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65 Synthesis, In-Silico Studies, of New Substituted Pyrazolone Based Hydrazone Derivatives and Their Biological Activities

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65 Synthesis, In-Silico Studies, of New Substituted Pyrazolone Based Hydrazone Derivatives and Their Biological Activities ORIGINAL RESEARCH SYNTHESIS, IN-SILICO STUDIES, OF NEW SUBSTITUTED PYRAZOLONE BASED HYDRAZONE DERIVATIVES AND THEIR BIOLOGICAL ACTIVITIES M Abrar Alam1, M M Alam2, M S Zaman3, Shah Alam Khan4, Mymoona Akhter5,* 1Dept. of Regulatory Affairs, 289, Bellasis Road, Mumbai Central, Mumbai, – 400 008, India. 2,3,5Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi- 110 062, India 4Department of Pharmacy, Oman Medical College, Muscat, Sultanate of Oman *Corresponding Author: Email: [email protected] Abstract In silico studies have been helpful in identifying the potential lead molecules with reduced cost. The title compounds were synthesized successfully by the reported method and the structures were confirmed on the basis of results of different spectral data. The in silico studies were carried out to find the possibility of the proposed activity using different software’s. Molinspiration, Osiris property explorer and PASS cheminformatics software’s were used to calculate bioactivity score, molecular and pharmacokinetic properties of compounds. Biological activity (anti-inflammatory and analgesic) was carried out by reported methods. Antimicrobial activity was determined by serial dilution method. The title compounds were tested for anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation actions. A good correlation was found between the in silico activity predication and observed activity. Compound 3b and 3g were found to have all the favorable properties to be a potential lead. This was also supported by in vivo studies where in compound 3b (% inhibition 69.56) was found to be more potent than the standard drug indomethacin (% inhibition 66.24) in exhibiting anti-inflammatory activity and equipotent in analgesic activity with good gastrointestinal tolerance. In antimicrobial activity, compound 3b was also found to be the most active with minimum inhibitory concentration (MIC) of 6.25 µg/mL against S. aureus, E. coli and 12.5 µg/mL against P. aeruginosa. Keywords: In silico studies, Anti-inflammatory, Analgesic, Pyrazolones, and Antibacterial INTRODUCTION (II), propyphenazone (III), and famorofazone (IV) Development of anti-inflammatory agents is (Fig. 1) are widely used as anti-inflammatory, one of the thrust areas in research as inflammation is analgesic, and antipyretic drugs [17, 18]. Pyrazolones involved in a large no of pathological conditions. The that have been found to possess significant anti- problem with existing non-steroidal anti- inflammatory activity include compounds (V) [19], inflammatory drugs (NSAIDs) make their use limited (VI) [1], (VII) [1], and (VIII) [3] (Fig.1). Thus, our and therefore a continual effort can be seen in main objective is to design novel pyrazolone designing of new anti-inflammatory agents. The derivatives to be further explored as powerful and pyrazolone moiety has attracted widespread attention novel non ulcerogenic anti-inflammatory lead because of the diversity of biological activity it candidates. possesses. Pyrazolone derivatives are reported to In silico studies are becoming more and exhibit anti-inflammatory [1-3], analgesic [4, 5], more important in drug development from its initial antitumor [6], antimicrobial [7, 8], hypoglycemic [9], stage to the approval of the drug. Recently a number antitubercular [10] and anti HIV [11] activities. of drugs have been developed using this technique Edaravone, a pyrazolone derivative [12] acts as a e.g. Sitagliptin, an anti-diabetic agent. Using in silico radical scavenger to interrupt the peroxidative chain tools to predict the biological activity and/or ADMET reactions and membrane disintegrations associated target for novel compounds has been a wide practice with brain ischemia [13-15]. The first synthetic as it helps in decreasing the cost/time related to drug organic compound having a pyrazolone nucleus that discovery. Therefore, we pursued to perform the in was used as an important drug was antipyrine (I) silico studies of the title compounds along with their [16]. Many other pyrazolones like aminophenazone synthesis and biological evaluation. International Journal of Pharmaceutical Chemistry and Analysis; April-June 2015;2(2):65-73 65 Alam et al. Synthesis, In-Silico Studies, of new Substituted Pyrazolone Based Hydrazone Derivatives and Their… N N N N N N O N N N N N O O O O N Edaravone I II III IV Cl N NO2 N N N N N N HN N O HN N N H CO CN N 3 O O N HN O O V VI VII VIII Figure 1: Known pyrazolone based drugs EXPERIMENTAL Chemistry: Melting points were determined in open capillary tubes and are uncorrected. The progress and purity of the compounds was checked by thin layer chromatography (TLC) on silica gel G plates, with the solvent system: toluene-ethyl acetate-formic acid (5:4:1, v/v/v). The spots were located under iodine vapors and UV light. 1H-NMR spectra were recorded on Varian E-360 MHz or Bruker spectropsin DPX-300MHz with tetramethylsilane (TMS) as an internal standard. The splitting pattern abbreviations are as follows: s, singlet; d, doublet; t, triplet; m, multiplet. Mass spectra were recorded on a Jeol JMS-D 300 instrument fitted with a JMS 2000 data system at 70 eV. Elemental analyses were performed on a Perkin-Elmer 240 analyzer and the values were in range of ±0.4% for each element analyzed (C, H, N). H3C NHNH2 O N Heat N O + CH2-C-CH2COOC2H5 110-120 OC (1) NaNO2/HCl N Cl NH2 2 Pyridine 0-50C R R (2) H N N H3C R N O N (3 a-k) Scheme 1: R= H, 4F, 2-OCH3, 4-OCH3, 2Cl, 4NO2, 4Cl, 3NO2, 4CH3, 4Br, 2CH3 International Journal of Pharmaceutical Chemistry and Analysis; April-June 2015;2(2):65-73 66 Alam et al. Synthesis, In-Silico Studies, of new Substituted Pyrazolone Based Hydrazone Derivatives and Their… Synthesis of 1-Phenyl-3-methyl -5-pyrazolone (1). 1- 4-(2-(4-methoxyphenyl) hydrazono)-3-methyl-1- Phenyl-3-methyl -5-pyrazolone was synthesized by phenyl-1H-pyrazol-5(4H)-one (3d) reported procedure [24a, b], yield- 75%, mp – 125- Light brown powder, Yield: 55%; mp: 170-172 oC; 270C (lit mp- 126-27oC) FTIR (KBr, cm–1): 1658 (C=O and C=N), 1599 1 Synthesis of diazonium salts (2). Diazonium salts of (C=C), 1220 (O–CH3); H NMR (400 MHz, DMSO- different amine were prepared by reported procedure d6) δ, ppm 2.33 (s, 3H, CH3), 7.21 (t, J= 14.4 Hz, 2H, and used for next step as such. [25a, b] Ar-H), 7.37-7.42 (m, 6H, Ar-H), 7.90 (d, J= 8.8 Hz, General procedure for Synthesis of 3-methyl-1- 2H, Ar-H), 13.56 (s, 1H, NH); MS: m/z 309.2(M++1); phenyl-5-pyrazolone derivatives (3a-k). Anal. C17H16N4O2, Calcd. C, 66.22; H, 5.23; N, A solution of compound 1 (0.01mol) in pyridine 18.17; found C, 66.35; H, 5.28; N, 18.23 (3mL) was cooled in ice to 0-5°C. This solution was slowly added to diazonium salt solution (0.01mol) 4-(2-(2-chlorophenyl) hydrazono)-3-methyl-1- drop wise with stirring. Stirring was continued for phenyl-1H-pyrazol-5(4H)-one (3e) another 30-45 minutes and the reaction mixture was White crystalline, Yield: 61%; mp: 120-122 oC; 1H kept overnight at room temperature. The product NMR (400 MHz, DMSO-d6) δ, ppm 2.36 (s, 3H, separated was filtered, washed with water, dried and CH3), 7.16 (t, J = 14.4 Hz, 2H, Ar-H), 7.40-7.42 (m, crystallized from ethanol. Physical, chemical and 6H, Ar-H), 7.89 (d, J = 8.8 Hz, 2H, Ar-H), 13.62 (s, + spectral data of newly synthesized compounds are 1H, NH); MS: m/z 312.9(M +1); Anal. C16H13ClN4O, given below. Calcd. C, 61.44; H, 4.19; N, 17.91; found C, 61.56; H, 4.25; N, 17.83 3-Methyl-1-phenyl-4-(2-phenylhydrazono)-1H- pyrazol-5(4H)-one (3a) 3-methyl-4-(2-(4-nitrophenyl) hydrazono)-1-phenyl- Cream colored powder, Yield: 52%; mp:115-117 oC; 1H-pyrazol-5(4H)-one (3f) FTIR (KBr), (cm–1): 1631 (C=O and C=N), 1595 Brown colored powder, Yield: 57%; mp: 160-162 oC; 1 –1 (C=C), (N–N); H NMR (400 MHz, DMSO-d6) δ, FTIR (KBr), m (cm ): 1659 (C=O and C=N), 1596 1 ppm 2.37(s, 3H, CH3), 7.19 (t, J= 14.4 Hz, 2H, Ar- (C=C),1504 and 1348 (NO2); H NMR (400 MHz, H), 7.39-7.44 (m, 6H, Ar-H), 7.94 (d, J= 8.8 Hz, 2H, DMSO-d6) δ, ppm 2.32 (s, 3H, CH3), 7.23 (t, J= 14.4 Ar-H),13.58 (s, 1H, NH); 13CNMR (100 MHz, Hz, 2H, Ar-H), 7.38-7.45 (m, 6H, Ar-H), 7.97 (d, J= DMSO-d6): 20.3, 120.3, 122.4, 124.3, 128.2, 130.6, 8.8 Hz, 2H, Ar-H), 13.55 (s, 1H, NH); MS: m/z 324.1 + 131.4, 133.5,140.6, 143.1, 148,168.2; MS: m/z (M +1); Anal., C16H13N5O3, Calcd.C, 59.44; H, 4.05; + 279.2(M +1); Anal.C16H14N4O, Calcd. C, 69.05; H, N, 21.66; found C, 59.39; H, 4.15; N, 21.59 5.07; N, 20.13; found C, 69.15; H, 5.17; N, 20.33. 4-(2-(4-chlorophenyl) hydrazono)-3-methyl-1- 4-(2-(4-fluorophenyl) hydrazono)-3-methyl-1- phenyl-1H-pyrazol-5(4H)-one (3g) phenyl-1H-pyrazol-5(4H)-one (3b) Cream colored powder, Yield: 47%; mp:140-142 oC; Cream solid, Yield: 55%; mp:140-142 oC; FTIR FTIR (KBr), m (cm–1): 1661 (C=O and C=N); 1604 -1 1 (KBr), m (cm ): 1659 (C=O and C=N); 1602 (C=C); (C=C); H NMR (400 MHz, DMSO-d6) δ, ppm 2.40 1 1507; H NMR (400 MHz, DMSO-d6) δ, ppm 2.35 (s, (s, 3H, CH3), 7.20 (d, J= 7.2 Hz, 2H, Ar-H), 7.38- 3H, CH3), 7.10 (d, J = 8.4 Hz, 2H, Ar-H), 7.17 (t, 1H, 7.41 (m, 3H, Ar-H), 7.43-7.45 (m, 2H, Ar-H), 7.93 J= 14.8 Hz, Ar-H), 7.40-7.45 (m, 4H, Ar-H), 7.90 (d, (d, J= 7.6 Hz, 2H, Ar-H), 13.64 (s, 1H, NH); MS: m/z + J= 7.6 Hz, 2H, Ar-H), 13.64 (s, 1H, NH); MS: m/z 313.4 (M +1); Anal.C16H13ClN4O, Calcd.
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