyl/6-bromo-2-phenyl/6,8-dibromo-2-methyl/ 6,8-dibromo-2-phenyl benzoxazines with compounds containing amino group were confirmed by IR, 1H-NMR, 13C-NMR, and mass spectral data and evaluated for their analgesic activity and they reported that compound 2 showed promising analgesic activity compared to standard drug Diclofenac sodium¹⁴.

Compound 2: 2,3-disubstituted quinazolinone derivatives

3. Quinazolinone as antipsychotic activity:

Based on systematic studies of the structure-activity relationships in the serotonin ligand aryl piperazine group, various new derivatives containing quinazolidin-4(3H)-one and 2-phenyl-2,3-dihydrophthalazine-1,4-dione or 1-phenyl-1,2-dihydropyridazine-3,6-dionefragments have been synthesized and the dual receptor ligand 5-HT1A/5-HT2A was further evaluated for its possible psychotropic function which showed a distinct anxiolytic activity in a conflict drinking test in rats and the effect observed was more powerful in terms of the active dose than that of diazepam used as a reference drug¹⁵.

4. Quinazolinone asCNS depressant activity:

Several new 1-(4-substituted-phenyl)-3-(4-oxo-2-phenyl/ethyl-(4H)-quinazolin-3-yl)urea was synthesized and screened for anticonvulsant, CNS depressant, and sedative-hypnotic activity in the mice. After i.p. injection to mice at doses of 30, 100, and 300 mg/kg body weight and synthesized compounds were examined in the maximal electroshock induced seizures (MES) and subcutaneous pentylenetetrazoleinduced seizure models in mice. The compound 13 was found to exhibit potent CNS depressant activity as indicated by increased immobility time. It was concluded that the newly synthesized compound possessed promising CNS activities¹⁶.

5. Quinazolinone as anticoccidial activity:

A sequence of 3-(2-(2-methoxyphenyl)-2-oxoethyl) quinazolinone derivatives as an anticoccidialagents by altering the febrifugine quinazoline ring in the chicken at a dose of 9 mg/kg against Eimeriatenella. 3-(2-(2-methoxyphenyl)2-oxoethyl) derivatives of quinazolinone (Compound 3) have a high anticocytic activity and can serve as a lead compound for the production of anticocytic drugs in the future¹⁷.

Compound 3: 3-(2-(2-methoxyphenyl)-2-oxoethyl) quinazolinone derivatives

6. Quinazolinone as anticonvulsant activity:

A series of 6-bromo-2-ethyl-3-(substitutedbenzo[d]thiazol-2-yl) quinazolin-4(3H)-one were synthesized using the appropriate synthetic route and evaluated experimentally by the maximal electroshock and the PTZ-induced seizuremethods. Among the tested compounds, 3-(benzo[d]thiazol-2-yl)-6-bromo-2 ethylquinazolin-4(3H)-one has shown significant activity against tonic seizure and 6-bromo-2-ethyl-3-(6-methoxybenzo[d]thiazol-2-yl)quinazolin-4(3H)-one against clonic seizure without any sign of neurotoxicity and hepatotoxicity by PTZ-induced seizure model¹⁸.

A series of 3-{[5-(alkylbenzylideneamino)-1,3,4-thiadiazol-2-yl]methylamino}-2-methyl-6 mono substituted quinazomethylquinazolin-4(3H)-one (Compound 4) have been synthesized and examined by supramaximalelectroshock seizure pattern test by using test drugs or phenytoin sodium 30 mg/kg i.p. and Pentylenetetrazole seizure pattern test with pentylenetetrazol in a dose of 70 mg/kg s.c. in the scruff of the neck. The compound was screened for their anticonvulsant activity and was compared with the standard drugs, phenytoin sodium, lamotrigine, and sodium valproate as a standard drug used in this model (74 mg/kg i.p.)¹⁹.

Compound 4: 3-{[5-(alkylbenzylideneamino)-1,3,4-thiadiazol-2-yl]methylamino}-2-methyl-6 mono substituted quinazo methyl mono substituted quinazolin-4(3H)-one

7. Quinazolinone as anti-hypertensive activity:

Quinazolinone and quinazolinedione derivatives are of considerable interest due to their wide array ofpharmacological properties. The previous isolation of two of these compounds, namely 1-methyl-3-(2'-phenylethyl)-1H,3H-quinazoline-2,4-dione and 1-methyl-3-[2'-(4'-methoxyphenyl)ethyl]-lH,3H quinazoline-2,4-dione, from the seed husks of Mexican Zanthoxylumarborescens species has been reported for anti-hypertensive activity²⁰.

8. Quinazolinone as anti-HIV activity:

A new series of synthesized 3-amino-2-methyl mercaptoquinazolin-4(3H)-one from anthranilic acid. Isatin (Indole 2,3-dione), its 5-chloro and 5-bromo derivatives were added to 3-amino-2-methylmercaptoquinazolin-4(3H)-one to form Schiff bases and the N-Mannich bases of these compounds were synthesized by reacting with formaldehyde and several secondary amines. The N-Mannich bases of the above Schiff bases were synthesized by condensing the acidic imino group of isatin with formaldehyde and secondary amines and evaluated for anti-HIV activity against HIV-1 III B in MT-4 cells.Among the compounds, tested 5-chloro-3-(3′,4′-dihydro-2′-methylmercapto-4′-oxoquinazolin-3′-yl)-1-morpholino methyl iminoisatin was the most active drug²¹.

9. Quinazolinone as antimicrobial activity:

a. Antibacterial and antifungal:

A new series of synthesized quinazolinone derivatives were synthesized and assessed for their in-vitro antibacterial and antifungal activity. The antimicrobial activity of the synthesized compounds was determined against gram-positive bacteria like Staphylococcus aureus (PTCC 1337), Bacillus subtilis (PTCC 1023), Listeria monocitogenes (PTCC 1165), Gram-negative bacteria like Escherichia coli PTCC 1338, Pseudomonas aeruginosa (PTCC 1074), Salmonella entritidis (PTCC 1091) and also, Candida albicans (PTCC 5027) as yeast-like fungi strain by using Alamar blue susceptibility test (MABA) method using ciprofloxacin and ketoconazole were used as reference antibacterial and antifungal agents, respectively. The results of antibacterial²² activity showed that the synthesized hybrid compounds were more active against the tested gram-positive bacteria, especially S. aureus, but with less potency against gram-negative bacteria, especially against E. coli.

b. Antibacterial activity:

Some novel 6,8-diiodo-2-methyl-3-substituted-quinazolin-4(3H)-ones derivatives were synthesizedtoevaluate their antibacterial activityby the agar well diffusion methodagainst two kinds of gram-positive microorganisms Staphylococcus aureus (MTCC 96) andStaphylococcus epidermis (MTCC 435) and two gram-negative microorganisms Pseudomonas aeruginosa(MTCC 741), and Escherichia coli (MTCC443) at 100 μg/ml concentration using dimethylsulfoxide (DMSO) as a solvent²³.

10. Quinazolinone as anticanthamoebic activity:

A series of new 3-aryl-8-methylquinazolin-4(3H)-ones and their antimicrobial activity against Acanthamoebacastellanii belonging to the T4 genotype. Amoebicidal assays performed at concentrations ranging from 50 to 100 μg/ml revealed that all derivatives of quinazolinone significantly decreased the viability of A. castellanii and compound 5 have efficient antiamoebic effects. Field emission scanning electron microscopy (FESEM) imaging of amoeba treated with compounds 5 showed that these compounds cause structural alterations on the walls of A. castellanii. Furthermore, quinazolinone derivatives inhibited the encystation and excystation as well as abolished A. castellanii mediated host cells cytopathogenicity in human cells. Whereas, these quinazolinone derivatives showed negligible cytotoxicity when tested against human cells in vitro. Hence, this study identified potential lead molecules having promising properties for drug development against A. castellanii²⁴.

Compound 5: 3-aryl-8-methylquinazolin-4(3H)-ones

11. Quinazolinone as anti-diabetic activity:

A novel series of quinazolinone-1,2,3-triazole hybrids were synthesized and evaluated for their invitroα-glucosidase inhibitory activity leading to efficient anti-diabetic agents and exhibited good inhibitory activity against yeast α-glucosidase IC₅₀ value in the range of 181.0-474.5μMmore potent than standard drug acarbose of IC₅₀ value 750.0 μM. Quinazolinone-1, 2, 3-triazole possessing 4-bromo benzyl moiety connected to 1, 2, 3-triazole ring demonstrated the most potent inhibitory activity towards α-glucosidase²⁵.

12. Quinazolinone as antileishmanial activity:

A new sequence of 3-aryl-2-(substitutedstyryl)-4(3H)-quinazolinones were synthesized and tested using Leishmaniadonovani strain for in vitroantileishmanial activity. The synthesized compound 6 showed better antileishmanial activity (IC50 = 0.0128 to 3.1085 μg/ml) compared to the standard drug miltefosine (IC50 = 3.1911 μg/ml), and showed the most promising antileishmanial activity (IC50 = 0.0128 μg/ml), which is about 4 and 250 times more active than the standard drugs amphotericin Bdeoxycholate (IC50 = 0.0460 μg/ml) and miltefosine (IC50 = 0.0128 μg/ml). Thus, 2,3-disubstituted-4(3H)-quinazolinones containing an aromatic substitution at 3-position andsubstituted styryl moiety at 2-position represent a promisingmatrix for the development of antileishmanial agents²⁶.

Compound 6: (E)-2-(4-chlorostyryl)-3-p-tolylquinazolin-4(3H)-one

13. Quinazolinone as anti-tubercular activity:

A series of novel 2-[4-substituted-piperazinyl-methyl]-3-[N-isonicotinamide-yl]quinazoline-4-one were synthesized, and evaluated for in vitro antitubercular activity against Mycobacterium tuberculosisH37Rv using rifampicin and isoniazid as a reference standard²⁷.

14. Quinazolinone asanti-histaminic activity (H₁ antagonist): The H₁-antihistaminicactivity of the synthesized compound was evaluatedin vitro by measuring their ability to inhibit thehistamine-induced contractions of isolated guinea-pig ileum. Antihistaminic actions were mediated by blocking histamine receptorsand the animals shown better recovered after the histamine aerosolization. The time spent for being for the normalreaction after aerosolization was more whencompared with the control animals. The synthesized compound was compared with the standard drug chlorpheniramine maleate. H₁-receptor, the p interaction was enhanced by hydrophobicsubstituents increasing the HOMO energy and is affected bythe size of thealkyl substituent. These studies have highlightedthe importance of the overall hydrophobicity of the compoundsin deciding the antihistaminic activity²⁸.

CONCLUSION:

From the above literature surveys, it is concluded that among all quinazolinone derivatives shows more potent and efficient pharmacological activities, hence their design and synthesis become a potential area of research. Also, a small change in quinazolinone moiety can cause an extensive change in biological activities and these modifications are used as potential therapeutic agents in the future. So, researchers move towards designing more potent, efficient with minimum side effects of quinazolinone derivatives.

REFERENCES:

1. Kennedy, John F. An introduction to medicinal chemistry. Carbohydrate Polymers. 2007; 68: 609–10.

2. Mhaske SB, Argade NP. The chemistry of recently isolated naturally occurring quinazolinone alkaloids.Tetrahedron. 2006; 62: 9787–826.

3. Wattanapiromsakul C, Forster PI, Waterman PG. Alkaloids and limonoids from Bouchardatianeurococca systematic significance. Phytochem. 2003; 64: 609-21.

4. Deng Y, Xu R, Ye YJ. Chin. A simple and efficient approach to quinazolinones under mild copper- catalyzed conditions. Pharm Sci. 2000; 9: 116-28.

5. Dewick PM, Wiley J.Synthetic studies of heterocyclic natural products.Med Nat Prod. 2009: 395-97.

6. Terashima K, Shimamura H, Kawase A, Tanaka Y, Tanimura T, Kamisaki T, Ishizuka Y, Sato M. Studies on antiulcer effects of 2-Benzylthio-5,6,7,8-tetrahydro-4(3H)-quinazolinones and related compounds. ChemPharmaceu Bulletin. 1995; 43(11): 2021-23.

7. MahdyHA, IbrahimaMK, MetwalyAM,Belal A, MehanyeABM, El-GamalKMA, El-Sharkawy A, ElhendawyMA, RadwanMM, ElsohlyMA, EissaaIH. Design, synthesis, molecular modeling, in vivo studies, and anticancer evaluation of quinazolin-4(3H)-one derivatives as potential VEGFR-2 inhibitors and apoptosis inducers.Bioorg Chem. 2020; 94: 1-25.

8. Le Y, Gan Y, Fu Y, Liu J, Li W, Zou X, Zhou Z, Wang Z, OuyangG, Yan L. Design, synthesis and in vitro biological evaluation of quinazolinone derivatives as EGFR inhibitors for antitumor treatment. J Enzyme Inhib Med Chem. 2020; 35(1): 555-64.

9. Deshmukh SU, Kharat KR, Kadam GG, Pawar RP.Synthesis of quinazolinones derivatives an antiproliferative agent against human lung carcinoma cells.Eur J Chem. 2017; 8(3): 317-20.

10. Ghodge B, Kshirsagar A, Navghare V. Synthesis, characterization, and investigation of the anti-inflammatory effect of 2,3-disubstituted quinazoline-4(1H)-one. J Basic Applied Sci. 2020; 9: 1-12.

11. Amin KM, Kamel MM, Anwar MM, Khedr M, Syamb YM. Synthesis, biological evaluation, and molecular docking of novel series of spiro[(2H,3H)quinazoline-2,10-cyclohexan]-4(1H)-one derivatives as anti-inflammatory and analgesic agents. Eur J Med Chem. 2010; 45(6): 2117–31.

12. Mohamed MS, Kamel MM, Kassem EMM, Abotaleb N, Nofal SM, Ahmed MF. Novel 3-(p-substituted phenyl)-6-bromo-4(3h)-quinazolinone derivatives of promising anti-inflammatory and analgesic properties.Acta Pol PharmDrug Res. 2009; 66(5): 487-500.

13. Rajan SG, Hardik MT, Giordano T, Williams J, Rogers D,Sudersanam V, Kamala KV. Design, synthesis, and characterization of novel 2-(2,4-disubstituted-thiazole-5-yl)-3-aryl-3H-quinazoline-4-one derivatives as inhibitors of NF-𝜅B and AP-1 mediated transcription activation and as potential anti-inflammatory agents.Eur J Med Chem. 2009; 44(5): 2184-89.

14. Hemalatha K, Girija K. Synthesis of some novel 2, 3-disubstituted quinazolinone derivatives as an analgesic and anti-inflammatory agents.Int J Pharm Pharm Sci. 2011; 3(2): 103-6.

15. Bojarski AJ, Kowalski P, Kowalska T, Duszynska B, Minol CS, Tatarczynska E, Klodzinska A, Chojnacka-Wo JE. Synthesis and pharmacological evaluation of new arylpiperazines 3-{4-[4-(3-chlorophenyl)-1-piperazinyl]butyl}-quinazolidin-4-one–a dual serotonin 5-HT1A/5-HT2A receptor ligand with an anxiolytic-like activity. Bioorg Med Chem. 2002; 10(12): 3817–27.

16. Kashaw SK, Kashaw V, Mishra P, Jain NK, Stables JP. Synthesis, anticonvulsant, and CNS depressant activity of some new bioactive 1-(4-substituted-phenyl)-3-(4-oxo-2-phenyl/ethyl-4H-quinazolin-3-yl)-urea.Eur J Med Chem. 2009; 44(11): 4335–43.

17. Ye C, You J, Li XF, You R, Weng Y, Li J, Wang Y. Design, synthesis, and anticoccidial activity of a series of 3-(2-(2-methoxyphenyl)-2-oxoethyl)quinazolinone derivatives. PesticBiochem Physiol. 2010; 97(3): 194–8.

18. Ugale VG, Patel HM, Wadodkar SG, Bari SB, Shirkhedkar AA, Surana SJ.Quinazolino-benzothiazoles: Fused pharmacophores as anticonvulsant agents. Eur J Med Chem. 2012; 53: 107-13.

19. Archana, Srivastava VK, Kumar A. Synthesis of newer thiadiazolyl and thiazolidinonyl quinazolin-4(3H)- ones as potential anticonvulsant agents. Eur J Med Chem. 2002; 37(11): 873-82.

20. Rivero A, Espinoza K, Somanathan R. Syntheses of quinazoline-2,4-dione alkaloids and analogues from MexicanZanthoxylum species. Molecules. 2004; 9: 609-16.

21. Pandeya SN, Sriram D, Nath G, Clercq ED. Synthesis antibacterial, antifungal, and anti-HIV evaluation of Schiff and Mannich bases of isatin derivatives with 3-amino-2-methylmercapto quinazolin-4(3H)-one. PharmaActaHelv. 1999; 74(1): 11–17.

22. Asadi P, Khodarahmi G, Najafabadi AJ, Saghaie L, Hassanzadeh F. Synthesis, characterization, molecular docking studies, and biological evaluation of some novel hybrids based on quinazolinone, benzofuran and imidazolium moieties as potential cytotoxic and antimicrobial agents. Iran J Basic Med Sci. 2017; 20(9): 975-89.

23. Zayed MF, Hassan MH. Synthesis and biological evaluation studies of novel quinazolinone derivatives as antibacterial and anti-inflammatory agents. Saudi Pharm J. 2014; 22: 157-62.

24. Anwar A, Shahbaz MS, Saad SM, Khan KKM, Siddiqui R, Khan NA. Novel antiacanthamoebic compounds belonging to quinazolinones. Euro J Med Chem. 2019; 182: 111-17.

25. Saeedi M, Khanaposhtani MM, Pourrabia P, Razzaghi N, Ghadima R, Imanparast S, Faramarzi MA, Bandarian F, Esfahani EN, Safavi M, Rastegar H, Larijani B, Mahdavi M, Akbarzadeh T. Design and synthesis of novel quinazolinone-1,2,3-triazole hybrids as new antidiabetic agents:In vitroα-glucosidase inhibition, kinetic and docking study. Bioorg Chem. 2019: 83; 161-9.

26. Birhan YS, Bekhit AA, Hymete A.Synthesis, and antileishmanial evaluation of some 2,3-disubstituted-4(3H)-quinazolinone derivatives. Org Med ChemLett. 2014; 4(10): 1-7.

27. Myangar KN, Akhaja TN, Naik DR, Raval JP. Novel piperazinyl-quinazoline-4-one analogs: design, synthesis, and evaluation of in vitro biological activity. ChemSci Trans. 2012; 1(3): 688-96.

28. Reddy VR, Rao NR, Reddy RR, Suthakaran R. Microwave-assisted synthesis, characterization, and pharmacological evaluation of imidazolo quinazoline-4-one derivatives. Int J Pharm Sci Rev Res. 2014; 29(2): 1-4.

Received on 01.10.2020 Modified on 14.03.2021

Research J. Pharm. and Tech 2022; 15(1):419-423.

DOI: 10.52711/0974-360X.2022.00069