1. INTRODUCTION:

Synthesis of substituted oxazole derivatives is important because of their diverse range of biological activities in pharmaceutical areas¹. Substituted oxazoles are important heterocycles that are biologically active molecules and synthetic bioactive molecules as well as in a number of organic building blocks including natural products, agrochemicals and pharmaceutical drugs^2,3. Many of oxazole containing compounds like Martfragin A and Almazol D had been isolated from plants Martensa fragile and marine natural origins such as red algae⁴. Oxazole-containing compounds have been used as diabetes II treatment e.g. Aleglitazar, platelets aggregation inhibitor e.g. Ditazole, as part of tyrosine kinase inhibitor such as Mubritinib, and as COX-2 inhibitors such as Oxaprozin⁵. The wide range of biological activities of oxazoles includes antibiotics⁶, antiproliferative⁷, anti-inflammatory⁸, analgesic⁹, antibacterial, antifungal¹⁰, hypoglycaemic, antiproliferative, muscle relaxant^11-12, HIV inhibitor activity¹³, RNA binding ligand activity¹⁴ and anti-tuberculosis¹⁵. Oxazole derivatives used as pesticides, fluorescent whitening agents, lubricants, dyes and pigments^16-18. In addition, oxazole derivatives are useful synthetic intermediates and can be used as diversity scaffolds in combinatorial chemistry¹⁹ and also as peptidomimetics²⁰. Thiophene substituted oxazole containing α-alkoxyacid derivatives were reported as dual PPARα/γ agonists²¹. Thiophene substituted oxazole derivatives have proven their potency and selectivity as renal (A498), lung (NCI-H226), kidney (CAKI-1), and breast (MDA-MB-468, MCF7) carcinoma cell lines²². Thiophene containing oxazole and isooxazole compounds have been reported to exhibit anti-depressant, antianxiety activities, MAO inhibitors²³. The biological activities of the thiophene based oxazole nucleus such anti-inflammatory, analgesic, antibacterial, antifungal anti-tuberculosis, muscle relaxant and HIV inhibitory properties have been explained in literature²⁴.

2. MATERIALS AND METHODS:

All the chemicals and solvents have been purified by standard literature procedures and moisture was removed from the glass apparatus using CaCl₂ drying tubes. The melting points determined in open capillary tubes with Gallenkamp melting point apparatus and are uncorrected. FT-IR spectra recorded on Bruker FTIR-TENSOR II spectrophotometer using Platinum attenuated total reflection (ATR) discs. 1H NMR spectra of synthesized compounds were recorded on a Bruker Ascend 500 NMR spectrophotometer at 500 MHz frequency in CDCl₃ or in dimethyl sulfoxide (DMSO-d6) using tetramethylsilane as internal standard. Chemical shifts recorded in δ ppm and multiplicities are given as s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet), or m (multiplet). Elemental analyses were performed on Thermo Quest Flash 1112 Series EA analyzer. Reactions monitored by thin layer chromatography using 0.2 mm silica gel 60 F₂₅₄ (Merck) plates using UV light (254 and 366nm) for detection. Microwave irradiation was carried out in Samsung domestic microwave oven. Common reagent grade available chemicals were utilized without further purification or prepared by standard literature procedures.

Literature survey revealed that amongst the 2,5-disubstituted oxazole incorporated with 3-amino thiophenes in particular needed to be studied. Hence, we have focused our plan towards the synthesis of 2,5-disubstituted oxazole incorporated with 3-amino thiophenes.

Synthesis of ethyl 3-amino-4-carbamoyl-5-(methylthio)thiophene-2-carboxylate, 2 was carried out by traditional protocol as well as by microwave irradiation green protocol. The functional group interconversion reaction such as nitrile to amide in compound 1 was done using conc.H₂SO₄. Thus ethyl 3-amino-4-cyano-5-(methylthio)thiophene-2-carboxylate 1 on reaction with conc. H₂SO₄which furnished 3-amino-4-carbamoyl-5-(methylthio)thiophene-2-carboxylate 2 in 70% yield²⁵. (Scheme 1)

Scheme 1: Synthesis of ethyl 3-amino-4-carbamoyl-5-(methylthio)thiophene-2-carboxylate, 2

Ethyl 3-amino-5-(methylthio)-4-(5-substituted phenyloxazol-2-yl)thiophene-2-carboxylate derivatives 4(a-g) were obtained in good yields (77-83%) by utilizing 3-amino-4-carbamoyl-5-(methylthio)thiophene-2-carboxylate 2 and various phenacyl bromide 3(a-g) under conventional and microwave irradiation method in dioxane (Scheme 2). The structures of products were elucidated by spectral and analytical methods like IR, ¹H NMR and ¹³C NMR.For example, IR spectrum of ethyl 3-amino-5-(methylthio)-4-(5-phenyloxazol-2-yl)thiophene-2-carboxylate, 4a showed stretching frequencies at 3483-3352 (2NH), 2978 (CH₂), 1666, 1670 (C=O), 1597, 1504 (aromatic C=C), 1292 (p C-O stretching), 802 ( =C-H twisting), 756 (aromatic C-H bending). Ethyl 3-amino-5-(methylthio)-4-(5-substituted phenyloxazol-2-yl)thiophene-2-carboxylate derivatives 4(a-g) were obtained in good yields (77-83%) by utilizing 3-amino-4-carbamoyl-5-(methylthio)thiophene-2-carboxylate 2 and various phenacyl bromide 3(a-g) under conventional and microwave irradiation method in dioxane (Scheme 2). The structures of products were elucidated by spectral and analytical methods like IR, ¹H NMR and ¹³C NMR.

Reaction Conditions:

Method A - Conc.HCl(cat), Dioxane, Reflux, 5-6 h;

Method B - Conc.HCl(cat), Dioxane, MWI, 300 W, 7-9 min

Scheme 2: Synthesis of Ethyl 3-amino-5-(methylthio)-4-(5-substituted phenyloxazol-2-yl) thiophene-2-carboxylate derivatives, 4(a-g)

Table 1: Practical yields of ethyl 3-amino-5-(methylthio)-4-(5-substituted phenyl oxazol-2-yl)thiophene-2-carboxylates, 4(a-g)

Comp. 4	Aryl (Ar)	% yield
Comp. 4	Aryl (Ar)	Conventional	MWI
a	Phenyl	60.6	77.0
b	4-Methoxyphenyl	62.9	78.8
c	4-Chlorophenyl	68.0	79.0
d	4-Nitrophenyl	65.8	78.3
e	2,4-Difluorophenyl	67.4	77.8
f	2-Oxo-2H-chromen-3-yl	64.6	80.1
g	6-Bromo-2-oxo-2H-chromen-3-yl	65.7	83.0

2.1 Antimicrobial Activity Screening:

The antimicrobial assay evaluation of the newly synthesized ethyl 3-amino-5-(methylthio)-4-(5-substituted phenyloxazol-2-yl)thiophene-2-carboxylate derivatives, 4(a-g) was done using agar well plate method²⁶.

Table 2: Antimicrobial screening of compounds 4(a-g): Zone of inhibition (mm)

Comp. 4	Conc. (μg/ml)	*Zone of Inhibition (mm)*
		*S. aureus*	*E. coli*	*P. aeruginosa*	*A. niger*	*C.albicans*
		ATCC 25923	ATCC 25922	ATCC 27853	MCIM 745	MTCC 277
4a	200	14.7	15.4	19.8	19.1	13.5
	100	14.5	15.2	19.6	19.0	13.3
	50	14.3	14.9	19.4	18.9	13.2
4b	200	20.7	14.9	20.5	12.5	15.1
	100	20.3	14.7	20.4	12.3	14.8
	50	20.2	14.4	20.3	12.0	14.4
4d	200	16.3	15.7	12.8	10.7	19.4
	100	16.1	15.4	12.5	10.5	19.2
	50	15.9	14.9	12.0	10.2	18.9
4e	200	15.2	20.2	15.2	9.8	19.3
	100	15.1	20.1	15.0	9.7	18.9
	50	14.9	19.9	14.6	9.6	18.6
DMSO	-----	12	14	12.5	10	10.5
Gentamicin		22	28	20	-----	-----
Fluconazole		-----	-----	-----	20	24

Zone of inhibition = 10-14 mm: low activity; 15-19 mm: Moderate activity; > 20 mm: Excellent activity

The antibacterial and antifungal assays were performed in Muller-Hinton broth and Crazek Dox broth as described literature²⁶. Ethyl 3-amino-5-(methylthio)-4-(5-substituted phenyloxazol-2-yl) and thiophene-2-carboxylate derivatives 4(a-g) were screened for antimicrobial activities against gram positive bacteria Staphylococcus aureus (ATCC 29737), gram negative bacteria Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853) and Candida albicans (MTCC 277), Aspergillus niger (MCIM 545) fungi. Compounds 4b, 4d containing chloro, methoxy and nitro functionalities showed excellent antibacterial activities against Gram positive bacteria Staphylococcus aureus with MIC50 μg/mL compared with standard antibiotic drug Gentamicin (20 μg/mL). Compounds 4a, 4b, 4e containing chloro, methoxy and amide functionalities showed excellent antibacterial activities against Gram negative bacteria Escherichia coli and Pseudomonas aeruginosa with MIC 50 μg/mL compared with standard antibiotic drug Gentamicin (20 μg/mL). Compounds 4c containing chloro group displayed moderate antibacterial activity against Gram positive bacteria Staphylococcus aureus with MIC 100μg/mL.

Table 3: Antimicrobial screening of compounds 4(a-g): MIC in μg/mL

Comp. No.	**Minimum Inhibitory Concentration (MIC-μg/ml)**
	*S. aureus*	*E. coli*	*P. aeruginosa*	*A. niger*	*C.albicans*
	ATCC 25923	ATCC 25922	ATCC 27853	MCIM 745	MTCC 277
4a	200	100	50	100	200
4b	50	200	50	200	200
4d	50	100	200	200	50
4e	100	50	100	200	100
Gentamicin		20	20	---	-----
Fluconazole		----	----	20	20

(MIC in μg / mL) = 50 μg / mL: excellent activity; 100 μg / mL: moderate activity; 200 μg / mL: slight activity

Similarly, compounds 4d containing chloro group showed excellent antifungal activities against Aspergillus niger and Candida albicans with MIC 50 μg/mL on comparison with standard drug Fluconazole (20 μg/mL). Compounds 4a, 4e containing chloro and methoxy groups showed moderate antifungal activities against Aspergillus niger and Candida albicans with MIC 100 μg/mL on comparison with standard drug Fluconazole (20 μg/mL). (Table 3)

3. EXPERIMENT AND RESULT:

Synthesis of ethyl 3-amino-4-carbamoyl-5-(methylthio)thiophene-2-carboxylate, 2

Ethyl 3-amino-4-cyano-5- (methylthio) thiophene-2-carboxylate, 1 (2.42 g, 0.01 mol) was stirred in 5 ml Conc.H₂SO₄at the room temperature for 4-5 hr. The reaction mixture was poured into cold water and stirred for 10 min. The solid product of compound 2 precipitated was isolated by filtration under vacuum, dried and recrystallized from ethanol as pale yellow solid²⁵.

Yield 85%, 2.9 g, M.P. 206°C; IR (Platinum ATR, ν_maxcm^-1): 3471, 3346, 3174, 2976, 2915,1670,1639 cm^-1; ¹H NMR (500 MHz CDCl₃) δ 1.32-1.35 (t, 3H, J = 7.5 Hz, CH₃), 2.64 (s, 3H, SCH₃), 4.26 - 4.31 (q, 2H, J=7.5 Hz & J=14 Hz, OCH₂), 6.5 (s, 2H, NH₂); 7.05 (s, 2H, CONH₂); ¹³C NMR (CDCl₃) 15.5, 18.4, 64.5, 75.1, 114.6, 158.1,194.1 δ ppm; MS m/z (%):260.03 (M+1,100), 261.03 (12.2), 262.02 (9); Anal. Calcd.for C₉H₁₂N₂O₃S₂: C, 41.52; H, 4.65; N, 10.76; Found: C, 41.49; H, 4.65; N, 10.83.

Ethyl 3-amino-5-(methylthio)-4-(5-phenyloxazol-2-yl)thiophene-2-carboxylate, 4a

Method A: Conventional Method:

Ethyl 3-amino-4-carbamoyl-5-(methylthio)thiophene-2-carboxylate, 2 (0.26g, 1 mmol), was dissolved in 1,4 dioxane (5 mL) and phenacyl bromide (0.2g, 1 mmol) and 1-2 drops of conc. HCl as catalyst was added. The reaction mixture refluxed at 115^oC for 5-6 hr. The progress of reaction was monitored by TLC (TLC check, n-hexane: ethyl acetate, 7:3). The reaction mass was poured in cold water and acidified with dilute HCl. The white solid product of compound 4a obtained thereafter was dried and recrystallized from ethanol: DMF (9.5: 0.5)

Method B: Microwave Irradiation Method:

Ethyl 3-amino-4-carbamoyl-5-(methylthio)thiophene-2-carboxylate, 2 (0.26g, 1 mmol), was dissolved in 1,4 dioxane (5 mL) and phenacyl bromide ( 0.2g, 1 mmol) and 1-2 drops of conc. HCl as catalyst was added. The reaction mixture irradiated at 300 W for 7 min at interval of 20 secs. The progress of reaction was monitored by TLC (TLC check, n-hexane: ethyl acetate, 7:3). The reaction mass was poured in cold water and acidified with dilute HCl. The white solid product of compound 4a obtained thereafter was dried and recrystallized from ethanol: DMF (9.5: 0.5).

White powder; Yield: Conventional: 0.219 g, 60.8%; MWI. 0.278 g, 77.0%; M.P. 180-182 ^oC; IR (Platinum ATR, ν_maxcm^-1): 3483-3352 (2NH), 2978 (CH₂), 1666, 1670 (C=O), 1597, 1504 (aromatic C=C), 1292 (p C-O stretching), 802 ( =C-H twisting), 756 (aromatic C-H bending); ¹H NMR (500 MHz, CDCl₃): δ ppm 1.33-1.36 (t, J = 7 Hz, 3H, -CH₃), 2.64 (s, 3H, - SCH₃), 4.27-4.31 (q, J = 7 & 14 Hz, 2H, OCH₂), 6.45 (s, 2H, -NH₂), 7.07 (s, 1H, oxazole =CH), 7.07 (s, 5H, ArH) ; ¹³C NMR (125 MHz, CDCl₃) δ ppm: 14.56 (-CH₃), 19.55 (-SCH₃), 60.18 (-OCH₂), 119.78 (Ar C), 148.79, 156.02, 163.39, (thiophene C, oxazole C), 165.66 (C=O); Anal. calcd. for C₁₇H₁₆N₂O₃S₂(Mol. Wt.360.45): C, 56.65; H, 4.47; N, 7.77; found: C, 56.60; H, 4.53; N, 7.82

Similar procedure was employed for synthesis of compounds 4 (b-g).

Ethyl 3-amino-4-(5-(4-methoxyphenyl)oxazol-2-yl)-5-(methylthio)thiophene-2-carboxylate, 4b

White powder; Yield: Conventional: 0.248 g, 62.9%; MWI 0.310 g, 78.80%; M.P. 134-136 ^oC; IR (Platinum ATR,ν_maxcm^-1): 3483-3352 (2NH), 2978 (CH₂), 1666, 1670 (C=O), 1597, 1504 (aromatic C=C), 1292 (p C-O stretching), 802 ( =C-H twisting), 756 (aromatic C-H bending); ¹H NMR (500 MHz, CDCl₃): δ ppm 1.33-1.36 (t, J = 7 Hz, 3H, -CH₃), 2.69 (s, 3H, - SCH₃), 3.79 (s, 3H, -OCH₃), 4.26-4.31 (q, J = 7 & 14 Hz, 2H, OCH₂), 7.27 (s, 2H, -NH₂), 8.11 (s, 1H, oxazole =CH), 7.07-7.09 (d, J = 8 Hz, 2H, ArH), 7.37-7.39 (d, J = 8 Hz, 2H, ArH) ; Anal. calcd. for C₁₈H₁₈N₂O₃S₂ (Mol. Wt.394.9): C, 51.71; H, 3.83; N, 7.09; found: C, 51.74; H, 3.77; N, 7.13.

Ethyl 3-amino-4-(5-(4-chlorophenyl)oxazol-2-yl)-5-(methylthio)thiophene-2-carboxylate, 4c

Yellow powder; Yield: Conventional: 0.265 g, 68.0%; MWI 0.313 g, 79.0%; M.P. 152-154 ^oC; IR (Platinum ATR, ν_maxcm^-1): 3483-3352 (2NH), 2978 (CH₂), 1666, 1670 (C=O), 1597, 1504 (aromatic C=C), 1292 (p C-O stretching), 802 ( =C-H twisting), 756 (aromatic C-H bending); ¹H NMR (500 MHz, CDCl₃): δ ppm 1.33-1.36 (t, J = 7 Hz, 3H, -CH₃), 2.69 (s, 3H, - SCH₃), 4.26-4.31 (q, J = 7 & 14 Hz, 2H, OCH₂), 6.89 (s, 2H, -NH₂), 7.17 (s, 1H, oxazole =CH), 7.27 (d, J = 8 Hz, 2H, ArH), 7.38 (d, J = 8 Hz, 2H, ArH); Anal. calcd. for C₁₉H₁₇ClN₄OS₂(Mol. Wt.394.9): C, 51.71; H, 3.83; N, 7.09; found: C, 51.60; H, 3.75; N, 7.01.

Ethyl 3-amino-4-(5-(3-nitrophenyl)oxazol-2-yl)-5-(methylthio)thiophene-2-carboxylate, 4d

Yellow powder; Yield: Conventional:0.266 g, 65.8%; MWI 0.316 g, 78.0%; M.P. 210-212 ^oC; IR (Platinum ATR, ν_maxcm^-1): 3483-3352 (2NH), 2978 (CH₂), 1666, 1670 (C=O), 1597, 1504 (aromatic C=C), 1292 (p C-O stretching), 802 ( =C-H twisting), 756 (aromatic C-H bending); ¹H NMR (500 MHz, CDCl₃): δ ppm 1.33-1.36 (t, J = 7 Hz, 3H, -CH₃), 2.69 (s, 3H, - SCH₃), 4.26-4.31(q, J = 7 & 14 Hz, 2H, OCH₂), 6.89 (s, 2H, -NH₂), 7.27 (s, 1H, oxazole =CH), 8.11-8.13 (m, J = 1.8 & 10 Hz, 1H, ArH), 8.16-8.17 (d, J = 1.8 & 10 Hz, 1H, ArH), 8.31-8.33 (d, 1H, ArH), 8.34-8.36 (d, J = 1.8 & 10 Hz, 1H, ArH); Anal. calcd. for C₁₉H₁₅N₃O₅S₂ (Mol. Wt.405.45): C, 50.36; H, 3.73; N, 10.36; found: C, 50.26; H, 3.56; N, 10.41.

Ethyl 3-amino-4-(5-(2,4-difluorophenyl)oxazol-2-yl)-5-(methylthio)thiophene-2-carboxylate, 4e

Faint brown powder; Yield: Conventional: 0.267 g, 67.4%; MWI 0.308 g, 77.8%; M.P. 172-174 ^oC; IR (Platinum ATR, ν_maxcm^-1): 3483-3352 (2NH), 2978 (CH₂), 1666, 1670 (C=O), 1597, 1504 (aromatic C=C), 1292 (p C-O stretching), 802 ( =C-H twisting), 756 (aromatic C-H bending); ¹H NMR (500 MHz, CDCl₃): δ ppm 1.32-1.36 (t, J = 7 Hz, 3H, -CH₃), 2.72 (s, 3H, - SCH₃), 4.29-4.35(q, J = 7 & 14 Hz, 2H, OCH₂), 7.19 (s, 2H, -NH₂), 7.29 (s, 1H, oxazole =CH), 8.19-8.21 (m, J = 2 & 10 Hz, 1H, ArH), 8.26-8.29 (d, J = 10 Hz, 1H, ArH), 8.34-8.36 (d, J = 2 Hz, 1H, ArH); Anal. calcd. for C₁₇H₁₄F₂N₂O₃S₂(Mol. Wt.396.43): C, 51.50; H, 3.56; N, 7.07; found: C, 51.52; H, 3.46; N, 7.13.

Ethyl 3-amino-5-(methylthio)-4-(5-(2-oxo-2H-chromen-3-yl)oxazol-2-yl)thiophene-2-carboxylate, 4f

Faint yellow powder; Yield: Conventional: 0.277 g, 64.6% ; MWI 0.343 g, 80.1%; M.P. 196-198 ^oC; IR (Platinum ATR, ν_maxcm^-1) 3483-3352 (2NH), 2978 (CH₂), 1666, 1670 (C=O), 1597, 1504 (aromatic C=C), 1292 (p C-O stretching), 802 ( =C-H twisting), 756 (aromatic C-H bending); ¹H NMR (500 MHz, DMSO-d₆): δ ppm 1.28-1.32 (t, J = 7 Hz, 3H, -CH₃), 2.70 (s, 3H, - SCH₃), 4.26-4.31 (q, J = 7 & 14 Hz, 2H, OCH₂), 7.14-7.16 (s, 1H, oxazole =CH), 7.38-7.40 (m, J = 1.5 & 8 Hz, 1H, ArH), 7.59 (s 1H, Chromenone =CH), 7.61-7.62 (m, J = 1.5 & 8 Hz, 1H, ArH), 7.65-7.68 (m, J = 1.6 & 8 Hz, 1H, ArH), 7.70-7.73 (m, J = 1.6 & 8 Hz, 1H, ArH), 12.02 (s, 2H, -NH₂); Anal. calcd. for C₂₀H₁₆N₂O₅S₂(Mol. Wt.428.48): C, 56.06; H, 3.76; N, 6.54; found: C, 56.26; H, 3.54; N, 6.23.

Ethyl 3-amino-4-(5-(6-bromo-2-oxo-2H-chromen-3-yl)oxazol-2-yl)-5-(methylthio) thiophene-2-carboxylate, 4g

Faint yellow powder; Yield: Conventional: 0.334 g, 65.7%; MWI 0.421 g, 83.0%; M.P. 178-180 ^oC; IR (Platinum ATR, ν_maxcm^-1): 3483-3352 (NH₂), 2978 (CH₂), 1666, 1670 (C=O), 1597, 1504 (aromatic C=C), 1292 (p C-O stretching), 802 ( =C-H twisting), 756 (aromatic C-H bending); ¹H NMR (500 MHz, DMSO-d₆): δ ppm 1.28-1.31 (t, J = 7 Hz, 3H, -CH₃), 2.69 (s, 3H, - SCH₃), 4.26-4.30 (q, J = 7 & 14 Hz, 2H, OCH₂), 7.44-7.46 (s, 1H, oxazole =CH), 7.88-7.90 (m, J = 9 Hz, 1H, ArH), 7.97 (s 1H, Chromenone =CH), 8.22 (d, J = 2 & 9 Hz, 1H, ArH), 8.61 (d, J = 2 Hz, 1H, ArH), 12.02 (s, 2H, -NH₂); Anal. calcd. for C₂₀H₁₅BrN₂O₅S₂(Mol. Wt.507.38): C, 47.34; H, 2.98; N, 5.52; found: C 47.14; H, 2.88; N, 5.65.

4. CONCLUSION:

We have reported a green facile, efficient microwave irradiation method for the synthesis of ethyl 3-amino-5-(methylthio)-4-(5-substituted phenyloxazol-2-yl)thiophene-2-carboxylate derivatives and also demonstrated antimicrobial activity with good results. Particularly compounds 4a, 4b, and 4e containing chloro and methoxy functionalities showed excellent antibacterial activities against Gram negative bacteria Escherichia coli and Pseudomonas aeruginosa with MIC 50 μg/mL compared with standard antibiotic drug Gentamicin (20 μg/mL). Similarly, compounds 4d containing chloro group showed excellent antifungal activities against Aspergillus niger and Candida albicans with MIC 50 μg/mL on comparison with standard drug Fluconazole (20 μg/mL). All these compounds showed promising bioactivities and after few modifications could be considered for future study.

5. ACKNOWLEDGMENT:

The author thanks to UGC; CIF, SPPU, Pune for spectral analysis; Secretary, Gokhale Education Society, Nashik- 422 005; Principal, R.N.C. Arts, J.D.B. Commerce and N.S.C. Science College, Nashik, India for facilities.

6. REFERENCES:

1. a) Sweta Joshi, Ajay Singh Bisht, Divya Juyal, Systematic scientific study of 1, 3-oxazole derivatives as a useful lead for pharmaceuticals: A review. The Pharma Innovation Journal 2017; 6(1): 109-117

b) Lubna Swellmeen. 1,3-Oxazole Derivatives: A Review of Biological Activities as Antipathogenic. Der Pharma Chemica, 2016; 8(13): 269-286

2. Avneet Kaur, Sharad Wakode, Dharam Pal Pathak. Benzoxazole: The Molecule of Diverse Pharmacological Importance. International J Pharm Pharm Sci., 2015; 7(1): 16-23

3. Stefano Bresciani, Nicholas C. O. Tomkinson. Transition Metal-Mediated Synthesis of Oxazoles. Heterocycles, 2014; 89(11): 2479-2543

4. Ambreen Ghani, Erum A. Hussain, Zubi Sadiq, Narjis Naz. Advanced synthetic and pharmacological aspects of 1,3-oxazoles and benzoxazoles. Indian J Chem, 2016; 55B (7): 833-853

5. Nishida A, Fuwa M, Naruto S, Sugaro Y, Saito H, Nakagawa M. Solid-phase synthesis of 5-(3-indolyl)oxazoles that inhibit lipid peroxidation. Tetrahedron Lett., 2000; 41: 4791-4794

6. Ivan H.R. Tomi, Jumbad H. Tomma, Ali H.R. Al-Daraji, Ammar H. Al-Dujaili. Synthesis, characterization and comparative study the microbial activity of some heterocyclic compounds containing oxazole and benzothiazole moieties. J Saudi Chem Soc., 2015; 19(4): 392-398

7. Xin H, Liu PChL., Jia-Yu X, Bao-An S, Hai-Liang Z. Novel 2,4,5-trisubstituted oxazole derivatives: Synthesis and antiproliferative activity. Eur. J. Med. Chem., 2009; 44(10): 3930-3935.

8. Shivendra Pratap Singh, Navneet Kumar Verma, Praveen Kumar Rai and Ashok Kumar Tripathi. Synthesis and pharmacological screening of some noval benzoxazole derivatives. Der Pharmacia Lettre, 2014; 6(6): 283-288.

9. Aniket P. Sarkate, Devanand B. Shinde. Synthesis and Docking Studies of 2-(Nitroxy)-ethyl-2-(substituted-2,5-diphenyl-oxazole)-acetate as Anti-Inflammatory Agents with Analgesic and Nitric Oxide Releasing Properties. Int J Pharm Pharm Sci, 2015; 7(10): 128-134.

10. Amira S. Abd El-All, Souad A. Osman, Hanaa M. F. Roaiah, Mohamed M. Abdalla, Abeer A. Abd El Aty, Wafaa H. AbdEl-Hady. Potent anticancer and antimicrobial activities of pyrazole, oxazole and pyridine derivatives containing 1,2,4-triazine moiety. Medicinal Chemistry Research, 2015; 24(12): 4093-4104.

11. Rajesh Kumar Singh, Ashish Bhatt, Ravi Kant, Pramod Kumar Chauhan. Design and Synthesis of some Novel oxazole derivatives and their biomedicinal efficacy. Chemistry and Biology Interface, 2016; 6, 4: 263-269

12. Sweta Joshi, Ajay Singh Bisht and Divya Juyal. Systematic scientific study of 1, 3-oxazole derivatives as a useful lead for pharmaceuticals: A review. The Pharma Innovation Journal, 2017; 6(1): 109-117

13. Supriya Tilvi, Keisham S. Singh. Synthesis of Oxazole, Oxazoline and Isoxazoline Derived Marine Natural Products: A Review Curr. Org. Chem., 2016; 20(8): 898-929

14. Fengqi Zhang, Kevin T. Chapman, William A. Schleif, David B. Olsen, Mark Stahlhut, Carrie A. Rutkowski, Lawrence C. Kuo, Lixia Jin, Jiunn H. Lin, Emilio A. Emini, James R. Tata. The design, synthesis and evaluation of novel HIV-1 protease inhibitors with high potency against PI-resistant viral strains. Bioorg. Med.Chem. Lett., 2003; 13(15): 2573-2576

15. Kevin D. Rynearson,Sanjay Dutta,Kiet Tran,Sergey M. Dibrov, Thomas Hermann. Synthesis of Oxazole Analogs of Streptolidine Lactam. Eur. J. Org. Chem. 2013; 7337–7342 DOI: 10.1002/ejoc.201300943

16. Suthakaran R., Raghvendra P., G. Veena, Graft. Microwave Synthesis and Anti-Inflammatory Evaluation of Some New Imidazolo Quinoline Analogs. Rasayan J Chem, 2011; 4: 91-102.

17. a) Smith R. A., Barbosa J. M., Blum C. L. Discovery of heterocyclic ureas as a new class of raf kinase inhibitors: identification of a second generation lead by a combinatorial chemistry approach. Bioorg. Med. Chem. Lett., 2001; 11(20): 2775-2778

b) Birone E. A., Chatterjee J. K., Kesselar H. A. Solid-Phase Synthesis of 1,3-Azole-Based Peptides and Peptidomimetics. Org. Lett., 2006; 8(11): 2417-2420

18. Elamina M., Uppal Z., A. Al-Badr. Antibacterial and antifungal activities of benzimidazole and benzoxazole derivatives. Antimicrobial Agents Chemotherapy.1981; 19: 29-32.

19. Ram Prasad S., Saraswathy T., Niraimathi V., Indumathi B. Synthesis, Characterization and Antimicrobial Activity of Some Hetero Benzocaine Dervivatives. Int. J. Pharm. Pham. Sci, 2012; Vol 4, Suppl 5: 285-287

20. Siddiqui N., Arshad M. F., Khan S. A. Synthesis of some new coumarin incorporated thiazolyl semicarbazones as anticonvulsants. Acta Pol. Pharm. 2009; 66: 161-167

21. Preeti Raval, Mukul Jain, Amitgiri Goswami, Sujay Basu, Archana Gite, Atul Godha,Harikishore Pingali, Saurin Raval, Suresh Giri, Dinesh Suthar, Maanan Shah, Pankaj Patel. Revisiting glitazars: Thiophene substituted oxazole containing α-ethoxy phenylpropanoic acid derivatives as highly potent PPARα/γ dual agonists devoid of adverse effects in rodents. Bioorg. Med Chem Letters 2011; 21: 3103–3109

22. Joseph Salamoun, Shelby Anderson, James C. Burnett, Rick Gussio, Peter Wipf, Synthesis of Heterocyclic Triads by Pd-Catalyzed Cross-Couplings and Evaluation of Their Cell-Specific Toxicity Profile. Org. Lett. 2014; 16: 2034−2037

23. Jagdish Kumar, Mymoona Akhtar, Chanda Ranjan, Gita Chawla. Design, Synthesis and Neuropharmacological Evaluation of Thiophene Incorporated Isoxazole Derivatives as Antidepressant and Antianxiety Agents. Int J Pharm Chem Analysis, 2015; 2(2): 74-83

24. Pervin Unal Civcir, Gulbin Kurtay, Kubra Sarikavak. Experimental and theoretical investigation of new furan and thiophene derivatives containing oxazole, isoxazole, or isothiazole subunits. Struct Chem, 2017; 28(3): 773–790 DOI 10.1007/s11224-016-0863-1

25. Chavan S.M.; Toche R.B.; Patil V. M.; Aware P.B.; Patil P.S. Reactions of ketene dithioacetal for a new versatile synthesis of 4,5-substituted 3-aminothiophene-2-carboxylate derivatives. J Sulfur Chem. 2016; 37(4): 426-437. https://doi.org/10.1080/17415993.2016.1156117

26. Mounyr Balouiri, Moulay Sadiki, Saad Koraichi Ibnsouda. Methods for in vitro evaluating antimicrobial activity: A review. J Pharm Analysis, 2016; 6: 71-79

Received on 07.02.2021 Modified on 27.02.2021

Research Journal of Science and Technology. 2021; 13(2):105-110.

DOI: 10.52711/2349-2988.2021.00016