Abstract
BackgroundUrease are responsible for several pathogenic states in human as well as in animals and its inhibition is utmost urgent. Clinically used drugs are associated with many side effects; recently several researches have shown that flavonoids have good urease inhibition properties. Morin, a natural flavonoid has been investigated for urease inhibition studies which includes designing of library of morin analogues and their in-silico evaluation with the help of Schrodinger’s maestro package of molecular docking software against crystallographic complex of plant enzyme Jack bean urease (PDB ID: 3LA4) followed by synthesis and in vitro evaluation.ResultsBest thirteen derivatives of morin were selected on the basis of their interaction energy and dock score for synthesis and further investigated for in-vitro antioxidant, urease inhibitory and Anti-H. Pylori activity. In-vitro results revealed that a large number of synthesized compounds were found to possess excellent antioxidant and urease Inhibition properties.ConclusionsAmong the synthesized compounds, N-(2-chlorophenyl)-N-((4E)-2-(2,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-ylidene)thiourea (M2b) and N-(4-bromophenyl)-N-((4E)-2-(2,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-ylidene)thiourea (M2i) were found to be most potent urease inhibitor and antioxidant with IC50 value 10.74 ± 0.018, 11.12 ± 0.033 and 7.37 ± 0.024, 7.73 ± 0.015and 7.795 ± 0.003 µM. Derivative M2i exhibited good anti-H. pylori activity having MIC = 500 μg/ml and zone of inhibition 15.00 ± 0.00 mm as compared to standard AHA having MIC = 1000 μg/ml and zone of inhibition 9.00 ± 0.50 mm determined against H. Pylori bacterium (ATCC 43504, DSM 4867) by well diffusion technique. Furthermore, molecular docking study explained the binding pattern of synthesized ligand within active cavity of jack bean protein and drug similarity was explained by ADME studies by quikprop module of molecular docking software.
Highlights
Urease is a nickel containing metalloenzyme brings catalytic hydrolysis of urea and leads to the formation of ammonia and carbamate which instinctively disintegrates, at normal functioning pH, to give another ammonia molecule and bicarbonate [1]
Chemistry In the current study, morin derivatives (M2a–i, M3–6) were synthesized by following the procedure illustrated in Scheme 1 [24–26]
Morin derivatives were synthesized in second step by reaction with equimolar concentration of arylthiourea(M2a-i)/ thiosemicarbazide(M3)/phenylthiosemicarbazide(M4)/ phenyhydrazine(M5)/benzylcarbazate(M6) in ethanol with glacial acetic acid as catalyst
Summary
Urease (urea amidohydrolase; E.C. 3.5.1.5) is a nickel containing metalloenzyme brings catalytic hydrolysis of urea and leads to the formation of ammonia and carbamate which instinctively disintegrates, at normal functioning pH, to give another ammonia molecule and bicarbonate [1]. It’s presence in soil was first reported by Rotini [2] It increases rate of biochemical dissociation of urea by 1 014 times [3]. High urease action is responsible for release of unusually a lot of ammonia into climate which may prompt natural and monetary issues [1, 4]. Urease are responsible for several pathogenic states in human as well as in animals and its inhibition is utmost urgent. Used drugs are associated with many side effects; recently several researches have shown that flavonoids have good urease inhibition properties. A natural flavonoid has been investigated for urease inhibition studies which includes designing of library of morin analogues and their in-silico evaluation with the help of Schrodinger’s maestro package of molecular docking software against crystallographic complex of plant enzyme Jack bean urease (PDB ID: 3LA4) followed by synthesis and in vitro evaluation
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