QSRT STUDIES OF 2-(5-ARYL-1, 3, 4-OXADIAZOL-2-YL)-N-(5-METHYLISOXAZOL-3-YL)-ACETAMIDE DERIVATIVES AS AN ANTIMICROBIAL AGENTSHTML Full Text
QSRT STUDIES OF 2-(5-ARYL-1, 3, 4-OXADIAZOL-2-YL)-N-(5-METHYLISOXAZOL-3-YL)-ACETAMIDE DERIVATIVES AS AN ANTIMICROBIAL AGENTS
Srinivas Marri 1, 2, Ramu Kakkerla * 3 and M. P. S. Murali Krishna 4
Department of Chemistry 1, JNTU, Kakinada - 533003, Andhra Pradesh, India.
Department of Chemistry 2, Siddhartha Degree & P. G. College, Narsampet, Warangal - 506132, Telangana, India.
Department of Chemistry 3, Satavahana University, Karimnagar - 505001, Telangana, India.
Department of Chemistry 4, Andhra Polytechnic College, Kakinada - 533003, Andhra Pradesh, India.
ABSTRACT: Quantitative structure relationship techniques (QSRT) is among the most widely used computational technology for analog-based drug design. A molecular modeling approach using theoretical, computational analysis through chem sketch ACD lab online software was done for determination of probable antimicrobial activity. To develop a pharmacophoric model for inhibition, QSRT parameters PCP, ADME, and toxicity has been used. BCF (Bioconcentration factor), adsorption coefficient, log P, log D values, plasma protein binding, P-gp inhibition, AMES test, hERg inhibition, estrogen receptor, and Lipinski’s type properties have been calculated. From a data set of 11 analogs, it has been concluded that all compounds are non-bio-accumulative, non-endocrine disruptors, non hERg inhibitors, genotoxic and within Lipinski’s criteria. None of the compounds are practically ionizable at various body pH values, and all are zwitterionic compounds. From these data and in-vitro antimicrobial data compounds, 5c and 5f can be exploited for the formulation of bactericide and fungicide with a slight modification in their structure.
QSRT studies, Isoxazolyl oxadiazoles, Antimicrobial agents, Bicyclic hetero cyclic compounds
INTRODUCTION: Besides biological reactivity against a target, which is the primary requirement, there are so many essential properties and characteristics that are mandatory to be possessed by a molecule to be considered as a drug. The use of computational methods for designing molecules with a desired activity, reactivity or property has been a growing area in chemistry and medicine.
In this direction QSRT analysis has been performed considering some important activity properties like BCF (Bioconcentration factor), adsorption coefficient, partition coefficients, probable plasma binding property, p-gp inhibiting characteristics, non genotoxicity, AMES test possibilities, hERg inhibiting probabilities, endocrinal disruptor tendency, and drug’s pharmacokinetics like adsorption, distribution, metabolism and elimination in the human body, and can be inferred from Lipinski’s rule molecular properties.
1, 3, 4-Oxadiazoles are of great practical significance, which is primarily due to their large number of uses, in the most diverse areas, such as in drug synthesis, scintillation materials, in the production of polymers and dyes, and uses in photography as light screening agents. 1, 3, 4-Oxadiazole derivatives are reported to exhibit antibacterial 1, antifungal 2, analgesic and anti-inflammatory 3, anticonvulsant 4, anticoagulant 5, and anticancer activity 6, 7. A large number of synthetic derivatives of this molecule are well documented in the literature. Similarly, isoxazole derivatives are found to possess a wide variety of biological activities 8, 9, 10, 11, 12.
Literature survey indicated that the compounds bearing the isoxazole moiety are endowed with various types of biological activities. The 1, 3, 4-oxadiazoles are heterocycles of current interest due to their broad-spectrum pharmacological activity. Therefore, in the current investigation, the QSRT studies of isoxazolyl 1, 3, 4-oxadiazoles have been undertaken to correlating antimicrobial activity In this paper, we present QSRT studies of 2-(5-aryl-1, 3, 4-oxadiazol-2-yl) -N -(5-methyl isoxazol-3-yl)-acetamides.
MATERIALS AND METHODS: Several isoxazolyl 1,3,4-oxadiazoles have been synthesized and characterized by spectral analysis Scheme I and evaluated for antibacterial Table 1 and antifungal activity 13 Table 2. The structures are drawn and submitted for theoretical, computational analysis using through chem sketch ACD-lab online software 14 analyzed QSRT parameters viz., BCF, adsorption coefficient 15, log P, log D values, Plasma protein binding 16, P-gp inhibition17, AMES test 18, 19, hERg inhibition20, estrogen receptor 21, 22 genotoxicity 23, 24 and Lipinski’s type properties 25. The data is tabulated and examined for analysis between the structural aspects of molecular activity. Under the light of changes of structural aspects of the molecule, the trends in the molecules are evaluated. This will help in designing new molecules with expected behaviors.
SCHEME I: SYNTHESIS OF 2-(5-aryl-1, 3, 4-oxadiazol-2-yl)-N-(5-methylisoxazol-3-yl)-acetamides. 4 & 5 Ar = a: C6H5; b: 4-ClC6H4; c: 4-OCH3C6H4; d: 4-NO2C6H4; e: 3-OCH3C6H4; f: 3-BrC6H4; g: 2-OH C6H4; h: 2-OH,3-OCH3C6H3; i: 3,4,5-(OCH3)3C6H2; j: 3,4-(OCH3)2C6H3; k: 2-CH3C6H4
TABLE 1: ANTIBACTERIAL ACTIVITY OF N-(5-methylisoxazol-3-yl)-2-(5-phenyl-1,3,4-oxadiazol-2-yl) acetamides 13 (5a-k)
|Compound||Minimum Inhibitory Concentration (MIC)a,b|
|P. aeruginosa||K. aerogenes||C. violaceum||B. subtilis||B. sphaericus||S. aureus|
aNegative control (acetone)- no activity, bConcentration in µg/mL
TABLE 2: ANTIFUNGAL ACTIVITY OF N-(5-methylisoxazol-3-yl)-2-(5-phenyl-1,3,4-oxadiazol-2-yl) acetamides 13 (5a-k)
|Compound||Zone of Inhibition mma,b|
|A. niger||C. tropicum||R. oryzae||F. moniliforme||C. lunata|
aNegative control (acetone)- no activity, bConcentration 100 µg/mL
RESULTS AND DISCUSSION:
QSRT Studies: In this paper, an attempt has been made to analyze 2-(5-aryl-1,3,4-oxadiazol-2-yl)-N-(5-methylisoxazol-3-yl)-acetamide derivatives (5a-5k) through the application of the quantitative structure relationship techniques (QSRT).
QSPR Studies: Table 3 shows the properties computed through quantitative structure-property relationship algorithm of ACD software. Very marginal variance is observed among all physical parameters.
QSAR Study: BCF of 5a-k structures is found to have a constant unity value concerning the change in pH. In the case of the adsorption coefficient, a consistent value unity has been maintained between pH range 1-9, besides that, it tends to approach a constant value, as shown in Table 4. Since, BCF is <1000, 5a -5k compounds are non bioaccumulative.
Therefore, there is very less chance to be incorporated into biological food chains from the environment. Since the bioconcentration factor is greater than 1; it is indicative of a hydrophobic or lipophilic chemical. In the case of 5a-5k derivatives as they have unity value indicating very low hydrophilic nature, but not having of lipophobic or hydrophilic nature.
TABLE 3: GENERAL PHYSICAL PROPERTIES OF COMPOUNDS 5a-5k
|Compound||Molar Refractivity||Molar Volume||Parachor||Index of Refraction||Surface Tension||Density||Polarizability|
TABLE 4: BCF, ADSORPTION COEFFICIENT, log P AND log D VALUES OF COMPOUNDS 5a-5k
|Compound||BCF BIO||log P||log D|
|BCF||K0C||log P||Reliability||pH 1.6||pH 4.6||pH 6.5||pH 7.4||pH 8.2|
The log P and log D computed values are found to be moderately reliable with reliability parameter between 0.56-0.65. For all compounds except for 5c, 5e, and 5j, whose reliabilities are found to be borderline. log D values for all of the derivatives at pH 1.7, 4.6, 6.5, 7.4 and 8 appears to be same for all the compounds (5a–5k) indicating that at all those pH s no practical ionization of molecule occurs Table 4. Partition coefficient values are found to be in-between 0.86 to 2.83. log P, log D, adsorption coefficient, and BCF increased when halogen groups are present. By halogen substitution molecule’s log P, log D, and aqueous solubility decreased. Presence of two methoxyl on aryl groups shown a decrease in log P value in 5j derivative on comparison with the un-substituted molecule, whereas the presence of either single methoxyl group or three methoxyl groups on aryl structural unit is showing a decreasing tendency.
TABLE 5: PLASMA PROTEIN BINDING AND P-gp INHIBITION POSSIBILITIES WITH RELIABILITIES OF COMPOUNDS 5a-5k
|PPB (%)||Reliability I||log KHSA||Reliability II||Probability||Reliability||Ki||Reliability|
% PPB of 5b is found to be moderately reliable in respect of plasma protein binding possibility and borderline for all other 5 series compounds. 5b has the highest value of 97.45, and 5h has the least value. The variation is very narrow for all as 94±4. No molecule is found to have a high probability of 0.8 or above reliability in respect to plasma protein binding parameter. log KHSA values of 5a-5k compounds are very narrowly distributed so synergetic effect on the availability of molecule concerning others is very less significant. Presence of 5b can enhance the percentage of 5h in blood as the difference in their Ki value is significant to consider. All (5a-5k) are Zwitterionic compounds. These drugs are likely to bind to the majority of plasma proteins.
Further one may work except that all may bind to human serum albumin, alpha1-acid glycoprotein, and albumin although in most cases the binding is not extensive. In compound 5d nitroarenes exhibit genotoxic activity after metabolic transformation to hydroxylamines Fig. 1.
FIG. 1: GENOTOXICITY OF COMPOUND 5d
In this series, a constant value of 0.1 has been observing for most of them. From this one can conclude that there will be a least binding tendency concerning P-glycoprotein, 5a, 5h and 5g are having 0.05 order of binding aptitude that is 10 fold less than other members of the same series.
Since probability of potent P-gp inhibition (Ki<1 micro-M): 0.01, Reliability: Moderate (RI = 0.56 to 0.49) and McGowan's volume is found to be less than 200 cm3/mol with high reliability for 5a, so it can classify as non-inhibitor, 5g, and 5h will be Probably non-inhibitor as they are weak hydrophilic acid or amphiprotic compound, acid pKa > 5, MW < 360, AB/logP < 2.5, with high reliability. In cases of 5b, 5c, 5d, 5e, 5f, 5i, 5j and 5k no prediction can be made unless data for similar compounds be available to predict through the use for probabilistic estimation 23, 26 Table 5.
All other molecules of this series have AMES test probabilities in the range of 0.12 to 0.16 with non-reliable values of 0.17 or 0.18, except 5d with a value of 0.68 with borderline reliability 0.38. So it may show carcinogen activity. hERg inhibiting probabilities are found to be reliable, which is borderline except 5c. Still, one may except non inhibiting character as their values estimated appear to be very low, (the range is 0.1-0.2). Only 5g has 0.09 value.
They are expected to have log RBA less than -3 and Ki less than 10 μM. Relative binding affinity values are within the criteria of expectation, so all the molecules of consideration do not tend to bind to alpha estrogens receptor Table 6. All compounds are found to be within the Lipinski’s criteria. It has found to be a topological surface area well below 145 and 142 (borderline value) in case of 5d; it may be associated with a reduction of genotoxicity by oxadiazole ring formation Table 7.
TABLE 6: AMES TEST PROBABILITIES AND ESTROGEN RECEPTOR PROBABILITIES WITH RELIABILITIES OF COMPOUNDS 5a-5k
|Compound||AMES test||hERg Inhibitors||Endocrine Disruptions|
|Probability||Reliability||Probability||Reliability||Log RBA>-3||Log RBA>0|
TABLE 7: LIPINSKI’S TYPE PROPERTIES OF COMPOUNDS 5a-5k
|Compound||Lipinski’s type properties|
CONCLUSION: QSAR and QSPR studies for 5a-5k were presented. All the Compounds (5a-5l) are found to be promising non bio-accumulative, nonendocrine disruptors, non hERg inhibitors, and within Lipinski criteria. None of the compounds are practically ionizable at various body pH values. All the compounds (5a-5k) are zwitterionic compounds. It can be concluded that compounds 5a-5k may exhibit potential antimicrobial activity based on QSRT studies. QSRT studies may help in designing the pharmacophore modes to identify more potent isoxazolyl oxadiazole as an antimicrobial agent, which will be useful for the formulation of bacteriocide and fungicide.
ACKNOWLEDGEMENT: The authors are thankful to Department of Chemistry, University College of Science, Satavahana University, Karimnagar, Department of Chemistry and Siddhartha Degree & P. G. College, Narsampet, Warangal for providing laboratory facilities and JNTU-Kakinada for their constant encouragement. All the authors are thankful to Prof. E. Rajanarendar for his valuable suggestions. The authors are also grateful to the ACD labs for providing software to analyze the structures.
CONFLICTS OF INTEREST: The authors declare no conflicts of interest.
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How to cite this article:
Marri S, Kakkerla R and Krishna MPSM: QSRT studies of 2-(5-aryl-1, 3, 4-oxadiazol-2-yl)-N-(5-methylisoxazol-3-yl)-acetamide derivatives as an antimicrobial agents. Int J Pharm Sci & Res 2019; 10(12): 5391-96. doi: 10.13040/IJPSR.0975-8232.10(12).5391-96.
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S. Marri, R. Kakkerla * and M. P. S. M. Krishna
Department of Chemistry, Satavahana University, Karimnagar, Telangana, India.
07 March 2019
12 June 2019
17 July 2019
01 December 2019