605-610A series of thiazoloylpyridine derivatives has been synthesized and analyzed to confirm the structure of the product using IR, 1H and 13C&nbsp;NMR, mass spectra and analytical data. Optimized structural and electronic parameters of all the compounds have been calculated by using B3LYP/ 6-31G basis set. The Mulliken charges of all atoms have been evaluated. The calculated IR spectrum has been analyzed by comparing the experimental IR. All the synthesized compounds have been examined for antioxidant activities. The antioxidant activity of 3-(2-alkylamino-4-aminothiazol -5-oyl)pyridines have been analyzed using DPPH radical scavenging assay. The compounds 6a and 6b possess higher radical scavenging activity

Brindha, J

Fen Reji, T F Abbs

Rani, S Mahil

NOPR

Indian Journal of Chemistry Vol. 60B, April 2021, pp. 605-610 Synthesis, computational studies and antioxidant activity of some 3-(2-alkylamino-4-aminothiazole-5-oyl)pyridines S Mahil Rania,b, J Brindhaa & T F Abbs Fen Reji*a a Department of Chemistry, Nesamony Memorial Christian College, Marthandam 629 165 Kanyakumari District, India b Manonmaniam Sundaranar University, Tirunelveli 627 012, India E-mail: abbsfen@gmail.comReceived 16 February 2020; accepted (revised) 3 March 2021 A series of thiazoloylpyridine derivatives has been synthesized and analyzed to confirm the structure of the product using IR, 1H and 13C NMR, mass spectra and analytical data. Optimized structural and electronic parameters of all the compounds have been calculated by using B3LYP/ 6-31G basis set. The Mulliken charges of all atoms have been evaluated. The calculated IR spectrum has been analyzed by comparing the experimental IR. All the synthesized compounds have been examined for antioxidant activities. The antioxidant activity of 3-(2-alkylamino-4-aminothiazol -5-oyl)pyridines have been analyzed using DPPH radical scavenging assay. The compounds 6a and 6b possess higher radical scavenging activity. Keywords: Thiazole, antioxidant, optimized structure, B3LYP All the heterocyclic compounds play an important role in drug discovery and design because of their diverse biological properties1. The pyridine derivatives occupy a unique place in the field of medical chemistry. Many of them are important class of antitumor compounds2-5. Pyridine is a fundamental building block in industrial organic chemistry, with its emphasis on solvent and regeneration in organic matter. Pyridine derivatives are significant role in many biological systems as components of many vitamins, enzymes, proteins and nucleic acid. Most of the 2-amiopyridine derivatives possess antibacterial, antifungal, cardiotonic, antimicrobial, analgesic, anti-inflammatory, antioxidant and anticancer activities6. Abdullah Jawad Kadhim reveals the 1,4-dihydro-pyridine drugs such as nimodipine and nefidine are favourable cardiovascular agents for the therapy of angina pectoris and hypertension7. Furthermore Adel M et al., reported that some of the pyridine derivative, like neonicotinoid insecticides was commonly used in insect control since their great protecting efficiency and low toxicity8. Thiazole derivatives are important source of many bio-acctive molecules such as Ritonavir, Sulfathiazol, Tiazofurin. Substituted diaminothiazole derivatives possess antitumor activity against 60 human tumor cell lines by the National Cancer Institute (NCI) and exhibit potential anticancer activity9-11. The 2-aminothiazole derivatives with various targets guide to the new anticancer agent12-15. Superoxide, and nitric oxide, hydroxyl are the oxygen centered free radicals, it is known as reactive oxygen species. They originate in the human body and can cause damage to lipids, proteins and DNA leading to a variety of diseases, including oncology, drug related toxicity and inflammation. In addition, radical reactions are key role in the development of a life time of cancer, aging, diabetes and other diseases16. The antioxidant treatment of diseases connected with oxidative stress has been demonstrated safe and effective. Consuming antioxidants reduces the risk of cancer, furthermore neurological and cardiovascular disease17. Antioxidant activity (AOA) of thiazole derivatives was recently acknowledged18. Some novel 4-(4-chlorophenyl)-2-aryl substituted metheniminothiazoles as potent antioxidant activities, reported by Kavitha et al.19 In the present study, we report on the coherent synthesis of 3-(2-alkylamino-4-aminothiazol-5-oyl) pyridines have aminothiazole, pyridine ring systems. The study was concentrated on the synthesis and biological assessment of the synthesized compounds. Experimental Section All chemicals used were of analytical reagent quality. All these chemicals were obtained from M/S E. Merck and used without purification. The IRspectra were recorded on a Perkin-Elmer 883 andINDIAN J. CHEM., SEC B, APRIL 2021   606Shimadzu infrared spectrophotometer in the 400–4000 cm−1 range as a KBr disc. The 1H and 13C NMR spectra were recorded on a Bruker 400MHz instrument utilising TMS as the internal reference. And also the elemental analysis was done. All the characterization studies were done by the CSIR-Central Drug Research Institute, Lucknow, India. Melting points were measured with an electrothermal melting point apparatus. The melting points were calculated using the Digital Program Rate melting point tool and are uncorrected.  Synthesis of 3-(2-alkylamino-4-aminothiazole-5-oyl)pyridines, 6a-e The reaction of 3-bromoacetylpyridine with 1-alkyl-3-(N-nitroamidino)thiourea in the presence of triethylamine, afforded an orange yellow solid. Crystallisation from methanol-water (2:1) gave an orange yellow crystalline compound. As a representative example, the reaction of 3-(2-bromoacetyl)pyridine with 1-(N-nitroamidino)-3-phenylthiourea is described below in detail. The reaction yielded an orange yellow crystalline compound.  Antioxidant activity The DPPH rating was based on the reported method. In Brief, 1 mM solution of 1,1-diphenyl-2-picryl hydrazyl radical (DPPH) in ethanol was prepared with five different concentration (0.05, 0.1, 0.25, 0.5 and 0.75 µM). Above sample mixture was shaken and permitted to 20 min under room temperature. In the presence of antioxidants, the deep violet colour of DPPH solution convert into yellow. The absorbance was then measured on spectrometer at 517 nm. The low absorption of the reaction mixture indicates high free radical scavenger activity. The ability to repel DPPH intensity was calculated using the following equation: DPPH scavenging effect (%) = A0 −A1/A0 × 100  Where, A0 - absorbance of the control reaction and  A1 - absorbance of the sample  3-(2-Ethylamino-4-aminothiazole-5-oyl)pyridine, 6a: Yellow solid. Yield 70%. m.p.122°C. Mol. Wt. 248.07. IR (KBr): 3444 (N-H), 3063(C-H), 1644 (C=O), 1599 cm−1 (C=N); 1H NMR: (DMSO-d6): δ 1.606 (t, J = 2.9Hz, 3H, -CH3), 2.512-2.494 (q, J = 1.6Hz, 2H, -CH2), 7.458 (s, 2H, -NH2), 7.279-8.118 (m, 3H, H-4, H-5, H-6 of pyridine), 7.688 (s, 1H, H-2 of pyridine), 8.525 (s, 1H, -NH); MS: m/z 248.07 (100.0%). Anal. C11H12N4OS: Calcd (Found %) C, 53.21 (53); H, 4.87 (4.85); N, 22.56 (22.55); O, 6.44 (6.42); S, 12.91 (12.9).  3-(2-Propylamino-4-aminothiazole-5-oyl) pyridine, 6b: Yellow solid. Yield 68%. m.p.135°C. Mol. Wt. 262.09. IR (KBr): 3397(N-H), 3045(C-H), 1622 cm−1 (C=O); 1H NMR: (DMSO-d6):  0.915(t, J = 10.1 Hz, 3H, -CH3), 1.588-1.530 (m, 2H, -CH2), 2.503 (t, J = 2.4 Hz, 2H, -CH2), 7.52 (s, 2H, -NH2), 7.560 (d, J = 6.4Hz, 1H, H-6 of pyridine), 7.610 (s, 1H, H-2 of pyridine), 7.642 (t, J = 4.8Hz, 1H, H-5 of pyridine), 7.651(d, J = 14.8Hz,1H, H-4 of pyridine), 9.074 (s, 1H, -NH); MS: m/z 262.09 (100.0%). Anal. C12H14N4OS: Calcd (Found %) C,54.94 (54.92); H, 5.38 (5.40); N, 21.36 (21.32); O, 6.10 (6.11); S, 12.22 (12.20).  3-(2-Isopropylamino-4-aminothiazole-5-oyl) pyridine, 6c: Yellow solid. Yield 62.5%. m.p.137°C. Mol. Wt. 262.09. IR (KBr): 3072(C-H), 1696(C=O), 1553 cm−1 (C=N); 1H NMR: (DMSO-d6):  1.046(d, J = 9.6Hz, 6 H, -CH3), 1.488-1.512(m, 1H, -CH), 7.102 (s, 2H, -NH2), 7.589(s, 1H, H-2 of pyridine), 7.979-8.018 (m, 3H, H-4, H-5, H-6 of pyridine), 8.519(s, 1H, -NH);  MS: m/z 262.09 (100.0%). Anal. C12H14N4OS: Calcd (Found %) C, 54.94 (54.93); H, 5.38 (5.36); N, 21.36 (21.33); O, 6.10 (6.9); S, 12.22 (12.18).  3-(2-Butylamino-4-aminothiazole-5-oyl)pyridine, 6d: Yellow solid. Yield 68%. m.p.140°C. Mol. Wt. 276.10. IR (KBr): 3271(C-H), 1682 cm−1 (C=O); 1H NMR: (DMSO-d6):  0.891 (t, J = 4.2Hz, 3H, -CH3), 1.106-1.034 (m, 2H, -CH2), 1.474-1.424 (m, 2H, -CH2), 2.5 (t, J = 4.8Hz, 2H, -CH2), 7.544 (s, 2H, -NH2), 7.573 (s, 1H, H-2 of pyridine), 7.913 (d, J = 2.3Hz, 1H, H-4 of pyridine), 8.006 (m, 2H, H-5 and H-6 of pyridine), 8.717(s, 1H, -NH); MS: m/z 276.10 (100.0%). Anal. C13H16N4OS: Calcd (Found %) C, 56.90 (54.88); H, 5.84 (5.86); N, 21.27 (21.24); O, 5.79 (5.77); S, 11.60 (11. 58).  3-(2-Allylamino-4-aminothiazole-5-oyl)pyridine, 6e: Yellow solid. Yield 70%. m.p.135°C. Mol. Wt. 260.07. IR (KBr): 3395(N-H), 3248(C-H), 1624 cm−1 (C=O); 1H NMR: (DMSO-d6):  2.206 (d, J = 1.8Hz, 2H, -CH2, 5.963-5.725 (m, 1H, -CH), 5.92 (d, J = 2.5Hz, 2H,-CH2), 7.461 (t, J = 7.1Hz, 1H, H-5 of pyridine), 7.528 (s, 2H, -NH2), 7.568 (d, J = 1.2Hz, RANI et al.: 3-(2-ALKYLAMINO-4-AMINOTHIAZOLE-5-OYL)PYRIDINES   6071H, H-4 of pyridine), 7.639 (s, 1H, H-2 of pyridine), 8.716 (d, J = 3.8Hz, 1H, H-6 of pyridine), 8.528 (s, 1H, -NH); MS: m/z 260.07 (100.0%). Anal. C12H12N4OS: Calcd (Found %) C, 55.37 (55.34); H, 4.65 (4.64); N, 21.52 (21. 5); O, 6.15 (6.10); S, 12.32 (12. 31). Results and Discussion According to our interest to plan with some new pyridine compounds, we have prepared a series of  3-acetyl pyridine derivatives (Table I) as expressed in Scheme I. In Scheme I, the reaction of 3-acetyl pyridine with various bases and thiourea is a modern method for synthesis of 3-(2-ethylamino-4-aminothiazole-5-oyl)pyridine derivatives. Electrophilic substitutions in pyridine do not proceed or only partially; however, heteroaromatic characterization can be activated by electron-donating group. Pyridine does not exhibit alkylations and acylations reactions because they lead only to the addition at the nitrogen atom. In the 3rd position substitution reaction is Table I — Structure of 3-(2-alkylamino-4-aminothiazole-5-oyl)pyridines Compd Mol. formula Structure Yield (%)  6a C17H16N4OS NSNNH2HNO  75  6b C12H14N4OS NOSNNH2HN  68  6c C12H14N4OS NOSNNH2HN  62  6d C14H20N4OS NSNHNNH2O  72  6e C14H20N4OS NSNNH2HNO  70 INDIAN J. CHEM., SEC B, APRIL 2021   608energetically favourable. The development of adequate synthetic methods to synthesis of target compounds using 3-acetyl pyridine. 3-acetylpyridine undergoes bromination using hydrobromic acid to form bromo compound. Thereafter, addition of alkylthiourea in the presence of suitable base gave the targeted compounds. The yellow product obtained was crystallized from ethanol-water (2:1).  DPPH Radical Scavenging Assay The fastest, simplest and inexpensive method for measuring the antioxidant capacity of a substance include the use of free radical, 2,2-diphenyl-1-picrylhydrazyl (DPPH). The main advantage of DPPH is to test the power of compounds to perform as hydrogen donors or free radical scavengers. The antioxidants tested in DPPH were also very effective in cell systems. It also provides information on the ability of compounds to donate electrons during the oxidation process. The mechanism of radical scavenging assay is based on the shifting of acid H atom from the mixture to the DPPH radical to form DPPH-H. Antioxidant activity of synthesized compounds, IC50 was also determined by measuring the values in Table II. All the synthesized compounds showed good and moderate activity. Compounds 6a and 6b showed good radical scavenging extent while compounds 6c exhibited moderate radical scavenging activity with the comparison of standard butylated hydroxyanisole. Hence the variation exhibited in the DPPH scavenging capacity can be attributed to the effect of different substitution present in the  amino group.  Computational studies The first task of the computational work is to determine the optimal geometry of the pyridinyl thiazole molecule. DFT method is used to evalute HOMO-LUMO studies utilize B3LYP method with the basis set 6-31G Gaussian 09 software20. DFT calculation has been recognized by the chemistry clique as a reputable and efficacious for the computation of optimized structure, vibration frequencies and Mulliken population analysis of chemical reactions21. In quantum mechanical chemistry, the HOMO-LUMO energies play a key role in chemical interactions. Frontier Molecular Orbital provides an insight into the reactivity of molecules and the active site can be revealed by the distribution of frontier orbital (Figure 1). The HOMO-LUMO molecular orbitals composition for synthesized compounds was calculated by DFT/6-31G energy level shown in Figure 2 and Figure 3. To   Scheme I  Table II — DPPH radical scavenging activity of 3-(2-alkylamino-4-aminothiazole-5-oyl)pyridines 6a-e Compd IC50 6a 79 6b 92 6c 146 6d 204 6e 474   Figure 1 — Optimized structure of 3-(2-ethylamino-4-aminothiazole-5-oyl)pyridine 6a    Figure 2 — HOMO of 3-(2-ethylamino-4-aminothiazole-5-oyl)pyridine 6a RANI et al.: 3-(2-ALKYLAMINO-4-AMINOTHIAZOLE-5-OYL)PYRIDINES   609analyze the energy level of the synthesized compounds, the values of HOMO and LUMO were calculated (Table III). In these evidences HOMO and LUMO are located in keto group and thiazole respectively. DFT studies also favorable for providing theoretical informations like electronegativity (χ), hardness (η), softness (S), electrophilicity index (ω). The compound 6e shows good biological activity because the softness and energy gap value is low compared with all other compounds. Mulliken population analysis on the molecule exhibits main influence of vibrational spectra (Figure 4). All the oxygen and nitrogen carries negative charge, all hydrogen atoms possess positive charge and the carbon atoms carries either positive or negative depends on the neighbouring atom.  Conclusion In summary, a series of 3-(2-alkylamino-4-aminothiazol-5-oyl)pyridines were synthesized from 3-acetyl pyridine with different thioureas. And all the compounds characterized for their structural investigations. The optimized structural parameters were calculated by B3LYP/ 6-31G basis set. Compounds 6a and 6b exhibit good antioxidant activity, and the IC50 values 79 and 92 respectively, all other compounds should be moderately active. The Highest Occupied Molecular Orbital (HOMO) and the Lowest Unoccupied Molecular Orbital (LUMO) are known as frontier molecular orbitals, which ensure the charge transfer within the molecule. The HOMO-LUMO energy gap is less; hence the compounds are more bioactive. The Mulliken population charge was analyzed.  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Table III — Electronic parameters of 3-(2-alkylamino-4-aminothiazol-5-oyl)pyridines Parametres (a.u) B3LYP/6-31G 6a 6b 6c 6d 6e HOMO −0.24985 −0.24938 −0.24985 −0.24912 −0.25089 LUMO −0.03520 −0.03464 −0.03622 −0.03439 −0.0 3775 HOMO-LUMO 0.21465 0.21474 0.21363 0.21473 0.21314 I 0.24985 0.24938 0.24985 0.24912 0.25089 A 0.03520 0.03464 0.03622 0.03439 0.0 3775 Χ 0.14252 0.14201 0.14303 0.14175 0.14432 Η 0.10732 0.10737 0.10685 0.10736 0.10825 S 4.65874 4.65679 4.67945 4.65701 4.61893   Figure 3 — LUMO of 3-(2-ethylamino-4-aminothiazole-5-oyl)pyridine 6a    Figure 4 — Mulliken charge of 3-(2-ethylamino-4-aminothiazole-5-oyl)pyridine 6a INDIAN J. 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Synthesis, computational studies and antioxidant activity of some 3-(2-alkylamino-4-aminothiazole-5-oyl)pyridines

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Synthesis, computational studies and antioxidant activity of some 3-(2-alkylamino-4-aminothiazole-5-oyl)pyridines

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