PONE-D-20-14557

New sulphonamide pyrolidine carboxamide derivatives: synthesis, molecular docking, antiplasmodial and antioxidant activities

PLOS ONE

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Academic Editor

PLOS ONE

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Reviewers' comments:

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Reviewer #1: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: N/A

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Reviewer #1: Yes

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Reviewer #1: Yes

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5. Review Comments to the Author

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Reviewer #1: The authors described the synthesis and biological evaluation of 32 dipeptides Ar1SO2-Pro-Ala-NHAr2. The synthesis is modular with moderate to good chemical yields. Some of these compounds exhibit single-digit micromolar IC50s against chloroquine sensitive strains of P. falciparum and act as radical scavengers well. Some computational studies were performed on the selected dipeptides.

One of the major concerns is that all the tested compounds are not very active against the malarial parasites or as antioxidant. It is hardly to call the functionalized dipeptide scaffold novel unless the authors can demonstrate they have good activity profiles. The screening of a 32-compound library with fixed amino acid backbone (Pro-Ala) is not diverse enough for SAR, and the expansion to a more inclusive compound set seems necessary to discover a more potent inhibitor. It is not entirely clear why the amino acid should be limited to Pro and Ala, at least some other amino acids should be considered. The toxicity of these test compounds should be evaluated.

The discussion in the Synthesis and characterization of new dipeptide derivatives (last paragraph under scheme 2) seems not delivering important information. It is focused on NMR data of the compounds. For example “Significantly, the methyl protons in toluenesulfonyl moiety integrated as singlet for three protons at about 2.40 ppm in the 1H NMR of compounds 9a-p and 10a-p”, why this information is significant? Do the authors try to confirm that the compounds are diastereomerically pure? And compounds 10a-p don’t even have a toluenesulfonyl moiety! The authors also tried to convey that a OMe is more deshielded than a Me on the aromatic ring, this is not necessary. In addition, the drawings in Scheme 2 need further improvement. First, as a medicinal chemistry manuscript, the identity of the test compounds is very important. No stereochemistry of the amino acid is labelled. The authors should clearly specify the configuration of the compounds since both enantiomers of the amino acids are available and different stereoisomers can alter the activity significantly. In structure 4/5, the X is missing. For the final products, the label should be changed as “9: X= Me, 10: X=NO2”. The current label is very confusing, since R’’=9 :x=Me is not correct.

Lipinski’s rule of five is an empirical guideline to assess the drug-likeness of a compound. However, there are many exceptions on both ways. Just using this guideline to evaluate the compounds conclude their drug likeness is not sufficient. One obvious liability is the instability of these peptide drugs in general: they are susceptible to enzymatic degradation. The authors should have a microsomal stability test on them.

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Reviewer #1: No

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New sulphonamide pyrolidine carboxamide derivatives: synthesis, molecular docking, antiplasmodial and antioxidant activities

PONE-D-20-14557R1

Dear Dr. Ibezim,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Mohammad Shahid, Ph.D.

Academic Editor

PLOS ONE

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