General Information of This Peptide-drug Conjugate (PDC)
PDC ID
PDC_00460
PDC Name
GYGVP - 3,4-Dihydro-4-oxo-2-quinazolinebutanoic acid conjugate 1
PDC Status
Investigative
Indication
In total 4 Indication(s)
Aspergillus niger infection
Escherichia coli infection
Fusarium moniliforme infection
Klebsiella pneumoniae infection
Structure
Peptide Name
GYGVP
 Peptide Info 
Drug Name
3,4-Dihydro-4-oxo-2-quinazolinebutanoic acid
 Drug Info 
Linker Name
Amide bond
 Linker Info 
Formula
C35H43N7O9
#Ro5 Violations (Lipinski): 3 Molecular Weight 705.769
Lipid-water partition coefficient (xlogp) 0.1277
Hydrogen Bond Donor Count (hbonddonor) 7
Hydrogen Bond Acceptor Count (hbondacc) 9
Rotatable Bond Count (rotbonds) 16
Full List of Activity Data of This Peptide-drug Conjugate
Revealed Based on the Cell Line Data
Click To Hide/Show 4 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [1]
Indication <i>Klebsiella pneumoniae</i> infection
Efficacy Data Zone of inhibition
26 ± 0.12 mm
Administration Time 24 h
Administration Dosage 30 μg/mL
MOA of PDC
We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities.

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Description
The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp.

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In Vitro Model Klebsiella pneumoniae infection Klebsiella pneumoniae 573
Experiment 2 Reporting the Activity Data of This PDC [1]
Indication <i>Escherichia coli</i> infection
Efficacy Data Zone of inhibition
28 ± 0.42 mm
Administration Time 24 h
Administration Dosage 30 μg/mL
MOA of PDC
We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities.

   Click to Show/Hide
Description
The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp.

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In Vitro Model Escherichia coli infection Escherichia coli 562
Experiment 3 Reporting the Activity Data of This PDC [1]
Indication <i>Aspergillus niger</i> infection
Efficacy Data Zone of inhibition
28 ± 0.36 mm
Administration Time 24 h
Administration Dosage 30 μg/mL
MOA of PDC
We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities.

   Click to Show/Hide
Description
The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp.

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In Vitro Model Aspergillus niger infection Aspergillus niger 5061
Experiment 4 Reporting the Activity Data of This PDC [1]
Indication <i>Fusarium moniliforme</i> infection
Efficacy Data Zone of inhibition
29 ± 0.29 mm
Administration Time 24 h
Administration Dosage 30 μg/mL
MOA of PDC
We designed novel low charge, high hydrophobic pentapeptides with varying amino acids in the 2nd position and conjugated them to quinazolinone analogues to produce antimicrobial candidates. Preliminary structure-activity relationship revealed that constructs containing tryptophan, tyrosine, and phenylalanine amino acids were better antimicrobial agents than the standards used. Most of the candidates showed selective inhibitory power towards Gram-negative microorganisms. Most of the compounds could be considered as anti-Fusarium monoliforme since slightly superior results were observed for this species compared to A. niger. The alkyl chain length of the heterocyclic unit was found to be crucial for good activity. Finally, the presence of C-terminal polar group (COOH) seems to be favorable for antimicrobial results. Generating such hybrid compounds can be a promising approach to develop good desired biological activities.

   Click to Show/Hide
Description
The activity results showed that most of the compounds produced significant effects on the growth of the tested bacterial and fungal strains. The structure- antimicrobial activity relationship of the compounds revealed that quinazolinone precursors (I) and (II) conjugated with GWGVP ((XV), (XX), (XXV), and (XXX)), GYGVP ((XVI), (XXI), (XXVI), and (XXXI)), and GFGVP ((XXVII), (XXII), (XXVII), and (XXXII)) showed potent activities compared to conjugates of GDGVP ((XXVIII), (XXIII), (XXVIII), and (XXXIII)) and GTGVP ((XIX), XXIV), (XXIX), and (XXXIV)) and respective standard drugs. This could be due to aromaticity of the amino acids Trp, Tyr, and Phe, which are considered to play an important role in antimicrobial effects. It can be suggested that the presence of more hydrophobic units along with other non-polar amino acids provide amphipathicity to the compounds, which may help them in binding to the bacterial cell membranes followed by disruption. This becomes more evident with the loss of activity when the three aromatic and hydrophobic amino acids are substituted by more polar and charged Asp and Thr units. Among the above three hybrid analogues, tryptophan conjugates exhibited high potency, which may be due to the large aromaticity, hydrophobicity, light instability, and the ability to stabilize the amphiphilic structure necessary for antimicrobial activity. Further debenzylation of these compounds ((XXV), (XXVI), (XXVII), (XXX), (XXXI), and (XXXII)) resulted in more polar structures, which showed slight superior results than the benzylated analogues (XV), (XVI), (XVII), (XX), (XXI), and (XXII). This increased activity could be due to their higher polarity, which helps the molecules to establish a larger network for penetration through the cell membranes of microbes. Further, the increase in chain length of quinazolinones decreased the activity. Overall, the antimicrobial activity decreases in the order of X = Trp > Tyr > Phe > Thr > Asp.

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In Vitro Model Fusarium moniliforme infection Fusarium moniliforme 117187
References
Ref 1 Effect of Low Charge and High Hydrophobicity on Antimicrobial Activity of the Quinazolinone-Peptide Conjugates. Russ J Bioorg Chem. 2018;44(2):158-164.