Synthesis, Characterisation and Biological Evaluation Of
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ry: C ist urr m en e t Prabhakar et al., Organic Chem Curr Res 2016, 5:4 h R C e c s i e n DOI: 10.4172/2161-0401.1000174 a a r Organic Chemistry c g r h O ISSN: 2161-0401 Current Research ResearchResearch Article Article Open Accesss Synthesis, Characterisation and Biological Evaluation of Quinazoline Derivatives as Novel Anti-Microbial Agents Prabhakar V1*, Sudhakar BK2, Ravindranath LK2, Latha J3 and Venkateswarlu B4 1Faculty of Engineering Chemistry, SVR Engineering College, Jawaharlal Nehru Technological University - Ananthapuramu (JNTU-A), Nandyal, Kurnool District, Andhra Pradesh, India 2Department of Chemistry, Sri Krishnadevaraya University, Anantapuramu, Andhra Pradesh, India 3Department of Environmental Science, Sri Krishnadevaraya University College of Engineering and Technology, Ananthapuramu, Andhra Pradesh, India 4Jawaharlal Nehru Technological University (JNTU-A), Kavali, Nellore District, Andhra Pradesh, India Abstract A novel series of Quinazolines were synthesised by cyclisation reaction of Anthranilic acid with urea to get 2,4 di hydroxy quinazoline (2) intermediate, which were further treated with POCl3 to get 2,4 di chloro quinazoline (3), which was treated with Thio-morpholine (4) for 3 hrs to get compounds (5), which are reacted with aqueous ammonia to get compound(6), which was further reacts with different boronic acids 7(a-j) by using Chan-Lam coupling reaction conditions to get Target Novel Quinazoline derivatives (8a-8j). The structures of new compounds were confirmed by IR and 1H NMR and 13C NMR spectral data. Anti-bacterial and anti-fungal activities were evaluated and compared with the standard drugs, compounds 8i, 8d, 8h, 8g exhibited promising anti-microbial and anti-fungal activity compared to standard drugs. Keywords: Quinazoline; Chan-Lam coupling; Anti-microbial activity; an R-adrenergic blocker [35] and Iressa as an epidermal growth factor 2,4-di chloro quinazoline; Synthesis receptor inhibitor was approved by the Food and Drug Administration in USA for the treatment of lung cancer [36]. Introduction The Quinazoline skeleton is present in a variety of biologically active Quinazoline (1) is a fused six-member aromatic ring (a benzene compounds, among these are several marketed drugs such as prazosin ring and a pyrimidine ring are fused). Quinazoline is a fused bicyclic (1), Gefitinib (2), Erlotinib (3), Vandetanib (4) (Figure 2). compound earlier known as benzo-1, 3-diazine. It was first prepared in the laboratory in 1903 by Gabriel [1]. Although its derivative were Encouraged by the diverse biological activities of Quinazoline known much earlier. The name quinazoline (German: Chinazolin) was Heterocyclic compounds, it was decided to prepare a new series of first proposed for this compound by weddige on observing that this Quinazoline derivatives. Literature survey revealed that incorporation was isomeric with the compounds cinnoline and quinoxaline. Paal and of different groups in Quinazoline Heterocyclic ring enhanced antibacterial and antifungal activity. In the present communication 2,4 Bush suggested the numbering of quinazoline ring system, which is Di Chloro Quinazoline (3) was reacted with meta-Amine Sulphonamide currently used [2-4]. The other less commonly used names for this ring (4) in tert-butanol at 90°C to form Compound (5), which was further system are ‘phenmiazine’ and 5, 6-benzopyrimidine. However, the name reacted with aqueous ammonia in THF(Tetra Hydro Furan) at 90°C quinazoline is now universally accepted (Figure 1). to get target compound (6), Which was further reacted with different Quinazoline derivatives, which belong to the N-containing boronic acids under Chan-Lam reaction conditions to form Target heterocyclic compounds, have caused universal concerns due to compounds (8a-8j). The synthesis of the compounds as per the following their widely and distinct biopharmaceutical activities. Researchers Figure 3 given below. have already determined many therapeutic activities of quinazoline The structures of all synthesized compounds were assigned on the derivatives, including anti-cancer [5-8], anti-inflammation [9,10], anti- basis of IR, Mass, 1H and 13C NMR spectral data analysis. Further these bacterial [11-14], analgesia [9,13], anti-virus [15], anti-cytotoxin [16], compounds were subjected for antifungal and antibacterial activity. anti-spasm [13,17], anti-tuberculosis [18], anti-oxidation [19], anti malarial [20], anti-hypertension [21], anti-obesity [22], anti-psychotic Materials and Methods [23], anti-diabetes [24], etc. Medicinal chemists synthesized a variety of quinazoline compounds with different biological activities by installing In this Investigation chemicals were purchased from local dealer various active groups to the quinazoline moiety using developing synthetic methods. And the potential applications of the quinazoline *Corresponding author: Prabhakar V, Faculty of Engineering Chemistry, SVR derivatives in fields of biology, pesticides and medicine have also been Engineering College, Jawaharlal Nehru Technological University - Ananthapuramu (JNTU-A), Nandyal-518 502, Kurnool District, Andhra Pradesh, India, Tel: explored. +918297140295; E-mail: [email protected] Quinazoline derivatives have attracted much attention for their Received: October 15, 2016; Accepted: October 30, 2016; Published: November various biological and medicinal properties. For example, they act 20, 2016 as the potent tyrosine kinase and cellular phosphorylation inhibitors Citation: Prabhakar V, Sudhakar BK, Ravindranath LK, Latha J, Venkateswarlu [25], and they are also used as ligands for benzodiazepine and GABA B (2016) Synthesis, Characterisation and Biological Evaluation of Quinazoline receptors in the central nervous system (CNS) [26] or as DNA binders Derivatives as Novel Anti-Microbial Agents. Organic Chem Curr Res 5: 174. doi: 10.4172/2161-0401.1000174 [27-29] Some of them show remarkable activity as anticancer [30], antiviral [31] and antitubercular agents [32,33]. Molecules containing Copyright: © 2016 Prabhakar V, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits the Quinazoline unit have been popular drugs. For example, Erlotinib unrestricted use, distribution, and reproduction in any medium, provided the original is used in the treatment of several types of tumors [34] Prazosin acts as author and source are credited. Organic Chem Curr Res, an open access journal ISSN:2161-0401 Volume 5 • Issue 4 • 1000174 Citation: Prabhakar V, Sudhakar BK, Ravindranath LK, Latha J, Venkateswarlu B (2016) Synthesis, Characterisation and Biological Evaluation of Quinazoline Derivatives as Novel Anti-Microbial Agents. Organic Chem Curr Res 5: 174. doi: 10.4172/2161-0401.1000174 Page 2 of 14 LCMS Data shows That 2, 4 di hydroxy Quinazoline [Compound N 2] Purity of 99.63%, RT 1.924, Mass 161.1 [M+, 100%]. N General procedure for synthesis of 2, 4 di chloro Quinazoline Figure 1: Quinazoline. [compound (3)] A mixture of quinazoline-2,4-diol(compound 2) (55 gms, 0.339 O mol), Phosphorous oxy chloride (550 mL), and catalytic amount of O N O N N O DMF (2 ml) was heated at reflux for 8 hrs, and the reaction was monitored O N N O N O N N O O by TLC. The reaction mixture was concentrated under reduced pressure N O Cl NH NH O and the residue was poured onto ice water with vigorous stirring yielding a NH 2 F precipitate. The mixture was then filtered to yield 2, 4 di chloro Quinazoline Gefitinib (2) Erlotinib (3) Prazosin (1) (compound 3) (Figure 9) as a white solid. N Yield: 75% (51 gms). O N N O M.p. 116-118°C; NH 1 H NMR (CDCl3-d1) δ ppm 8.30-8.20 (d, IH), 8.10-8.00 (m, 2H), Br F Vandetanib (4) 7.80-7.70 (d, I H) (Figures 10 and 11). 3 Figure 2: Quanazoline skeleton is present in a biologically active compounds. C NMR (CDCl3-d1) (δ/ppm): 120(Ar C), 125 (Ar C), 128.6 (Ar C),136.5(Ar C), 151 (Ar C), 157(Ar C), 161.3(Ar C-) (Figures 12 and 13). OH IR (KBr, ν/cm–1): 755 (C-Cl), 3040 (Ar C-H), 1619 (C=N); N GCMS Purity 89.75%, RT 8.738, Mass 198 [M+], 200 [M+2], 202 N OH [M+4], 9:6:1 It indicates molecule contains Two chlorine atoms and (2) Even no. of Nitrogen atoms According to Nitrogen rule. Figure 3: Structure of 2,4 di hydroxy Quinazoline (compound 2). General procedure for synthesis of 4-(2-chloroquinazolin-4- yl) thiomorpholine [Compound 5] with S.D fine make was used. Chemicals were 99% pure; purity has To the mixture of 2,4 di chloro Quinazoline (Compound 3) (10 been checked by Thin layer chromatography and melting point. gms, 0.0505 mol), Na2CO3 (0.1262 mol,13.5 gms) and MeOH (100 mL), Conventional method has been used for synthesis of Quinazoline Thiomorpholine (2.1 eq, 0.106 mol, 10.93 gms), was added drop wise at derivatives. Stirring and reflux method were used for synthesis of 0°C. Then the reaction mixture was Stirred at Room Temperature for Quinazoline derivatives 8(a-j) respectively. The Nomenclature was 3 hrs. After completion of reaction as indicated by TLC, the reaction given for Synthetic compounds from compound (1) to Compounds mixture was concentrated under reduced pressure and the residue was 8a-8j by using Chem Bio draw Ultra -12 version. poured onto ice water with vigorous stirring yielding a precipitate. The The title compounds 8 (a-j) were synthesized in Seven steps using precipitate was then filtered to yield the title compound (Compound 5) (Figure 14) as a white solid (12.85 g, 96% yield). different reagents and reaction conditions, the 8 (a-j) were obtained in moderate yields. The structure were established by spectral (IR, M.p. 226-227°C. 1H-NMR, 13C-NMR and mass) and analytical data (Scheme 1). ESI-MS m/z 266 [M+H]+, 288[M+Na]+ General procedure for synthesis of 2,4 di hydroxy Quinazoline 1H NMR (400 MHz, DMSO-d ) δ ppm 2.7 (4H, t, 2 × CH –S), 3.5 [compound (2)] 6 2 (4H, t, 2 × CH2–N), 7.6 (1H,t, Ar-H), 7.85 (2H,m, Ar-H), 8.2 (1H,d, A mixture of 2-aminobenzoic acid (1) (50 g, 0.364 mole) and urea Ar-H).