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I have difficulties with part b).

For C, it's clear to make a bulky dimethoxybenzene group in order to block the C=O group from reacting with b-lactamase.

  • However, in A, how does the structure of sulfonamide affect the bacterial activity in general?

  • Is there an alternative for C as well?

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  • $\begingroup$ I suspect you are reffereing to B on your second paragraph. Also I think 2 structures being refered here are A and B, they can be directly modified. C on its own has very weak antibacterial activity but serves a useful purpose when used in synergy with potent antibiotics e.g amoxicillin $\endgroup$ – xavier_fakerat Jun 3 '18 at 18:33
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Essentially the basis of antibacterical activity of sulfonamides is the inhibition of the enzyme dihydropteroate synthase, an important enzyme needed for the biosynthesis of folic acid derivatives and, ultimately, the thymidine required for DNA.

Now they do this by competing at the active site with p -aminobenzoic acid (PABA), a normal structural component of folic acid derivatives.

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PABA

So how does the structure of sulfonamide affect the bacterial activity in general?

The basis of the structural resemblance of sulfonamides to PABA is clear. The functional group that differs in the two molecules is the carboxyl of PABA and the sulfonamide moiety of sulfanilamide.

Now there are requirements that are vital for activity:

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Para-amino group:

  • unsubstituted (i.e $\ce{NH2}$).
  • very important for activity because any modification of it other than to make prodrugs results in a loss of activity. For example, all of the N4-acetylated metabolites of sulfonamide are inactive.

Sulfonamide:

  • $\ce{N}$ must be primary or secondary
  • $\ce{R2}$ can be substituted

Aromatic ring:

  • Para substituted

Modifications

The pKa of the carboxyl group of PABA is approximately 4.9 thus an optimised sulfonamide has a pKa somewhere close to this value.

It was observed that replacement of one of the $\ce{NH2}$ hydrogens by an electron-withdrawing heteroaromatic ring enhanced the acidity of the remaining hydrogen and dramatically enhanced potency.

With suitable groups in place, the pKa is reduced to the same range as that of PABA itself. Not only did this markedly increase the antibacterial potency of the product, but it also dramatically increased the water solubility under physiologic conditions.

Structural variation among the clinically useful sulfonamides is restricted primarily to installation of various heterocyclic aromatic substituents on the sulfonamide nitrogen.

An example is Sulfisoxazole (pKa 5.0) which can also be formulated as a prodrug, by inclusion of N-acetyl groups. Another advantage is the acetyl derivative is tasteless and, therefore, suitable for oral administration, especially in liquid preparations.


Is there an alternative for C as well?

Clavulanic acid is a naturally occurring, mechanism based inhibitor , which causes potent and progressive inactivation of β-lactamases.

There are alternatives e.g sulbactam (A synthetic derivative of penicillins undergone the oxidation of the sulfur atom to a sulfone which greatly enhances the potency) or tazobactam.

References

  1. The 12th Edition of Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry
  2. Foye’s Principles of Medicinal Chemistry 7th ed.
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