Letters in Drug Design & Discovery, 2009, 6, 21-28 21 1570-1808/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd. Synthesis, Antibacterial Activity of 2,4-Disubstituted Oxazoles and Thiazoles as Bioisosteres Mohamed Kaspady a , Venugopala Katharigatta Narayanaswamy b , Mohana Raju* ,a and Gopal Krishna Rao b a Department of Polymer Science and Technology, Sri Krishnadevaraya University, Anantapur, Andhra Pradesh - 515 003, India b Department of Pharmaceutical Chemistry, Al-Ameen College of Pharmacy, Hosur Road, Opp. Lalbagh Main Gate, Bangalore - 560 027, India Received July 27, 2008: Revised October 13, 2008: Accepted October 13, 2008 Abstract: Two series of 2-substituted aryl, heteroaryl and alkyl, 4-substituted aryl 1,3-oxazole (2a-k) and thiazole (4a-k) molecular scaffolds containing divalent bioisosteres, viz., oxygen and sulphur were synthesized by condensing substituted amides and thioamides with substituted phenacyl bromide in absolute ethanol medium. The structure of newly synthesized compounds was characterized by analytical and spectral (IR, 1 H-NMR, 13 C-NMR and LC-MS) methods. The synthesized compounds were evaluated for qualitative (zone of inhibition) and quantitative antibacterial activity (MIC) by agar cup plate and micro-titration methods, respectively. Preliminary pharmacological observations revealed that some of the sub- stituents such as 2-alkyl and heteroaryl at second position, chloro and bromo at the fourth position of the aryl moiety and a divalent sulphur atom in the five-membered heterocyclic ring system influenced significantly the antibacterial activity when compared to its bioisostere counterpart 2-substituted aryl, heteroaryl and alkyl, 4-substituted aryl 1,3-oxazole sys- tems. Keywords: Oxazole, Thiazole, Bioisostere, Antibacterial activity, Minimum Inhibitory Concentration. INTRODUCTION Oxazoles and thiazoles are compounds useful in pharma- ceutical and agricultural chemistry. For example, the aminothiazole ring system is a useful structural element in medicinal chemistry and has found broad applications in drug development as antiallergies [1], antihypertensive [2], anti-inflammatory [3], antibacterial [4] and anti-HIV agents [5]. Different thiazole-bearing compounds possess analgesic and anti-inflammatory properties [6] and some are used as pharmaceutical as well as agrochemical products [7–12]. Among them, Ritonavir is a well-known anti-HIV drug and Imidacloprid is an important insecticide. Substituted oxazole derivatives are found to be associated with various biological activities such as antibacterial, antifungal [13], antitubercular [14] and anti-inflammatory activities [15]. Prompted by the above investigation and in continuation of our search for bioactive molecules [16, 17] and concomitant polymorphism in drug molecules [18], we envisaged the synthesis of 2-substituted aryl, heteroaryl and alkyl, 4- substituted aryl 1,3-oxazoles (2a-k) and thiazoles (4a-k) by condensing substituted amide and thioamide [19] with sub- stituted phenacyl bromide in absolute ethanol medium. Fi- nally, title compounds were subjected for in-vitro antibacte- rial properties against two gram-positive and two gram- negative strains of cultured organisms such as Bacillus sub- tilis (NCIM, 2063; ATCC 6633), Staphylococcus aureus (NCIM, 2079; ATCC 6538P), Escherichia coli (NCIM, *Address correspondence to this author at the Department of Polymer Sci- ence and Technology, Sri Krishnadevaraya University, Anantapur, Andhra Pradesh - 515 003, India; Tel: +91-08554-255655; Fax: +91-08554-255710; E-mail: kmrmohan@sify.com 2065; ATCC 8739) and Klebsiella pneumoniae (NCIM, 2957). RESULTS AND DISCUSSION Chemistry The synthetic route of the compounds (2a-k and 4a-k) is outlined in Schemes 1 and 2, respectively. Substituted aryl, heteroaryl and alkyl nitriles and solid support silica- gel G- sulphuric acid [19] were refluxed with toluene to obtain sub- stituted amides (1a-f), the latter refluxed with substituted phenacyl bromide to obtain the title compounds (2a-k) in nitrogen atmosphere condition. Their bioisostere counterpart (4a-k) was obtained by a similar method in which the substi- tuted thioamides (3a-f) and substituted phenacyl bromide were refluxed in absolute ethanol to obtain title compounds (4a-k). Thioamides are prepared by refluxing a mixture of substituted aryl, heteroaryl and alkyl nitriles, thioacetic acid, boron trifluoride diethyletherate and 1,2 dichloro ethane at 80 0 C for 1 h. The structures of the synthesized compounds were characterized by analytical (Tables 1 and 2) and spec- tral data (IR, 1 H-NMR, 13 C-NMR and LC-MS). In the IR spectra, the N=CH and C=C peaks were ob- served in the range 1680–1648cm -1 and 1600–1568cm -1 , respectively. Compounds 2b, 2d, 4b and 4d have shown – NH 2 doublet peak in the range 3428–3420cm -1 and 3312– 3309cm -1 . In the 1 H-NMR spectra  range 4.73–4.75 ppm for compounds 2b, 2d, 4b and 4d confirmed the availability of NH 2 group. In 13 C-NMR spectra compounds, 2a, 2c, 4a and 4c revealed the appearance of carbonyl carbon (C=O) at  range 170.01–169.51 ppm. In compound 2j-k and 4j-k  values for tertiary carbon and alkyl carbon were observed in