Bioorganic & Medicinal Chemistry Letters xxx (2011) xxxxxx

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Molecular properties prediction and synthesis of novel 1,3,4-oxadiazole analogues as potent antimicrobial and antitubercular agentsMohamed Jawed Ahsan a,b,, Jeyabalan Govinda Samy a, Habibullah Khalilullah a, Md. Shivli Nomani a, Pankaj Saraswat a, Ramakant Gaur a, Abhimanyu Singh aa b

New Drug Discovery Research, Department of Medicinal Chemistry, Alwar Pharmacy College, Alwar, Rajasthan 301 030, India Department of Pharmaceutical Sciences, National Institute of Medical Sciences University, Jaipur 303 121, India

a r t i c l e

i n f o

a b s t r a c tIn the present investigation, a series of 1,5-dimethyl-2-phenyl-4-{[(5-aryl-1,3,4-oxadiazol-2-yl)methyl]amino}-1,2-dihydro-3H-pyrazol-3-one were subjected to molecular properties prediction, druglikeness by Molinspiration (Molinspiration, 2008) and MolSoft (MolSoft, 2007) software, lipophilicity and solubility parameters using ALOGPS 2.1 program. The compounds followed the Lipinski Rule of ve were synthesized for antimicrobial and antitubercular screening as oral bioavailable drugs/leads. Maximum drug-likeness model score (0.95) was found for compound, 4a. All the synthesized compounds were characterized by IR, NMR and mass spectral analysis followed by antimicrobial and antimycobacterial screening. Among the title compounds, compound 4d showed pronounced activity against Mycobacterium tuberculosis H37Rv and isoniazid resistant M. tuberculosis (INHR-TB) with minimum inhibitory concentrations (MICs) 0.78 lM and 1.52 lM, respectively. The compound, 4a showed maximum activity against all bacterial strains with MIC 48 lg/mL comparable to standard drug ciprooxacin, while the compounds, 4e and 4k showed maximum antifungal activity with MIC 816 lg/mL less active than standard drug uconazole. 2011 Elsevier Ltd. All rights reserved.

Article history: Received 10 July 2011 Revised 14 September 2011 Accepted 17 October 2011 Available online xxxx Keywords: Oxadiazoles Antimicrobial agents Antitubercular agents Molecular properties prediction Lipinski Rule of ve

The pathogenic agent of tuberculosis (TB), Mycobacterium tuberculosis (MTB) is responsible for death of 23 million people annually.1 There are estimated 1.3 million multi/extensively drug resistant TB (M/XDR-TB) cases will need to be treated between 2010 and 2015.2 Antibacterial resistance is a cause of increased mortality.3 Fungal infections like Candidiasis, Crytococcosis and Aspergillosis are more common in immuno-compromised patients.4 Life threatening infectious disease caused by multidrug-resistant pathogenic bacteria (Gram-positive/Gram-negative) increased an alarming level around the world. Owing to this increased microbial resistance, new classes of antimicrobial agents with novel mechanisms are todays need to ght against the multidrug-resistant infections. Oxadiazoles are important classes of compounds which have long attracted attention, owing to their remarkable biological and pharmacological properties, such as antitubercular, antibacterial, antiviral, anti-inammatory, antifungal and insecticidal activities.513 Also the azole group of heterocyclic compounds possess signicant pharmacokinetic property, lipophilicity that inuence the ability of drug to reach the target by transmembrane diffusion and show promising activity against resistant TB by inhibiting the

Corresponding author. Tel.: +91 9694087786; fax: +91 144 5121120.E-mail address: jawedpharma@gmail.com (M.J. Ahsan). 0960-894X/$ - see front matter 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2011.10.057

biosynthesis of lipids.14,15 Most of the antitubercular drugs (isoniazid, pyrazinamide, etc.) are inhibitors of mycobacterial cell wall synthesis by inhibiting fatty acid synthetase. In the present investigation it has been tried to design and synthesized such novel compounds which include both the advantage of pyrazole and oxadiazole nucleus in the single molecule. All the title compounds (4a4n) were subjected to molecular properties prediction by Molinspiration and MolSoft (MolSoft, 2007) software in order to lter the drugs for synthesis and biological screening and to reduce enormous wastage of expensive chemicals and precious time. Earlier we have reported the antimycobacterial activity of diketones and pyrazoline.16,17 A good bioavailability can be achieved with an appropriate balance between solubility and partitioning properties. The computed log P values (P is the partition coefcient of the molecule in the water/octanol system) are shown in Table 1. The ALOGPS method is part of the ALOGPS 2.1 program used to predict lipophilicity and aqueous solubility of compounds. The lipophilicity calculations within this program are based on the associative neural network approach and the efcient partition algorithm. The Log Kow (Kow-WIN) program estimates the log octanol/water partition coefcient (log P) of organic chemicals and drugs using an atom/ fragment contribution method developed at Syracuse Research Corporation. The XLOGP2 is an atom additive method applying corrections. Computed partition coefcients for drugs studied varied

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Table 1 Physical constants and calculated partition coefcients, solubilities and drug likeness model score of the synthesized compounds

N N O

NH

N

N O

Ar

4a-nCompound 4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m 4n Ar 2-Chlorophenyl4-Chlorophenyl4-Aminophenyl4-Pyridinyl2-Hydroxyphenyl2-PhenylacetatePhenyl4-Methoxyphenyl2-Methylphenyl3-Methylphenyl4-MethylphenylBenzylPhenoxymethyl2-ThiophenylYield (%) 65 78 82 78 67 62 82 85 89 69 77 80 84 89 Mp (C) 154 132 124 186 114 108 98 118 164 198 212 112 116 102 ALOGPS 4.48 4.48 3.82 3.08 3.03 4.05 3.75 3.77 4.09 4.09 4.09 3.31 3.22 3.67 (12.99 mg/L) (12.99 mg/L) (56.46 mg/L) (0.30 g/L) (0.35 g/L) (37.56 mg/L) (64.57 mg/L) (67.10 mg/L) (30.38 mg/L) (30.38 mg/L) (30.38 mg/L) (0.19 g/L) (0.22 g/L) (78.74 mg/L) KoW-WIN 1.09 1.09 0.47 0.74 0.03 0.05 0.45 0.53 1.00 1.00 1.00 0.94 0.47 0.27 XLOP2 4.70 4.70 3.26 2.83 3.68 3.87 4.08 4.00 4.52 4.52 4.52 3.89 3.76 3.11 Drug-likeness model score 0.95 0.79 0.61 0.60 0.47 0.17 0.44 0.37 0.93 0.82 0.69 0.56 0.85 0.86

between 2.83 and 4.70 (XLOGP2 method) and between 0.74 and 1.09 (KoW-WIN method) is presented in Table 1. Both the XLOGP2 method and KoW-WIN best supported for most of the compounds on the basis of lipophilicity (65) to consider an oral drug/lead. Also the absorption of a drug is usually very low if the calculated solubility is 512 512 256 128 16 4 E. coli 4 4 16 16 128 256 512 256 256 512 256 256 64 8 4 P. aeruginosa 8 8 64 32 128 512 512 >512 512 >512 512 256 128 8 4 A. niger 256 256 128 256 8 512 512 16 8 128 4 512 >512 128 2 Antifugal C. albicans 256 128 128 256 16 512 512 32 16 256 4 512 512 256 1 MIC (lM) Antitubercular MTBa 1.97 3.94 4.15 0.78 >13.25 >12.78 10 >12.78 >13.31 >13.31 10 10 12.78 6.81 0.78 MTBb 12.65 12.65 8.29 1.52 NT NT 13.8 NT NT NT 13.31 >13.31 12.78 13.62 11.58

NT = not tested. a Mycobacterium tuberculosis H37Rv. b INHR-TB.

low to high antibacterial activity. The compound 4a showed good antibacterial activity while compounds 4c, 4d and 4n showed moderate activity with MICs 864 lg/mL against various bacterial strains. The activity of compound, 4a (MIC 4 lg/mL) against S. aureus, B. subtiltis and E. coli and the activity of compound, 4b (MIC 4 lg/mL) against E. coli was found to be comparable with that of the standard drug ciprooxacin. The N-aryl with electronegative group substitution such as 2-chlorophenyl, 4-chlorophenyl and 2-thiophenyl group showed maximum antibacterial activity. The antifungal activity of the title compound was found to be low to moderate. The compounds, 4e, 4i and 4k showed moderate antifungal activity with MICs, 416 lg/mL. The compound, 4k showed maximum antifungal activity, albeit less active than the standard drug uconazole. The N-aryl with 2-hydroxyphenyl, 4-methylphenyl and 2-methylphenyl group substitution showed maximum antifungal activity than electronegative group substitution. When the biological activities were related with computational calculated drug-likeness score model it was found out that the compound, 4a with maximum drug-likeness score model (0.95) showed maximum antibacterial activity. The compounds, 4i and 4k showed maximum antifungal activity have drug-likeness score model of 0.93 and 0.69, respectively. The compound 4a, 4b, 4c and 4d showed maximum antimycobacterial inhibition had drug-likeness score model 0.95, 0.79, 0.61 and 0.60, respectively. All the active compounds were tested for cytotoxicity (IC50) in VERO cells at concentrations of 62.5 lg/mL or 10 times the MIC. After 72 h exposure, viability was assessed on the basis of cellular conversion of MTT into a formazan product using the Promega Cell Titer 96 Non-radioactive Cell proliferation method. Most of the active compounds were found to be non-toxic up to 62.5 lg/mL.28 The molecular docking simulation for possible action on InhA are currently under investigation. Also studies to acquire more information about quantitative structureactivity relationships (QSAR) and MDR are in progress in our laboratory. The oxadiazole derivatives discovered in this study may provide valuable therapeutic intervention for the treatment of tubercular disease. Acknowledgments Authors are thankful to the management people of Alwar Pharmacy College, Alwar, Rajasthan, India for providing research

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