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Antibacterial and Antifungal Activities of 22 Arylidene -4-(4-Methylphenyl)but -3en-4olides and Arylidene-4-(4-Methylphenyl)but -4-(4-Methylphenyl)but-3-3-en-4en-4-olides their Pyrrolone Derivatives A. HUSAIN*, S. M. HASAN, S. LAL 1 AND M. M. ALAM Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, New Delhi-110 062, 1Department of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra, Haryana, India.
Starting from 3-3-(4-methyl-benzoyl)propionic acid and using appropriate reagents, some new 2-arylidene-4-(4 methylphenyl)but-3-en-4-olides (IIIa-g) and their corresponding pyrrolone derivatives (IVa-d) have been synthesized. These compounds were evaluated for their antibacterial activity against Staphylococcus aureus and Escherichia coli as well as antifungal activity against Candida albicans. The compounds have considerable antifungal activity and moderate antibacterial activity.
γ-Lactones are well-known heterocycles of biological interest. Butenolides consist of unsaturated γ-lactone rings, which are also known as 2, 3 and 2, 5 dihydrofuran-2-ones. Some well-known lactones of natural origin are santonin, cardiac glycosides, sesquiterpene lactones and patulin (an antibiotic)1-3. A wide range of biological activities are exhibited by this class of compounds, such as anthelmintic, ascaricidal, antifungal, antiinflammatory, antitumor and antiviral1-7. The γ-lactone ring present in butenolide derivatives is significantly reactive and can be utilized for the synthesis of nitrogen heterocycles, i.e., pyrrolones of potential biological activities 8-12 like antifungal, antibacterial and antiinflammatory. In view of potential biological activity of members of γ-lactone ring system, it was of interest to us to prepare some new derivatives in this class.
phenyl)but-3-en-4-olides (IIIa-g) were synthesized from 3 (4-methyl-benzoyl)propionic acid (II) by treating it with different aromatic aldehydes in the presence of triethylamine in acetic anhydride. Some of the selected butenolides (IIIa-d) were treated with dry ammonia gas at room temperature to obtain 3-arylidene-5-(4-methyl phenyl)-2(3H)-pyrrolones (IVa-d). The synthesized compounds were characterized by elemental analysis, IR, 1 H NMR and mass spectral data. The compounds were synthesized according to Scheme 1.
The starting compound, i.e., 3-(4-methyl-benzoyl) propionic acid (II), was obtained by the condensation of succinic anhydride with dry toluene in presence of anhydrous aluminium chloride, following Friedel-Craft’s acylation reaction conditions. 2-Arylidene-4-(4-methyl
All the compounds were screened for their antimicrobial activity against the microorganisms, viz, Staphylococcus aureus (NCTC-6571), Escherichia coli (ATCC-25922) and Candida albicans (ATCC-10231), in meat peptone agar medium at a concentration of 100 µg/ml by cup plate method14. Compounds inhibiting growth of one or more of the above microorganisms were further tested for minimum inhibitory concentration (MIC). A solution of the compounds was prepared in dimethylformamide (DMF) and a series of doubling dilutions prepared with sterile pipettes. To each of a series of sterile stoppered test tubes, a standard volume of nutrient broth medium was added. A control tube containing no antimicrobial agent was included. The inoculum consisting of an overnight broth culture of microorganisms was added to separate tubes. The tubes were incubated at 37° for 24 h and examined for turbidity. The tube with highest dilution showing no turbidity was the one containing compound with MIC. Results are presented in Table 1.
*For correspondence E-mail:
[email protected]
3-(2,4-Dichloro-benzylidene)-5-(4-methylphenyl)-2(3H) pyrrolone (compound IVb) showed excellent activity
In the present communication, a series of 2-arylidene-4 (4-methylphenyl)but-3-en-4-olides (IIIa-g) and 3-arylidene 5-(4-methylphenyl)-2(3H)-pyrrolones (IVa-d) were screened for antibacterial activity against Staphylococcus aureus and Escherichia coli as well as antifungal activity against Candida albicans, the synthesis of which has been reported in our previous communication13.
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H3C
Toluene
H3C
Anhy.AlCl3 Succinic anhydride
OH O
O
3- (4-Methyl-benzoyl) propionic acid (II) Ac2O
O
Triethylamine R
H
R
H3C
O O
2-Arylidene -4-(4-methylphenyl)-but-3-en-4-olides (IIIa-g) Dry ammonia gas Dry Ethanol R
H3C
O N H
3-Arylidene-5-(4-methylphenyl)-2-(3H)-pyrrolone (IVa-d) Scheme 1: Synthetic route of title compounds
against Candida albicans with MIC-25 µg/ml and good activity against Staphylococcus aureus with MIC-50 µg/ml. 3 Benzylidene-5-(4-methylphenyl)-2(3H) pyrrolone (compound IVa) exhibited good activity against Staphylococcus aureus and Candida albicans with MIC-50 µg/ml. Both the compounds were active against Escherichia coli with MIC 100 µg/ml. Majority of the compounds were insignificant in their action against Escherichia coli. TABLE 1: ANTIMICROBIAL ACTIVITY (MIC*) OF THE COMPOUNDS IIIA-G AND IVA-D Compound No.
R
IIIa IIIb IIIc IIId IIIe IIIf IIIg IVa IVb Ivc IVd
H 2,4-(Cl)2 3,4-(OCH 3) 2 2-OCOCH 3 2,4-(OCOCH 3) 2 4-Br 4-N-(CH3)2 H 2,4-(Cl)2 3,4-(OCH 3) 2 2-OH
Antibacterial activity S. aureus E. coli >100 >100 50 50 >100 -
*= in µg/ml; -= insignificant activity
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>100 >100 >100 -
Antifungal activity Candida albicans >100 >100 >100 50 25 >100
An analysis of results showed that introduction of chloro groups (electron withdrawing) in arylidene ring increases antimicrobial action, while introduction of hydroxyl and methoxy group (electron donating) decreases the antimicrobial activity. The replacement of oxygen atom in the butenolide ring by nitrogen atom (pyrrolones) enhances antimicrobial action.
ACKNOWLEDGEMENTS The authors are thankful to (late) Hakim Abdul Hameed Sahib (Founder, Chancellor of Jamia Hamdard) and Mr. A. Mueed (President, Hamdard National Foundation) for providing facilities to carry out this work. Two of the authors (MMA and SL) are grateful to the University Grant Commission (UGC), New Delhi, for providing research fellowships.
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Accepted 10 August 2006
Revised 29 September 2005
Received 11 April 2005
Indian J. Pharm. Sci., 2006, 68 (4): 536-538
Preliminary Report of Anti-Hepatitis C Virus Activity of Chloroquine and Hydroxychloroquine in Huh-5-2 Cell line M. CHANDRAMOHAN*, S. C. VIVEKANANTHAN 1 , D. SIVAKUMAR 1 , P. SELVAM 2 , J. NEYTS 3 , G. KATRIEN 3 AND E. DE CLERCQ 3 1
Bharat Ratna Kamarajar Jaundice, Liver Hospital and Research Centre, Madurai-625 001, 2Arulmigu Kalasalingam College of Pharmacy, Krishnankoil-626 190, India, 3Rega Institute of Medical Research, Katholieke University, B-3000, Leuvan, Belgium.
Chloroquine and hydroxychloroquine screened for antiviral activity against Hepatitis C virus in Huh-5-2 cells. Chloroquine and hydroxychloroquine reduces the HCV RNA and promote the cell growth with respect to untreated control at concentration of 10.75 µM and 6.6 µM respectively
Chloroquine is a versatile bioactive agent and reported to possess antiviral activity against human immunodeficiency virus (HIV)1, Hepatitis A virus (HAV)2,3 and severe acute respiratory syndrome virus (SARS)4 infections. The documented antiviral activities of chloroquine are by the following mechanisms (a) Viral particles entry into target cells by endocytosis is blocked by chloroquine 5-8 , (b) As lysosomotrophic agent chloroquine accumulates in lysosome of host cell and increases the lysosomal pH and renders lysosomal enzymes inactive and prevent the viral decoating8-10 (c) Intercalating action; chloroquine intercalates the HBV*For correspondence E-mail:
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DNA polymerase and inhibits the enzyme activity of the virus and blocks the multiplication of HBV 11 (d) Chloroquine inhibits Duck hepatitis B virus super coiled DNA (DHBV-sc DNA) and Duck hepatitis B surface antigen also (DHBsAg)12. Chloroquine inhibits the replication of HIV-1 and 2 at clinically achievable concentration and antiHIV activity is by (a) inhibition of synthesis of surface antigen GP120 of HIV13 (b) by inhibition of HIV Integrase14, Chloroquine also inhibits the replication of both DNA and RNA human pathogenic viruses8,9,15. In view of antiviral activities of chloroquine against many viruses the present work is to evaluate the antiviral activity against Hepatitis C virus in Huh-5-2 cells. Replicon assay undertaken with Huh-5-2 cells16-19 [a cell
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