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EHOOPrAHH^ECKAa XHMH3, 2015, moM 41, № 2, c. 235-248
SYNTHESIS AND IN VITRO ANTIMICROBIAL EVALUATION OF PIPERAZINE SUBSTITUTED QUINAZOLINE-BASED THIOUREA/THIAZOLIDINONE/CHALCONE HYBRIDS
© 2015 D. R. Shah, H. P. Lakum, and K. H. Chikhalia#
Department of Chemistry, School of Sciences, Gujarat University, Ahmedabed, Gujarat, 380009 India
Received June 11, 2014; in final form, 23.07.2014
In frames of the search for new biological entities to fight against recent drug-resistant microbial strains, we report a library of quinazoline-based thiourea/4-thiazolidinone/chalcone hybrids. The newly synthesized compounds were studied for efficacy against several bacteria (Staphylococcus aureus, Bacillus cereus, Pseudomonas aeruginosa, and Klebsiella pneumoniae) and fungi (Candida albicans and Aspergillus clavatus) using the broth dilution technique. From the biological evaluation, (E)-3-(3,4-dimethoxyphenyl)-1-(4-((4-(4-ethylpiperazin-1-yl)quinazolin-2-yl)amino)phenyl)prop-2-en-1-onewas found to be the most active analogue (microbial inhibition concentration 3.12 ^g/mL) to inhibit the bacterial growth. The rest of the compounds showed equipotent efficacy (3.12—12.5 ^g/mL) as compared to the standard. Final compounds were characterized by FT-IR, XH NMR, 13C NMR, mass spectroscopy, and elemental analysis.
Keywords: 4-thiazolidinone, antibacterial activity, antifungal activity, chalcone, quinazoline, thiourea. DOI: 10.7868/S013234231502013X
INTRODUCTION
During the past few decades, the growing population is affected with significant increase in the frequency of severe infectious diseases because of the increasing number of multi-drug-resistant (MDR) microbial pathogens. Increasing number of MDR strains developed by the microbes makes currently used antimicrobial drugs ineffective. Over the past years, alleviation of opportunistic microbial infections became an imperative and challenging problem due to the inac-tiveness of susceptible microorganism. Rapid multiplication of drug resistant strains poses a severe threat in recent years [1—3]. Such infection readily affects debilitated and immune compromised patients. Hence, there is an urgent need to alleviate drug resistance by providing more effective potential therapeutic agents [4, 5].
The search for novel bioactive agents with higher selectivity and lower toxicity continues to be an area of intensive investigation in synthetic medicinal chemistry. On the path of identifying various chemical substances that may serve as leads for designing novel bio-active agents, nitrogen-containing heterocycles are of particular interest. Quinazoline scaffold has been extensively studied for its many pharmacological properties [6], which include anti-cancer [7], anti-inflammatory [8], anti-bacterial [9], antiviral [10], anti-tubercular [11], anti-malarial [12], and anti-diuretic [13] activities. Quinazoline linked thiourea hybrid derivatives have been identified as impressive antimicrobial agents [14]. Furthermore, the presence of piperazine substit-uents atC-4 position of quinazoline core has proved to
# Corresponding author (tel: +91-79-26300969/9427155529, fax: +91-79-26308545, e-mail: chikhalia_kh@yahoo.com).
be the active key in various biological effects [15]. Moreover, quinazoline and their condensed products with thiazolidinone derivatives have been reported to possess interesting antimicrobial activity [16, 17].
Encouraged by our previous successful research efforts [10, 18, 19] in this regard, we decided to further extend the above methodology to identify more quinazolinyl hybrids. In view of the above-mentioned knowledge of different pharmacophores and in continuation of our research program, we have designed (figure) and synthesized quinazoline-thiourea/thiazo-lidinone/chalcone hybrids and incorporated pipera-zine and electronic environment to get single bioactive molecule framework. Compounds were subjected to evaluation of their antibacterial and antifungal potency against various bacterial strains. As a result, some of the derivatives showed excellent activity in the range of 3.12-12.5 ^g/mL of MIC.
RESULTS
Chemistry
Scheme outlines the synthetic pathway used to obtain compounds (Va—e, VIIIa-e, Xa-e, and XIIIa-e). The first step comprises formation of quinazoline-2,4(1H,3H)-dione (1) in very good yield by the reaction of anthranilic acid and urea [20]. Cyclization of intermediate (I) with POCl3 forms the 2,4-dichloro-quinazoline (II). This was further reacted to ^-phenyl piperazine in isopropyl alcohol to form 2-chloro-4-(4-phenylpiperazin-1-yl)quinazoline(III). Compound (III) was then reacted to ammonium thiocyanate and various amines to give final thiourea derivatives (Vk—e).
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Scheme. Synthetic route for the synthesis of quinazoline-based final hybrid (Va—e, Villa—e, Xa—e, and Xllla—e) derivatives.
Intermediated (II) was then further reacted to Methyl piperazineforming 2-chloro-4-(4-ethylpiperazin-1-yl)quinazoline (VI) further reacted with ammonium thiocyanate and piperazine to give final (Villa—e) compounds. Intermediate 2-chloro-4-(4-ethylpiperazin-1-yl)quinazoline (VI) was refluxed to replace 2-Cl position with 4-amino acetophenone and hydrazine hydrate that gives 1-(4-((4-(4-ethylpiperazin-1-yl)quinazolin-2-yl)amino)phenyl)ethanone (IX) and 4 - (4 - ethylpiperazin-1 -yl) - 2-hydrazinylquinazo -line (XI), respectively. Out of them, (IX) was then condensed to various aldehydes to form chalcone (Xa—e) analogues, whereas intermediate (XI) was reacted with
various phenyl isothiocyanate and further cyclized with chloroethylacetate and sodium acetate to form desired thiazolidinone (Xllla—e) derivatives. The accuracy of the synthesis of final compounds was confirmed on the basis of XH NMR, 13C NMR, and mass spectra and the purity was ascertained by elemental analysis. Physical and analytical data of title compounds are elaborated in Table 1.
Biological Evaluation
All newly synthesized quinazoline derivatives (Va—e, Villa—e, Xa—e, and Xliia—e) were examined for an-
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Design of the title quinazoline-based hybrids.
timicrobial activity against two Gram-positive bacterial strains (Staphylococcus aureus MTCC 96, Bacillus cereus MTCC 430), two Gram negative bacterial strains (Pseudomonas aeruginosa MTCC 741, Klebsiella pneumoniae MTCC 109), and two fungal strains (Aspergillus clavatus MTCC 1323, Candida albicans MTCC 183) using agar dilution method [21]. Ciprofloxacin was used as standard control drug for antibacterial activity, whereas Ketoconazole was used as standard control drug for antifungal activity.
In vitro antibacterial activity. Table 2 shows that all the newly synthesized quinoline scaffolds were found to exhibit good to moderate activity against the specific microbial strain. Bioassay results of the series of (Va—e) compounds revealed that final analogue (Ve), bearing electron donating methyl group at para position of phenyl ring, was found to be the most active compound that inhibits the gram-positive S. aureus bacterial growth at the lowest minimum inhibitory concentration (MIC) value of 3.12 |g/mL. Compound (VC) with chloro group showed lower effective-
ness with 12.5 |g/mL MIC against the same bacteria. The presence of an electron snatching substituent, like nitro group (Vb), proved to be intrinsic to conduce noteworthy activity at 12.5 |g/mL of MIC against the B. cereus strain. Compound (Vd) containing chloro group at para position of the phenyl ring showed half-fold (6.25 |g/mL MIC) inhibitory activity against gram negative P. aeruginosa strain as compared to standard ciprofloxacin drug (3.12 |g/mL MIC), respectively. Analogue (Va )manifested excellent inhibition of gram-negative K. pneumoniae strain at 12.5 |g/mL of MIC.
For the series (Villa—e) derivatives, compound (Vllld) bearing ^-ethyl piperazine ring showed the strong inhibitory action at 3.12 |g/mL of MIC against Gram-positive S. aureus strain. Analogues (VI—IIb) with ^-ethoxy carbonyl piperazine showed slightly reduced activity of 6.25 |g/mL MIC against the same bacteria. Compound (VIIIc) bearing ^-me-thyl piperazine moiety appeared with half-fold growth inhibition (6.25 |g/mL MIC) of Gram-posi-
Table 1. Physical and analytical data of final synthesized quinazolinyl derivatives (Va—e, Villa—e, Xa—e, and Xllla—e)
Elemental analysis
Entry R Mol. formula Mol. weight Yield, % mp (°C) calcd. found
%C %H %N %C %H %N
(Va) H C25H24N6S 440.56 72 129-133 68.16 5.49 19.08 68.32 5.47 19.03
(Vb) 2-NO2 C25H23N7O2S 485.56 67 162-164 61.84 4.77 20.19 61.67 4.76 20.13
(Vc) 3-Cl C25H23ClN6S 475.01 65 163-165 63.21 4.88 17.69 63.03 4.87 17.65
(Vd) 4-Cl C25H23ClN6S 475.01 65 130-131 63.21 4.88 17.69 63.31 4.89 17.64
(Ve) 4-CH3 pro C26H26N6S 454.59 67 213-215 68.69 5.76 18.49 68.76 5.77 18.44
(Viiia) J> 1 C29H39N7O3S 565.73 66 139-141 61.57 6.95 17.33 61.39 6.96 17.29
0
(Viiib) C22H31N7O2S 457.59 65 162-164 57.74 6.83 21.43 57.86 6.81 21.39
(Viiic) rf C20H29N7S 399.56 64 201-203 60.12 7.32 24.54 59.95 7.31 24.48
(Viiid) C21H31N7S 413.58 67 110-112 60.99 7.55 23.71 61.09 7.53 23.64
(Viiie) On^n^ C2
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