Abstract:Background:
Bacterial resistance to the available antibiotics is a life threatening issue and
researchers are trying to find new drugs to overcome this problem. Amongst the different structural
classes, thiazolidinone-4-one, as a new effective pharmacophore against various bacteria, has been introduced.
Objective:
A new series of 2-(5-(5-nitrothiophene-2-yl)-1,3,4-thiadiazole-2-ylimino)-5-arylidenethiazolidin-
4-one derivatives were designed and synthesized as new antibacterial agents.
Method: Target c… Show more
“…The target 2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one derivatives were synthesized according to the multistep reaction procedure indicated in our previous paper (Scheme 1 ) [ 3 ]. Scheme 1 Synthesis of 2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one derivatives 7–31 .…”
Section: Resultsmentioning
confidence: 99%
“…Thiazolidinone ring is a promising pharmacophore that has possessed a broad spectrum of pharmacological actions such as antimicrobial (compound A) (Fig. 1 ) [ 3 – 5 ], antiviral [ 6 ], antiparasitic [ 7 , 8 ], analgesic, anti-inflammatory [ 9 ], antioxidant [ 10 ], anticancer [ 6 , 7 , 11 ], antidiabetic [ 12 ], antihypertensive, anti-hyperlipidemic, anti-arrhythmic [ 13 ], anti-convulsant activities [ 14 , 15 ]. In the last two decades, 4-thiazolidinone pharmacophore has received great attention for its inhibitory effect on MurB and various substituted 4-thiazolidinones were explored for their antibacterial activity.…”
Section: Introductionmentioning
confidence: 99%
“…It reduces UDP-N-acetylglucosamine enolpyruvate to UDP-N-acetylmuramic acid, a crucial precursor in peptidoglycan biosynthesis process. Presence of MurB in both Gram positive and negative bacteria and its absence in eukaryotic cells makes it a potential target for designing new antibacterial agents [ 3 , 16 , 17 ]. It appears that 4-thiazolidinone moiety interacts with MurB active site by imitating diphosphate moiety of UDP-N-acetylglucosamine enolpyruvate; It was also observed that presence of aromatic rings bearing electron withdrawing groups and heterocyclic cores could improve antibacterial activity of 1,3-thiazolidin-4-ones [ 18 ].…”
Section: Introductionmentioning
confidence: 99%
“…1 ) [ 13 , 19 – 21 ]. In addition, several studies have revealed that derivatives containing thiadiazole ring attached to thiazolidinone moiety offer good antibacterial effects [ 3 , 22 ].…”
Section: Introductionmentioning
confidence: 99%
“…In our previous study, several new compounds bearing 5-nitrothiophen moiety in conjugation with 1,3,4-thiadiazole-2-ylimino-4-thiazolidinone scaffold have been found to exhibit notable antibacterial activities against S.aureus , S.epidermidis , B.cereus and B.subtilis as Gram-positive bacteria and H. pylori [ 3 ]. According to the former mentioned study and by means of molecular hybridization and incorporation of different mentioned active pharmacophores in a new structure, the target 2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one derivatives 7–31 (Fig.…”
In this work, we have synthesized twenty five new 2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one derivatives bearing an aryl or heteroaryl methylene group on position 5 of thiazolidinone and evaluated their antimicrobial activity against Gram-positive and -negative bacteria as well as three metronidazole resistant Helicobacter pylori strains. Most of the compounds were very potent towards tested Gram-positive bacteria and showed an antibacterial efficacy substantially greater than ampicillin as the reference drug. However, no effectiveness was observed for the Gram-negative microorganisms. The compounds 9, 20 and 29 exhibited strong antimicrobial activity against Helicobacter pylori strains (inhibition zone > 30 mm) in 100 μg/disc and (inhibition zone > 20 mm) in 50 μg/disc. Taking these findings together, it seems that these potent antibacterial derivatives could be considered as promising agents for developing new anti-infectious drugs against microorganisms resistant to currently available antibiotics.
Graphical Abstract
“…The target 2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one derivatives were synthesized according to the multistep reaction procedure indicated in our previous paper (Scheme 1 ) [ 3 ]. Scheme 1 Synthesis of 2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one derivatives 7–31 .…”
Section: Resultsmentioning
confidence: 99%
“…Thiazolidinone ring is a promising pharmacophore that has possessed a broad spectrum of pharmacological actions such as antimicrobial (compound A) (Fig. 1 ) [ 3 – 5 ], antiviral [ 6 ], antiparasitic [ 7 , 8 ], analgesic, anti-inflammatory [ 9 ], antioxidant [ 10 ], anticancer [ 6 , 7 , 11 ], antidiabetic [ 12 ], antihypertensive, anti-hyperlipidemic, anti-arrhythmic [ 13 ], anti-convulsant activities [ 14 , 15 ]. In the last two decades, 4-thiazolidinone pharmacophore has received great attention for its inhibitory effect on MurB and various substituted 4-thiazolidinones were explored for their antibacterial activity.…”
Section: Introductionmentioning
confidence: 99%
“…It reduces UDP-N-acetylglucosamine enolpyruvate to UDP-N-acetylmuramic acid, a crucial precursor in peptidoglycan biosynthesis process. Presence of MurB in both Gram positive and negative bacteria and its absence in eukaryotic cells makes it a potential target for designing new antibacterial agents [ 3 , 16 , 17 ]. It appears that 4-thiazolidinone moiety interacts with MurB active site by imitating diphosphate moiety of UDP-N-acetylglucosamine enolpyruvate; It was also observed that presence of aromatic rings bearing electron withdrawing groups and heterocyclic cores could improve antibacterial activity of 1,3-thiazolidin-4-ones [ 18 ].…”
Section: Introductionmentioning
confidence: 99%
“…1 ) [ 13 , 19 – 21 ]. In addition, several studies have revealed that derivatives containing thiadiazole ring attached to thiazolidinone moiety offer good antibacterial effects [ 3 , 22 ].…”
Section: Introductionmentioning
confidence: 99%
“…In our previous study, several new compounds bearing 5-nitrothiophen moiety in conjugation with 1,3,4-thiadiazole-2-ylimino-4-thiazolidinone scaffold have been found to exhibit notable antibacterial activities against S.aureus , S.epidermidis , B.cereus and B.subtilis as Gram-positive bacteria and H. pylori [ 3 ]. According to the former mentioned study and by means of molecular hybridization and incorporation of different mentioned active pharmacophores in a new structure, the target 2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one derivatives 7–31 (Fig.…”
In this work, we have synthesized twenty five new 2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one derivatives bearing an aryl or heteroaryl methylene group on position 5 of thiazolidinone and evaluated their antimicrobial activity against Gram-positive and -negative bacteria as well as three metronidazole resistant Helicobacter pylori strains. Most of the compounds were very potent towards tested Gram-positive bacteria and showed an antibacterial efficacy substantially greater than ampicillin as the reference drug. However, no effectiveness was observed for the Gram-negative microorganisms. The compounds 9, 20 and 29 exhibited strong antimicrobial activity against Helicobacter pylori strains (inhibition zone > 30 mm) in 100 μg/disc and (inhibition zone > 20 mm) in 50 μg/disc. Taking these findings together, it seems that these potent antibacterial derivatives could be considered as promising agents for developing new anti-infectious drugs against microorganisms resistant to currently available antibiotics.
Graphical Abstract
Background:
Although, a great number of the targets of antimicrobial therapy have been achieved, it remains
among the first fields of pharmaceutical research, mainly because of the development of resistant strains. Docking analysis
may be an important tool in the research for the development of more effective agents against specific drug targets or multitarget agents 1-3.
Methods:
In the present study, based on docking analysis, ten tetrahydrothiazolo[2,3-a]isoindole derivatives were chosen
for evaluation of antimicrobial activity.
Results:
All compounds showed antibacterial activity against eight Gram positive and Gram negative bacterial species being
in some cases, more potent than ampicillin and streptomycin against all species. The most sensitive bacteria appeared to be
S. aureus, and En. cloacae while M. flavus, E. coli and P. aeruginosa were the most resistant ones. The compounds were
also tested for their antifungal activity against eight fungal species. All compounds exhibited good antifungal activity better
than reference drugs bifonazole (1.4 – 41 folds) and ketoconazole (1.1 – 406 folds) against all fungal species. In order to
elucidate the mechanism of action docking studies on different antimicrobial targets were performed.
Conclusion:
According to docking analysis, the antifungal activity can be explained by the inhibition of the CYP51 enzyme
for most of the compounds with better correlation of the results obtained for the P.v.c. strain (linear regression between
estimated binding Energy and log(1/MIC) with R 2 =0.867 and p=0.000091 or R 2 = 0.924, p= 0.000036, when compound
3 is excluded. Introduction.
Synthesis of thiazolidinone based on quinolone moiety was established starting from 4-hydroxyquinol-2-ones. The strategy started with the reaction of ethyl bromoacetate with 4-hydroxyquinoline to give the corresponding ethyl oxoquinolinyl acetates, which reacted with hydrazine hydrate to afford the hydrazide derivatives. Subsequently, hydrazides reacted with isothiocyanate derivatives to give the corresponding N,N-disubstituted thioureas. Finally, on subjecting the N,N-disubstituted thioureas with dialkyl acetylenedicarboxylates, cyclization occurred, and thiazolidinone derivatives were obtained in good yields. The two series based on quinolone moiety, one containing N,N-disubstituted thioureas and the other containing thiazolidinone functionalities, were screened for their in vitro urease inhibition properties using thiourea and acetohydroxamic acid as standard inhibitors. The inhibition values of the synthesized thioureas and thiazolidinones exhibited moderate to good inhibitory effects. The structure−activity relationship revealed that N-methyl quinolonyl moiety exhibited a superior effect, since it was proved to be the most potent inhibitor in the present series achieving (IC50 = 1.83 ± 0.79 µM). The previous compound exhibited relatively much greater activity, being approximately 12-fold more potent than thiourea and acetohydroxamic acid as references. Molecular docking analysis showed a good protein−ligand interaction profile against the urease target (PDBID: 4UBP), emphasizing the electronic and geometric effect of N,N-disubstituted thiourea.
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