New Penicillins Stable towards Both Acid and Penicillinase

FOLLOWING on the isolation in these Laboratories of 6-aminopenicillanic acid1, we have used it to synthesize many novel penicillins, with particular emphasis on structures which resist

inactivation by staphylococcal penicillinase. One class of penicillins possessing this valuable property has been obtained by acylating 6-aminopenicillanic acid with aromatic or

heteroaromatic carboxylic acid chlorides substituted in both ortho positions. When the ring structure of the side-chain acid is six-membered, almost any pair of ortho substituents confer

marked stability towards penicillinase, but when it is five-membered one or both of the substituents must be relatively bulky, for example, phenyl or substituted phenyl. Such findings

illustrate the primary importance of steric effects in determining stability towards penicillinase. In this respect the chemical constitution of the side-chain is of much less significance,

although it has a profound influence on antibacterial activity and on stability towards acids.

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