Crumplin G C
Biology Department, University of York, Heslington, England.
Rev Infect Dis. 1988 Jan-Feb;10 Suppl 1:S2-9.
The evolutionary route followed in the development of the new generations of 4-quinolone antibacterial agents, from the precursor of nalidixic acid to ciprofloxacin and ofloxacin (and beyond), is characterized by a paramount role for serendipity. All of the high-technology features such as fluorination, the presence of a piperazine ring at position 7, and the stereoisomerism of the molecule, represent only the combination of characteristics incorporated in earlier generations of nalidixic acid analogues. Although almost unprecedented levels of potency per mole have been attained along with effective broad-spectrum antibacterial activity and acceptable pharmacokinetic properties, all developments have been made and are being made in the absence of a proper knowledge of how these agents work against susceptible bacteria. The absence of this knowledge, along with our almost total ignorance of how the antibacterial activity relates to possible effects in Homo sapiens, is at present a barrier to the rational development of truly optimized 4-quinolones.
新一代4-喹诺酮类抗菌剂的发展所遵循的进化路线，从萘啶酸的前体到环丙沙星和氧氟沙星（及其他），其特点是意外发现起到了至关重要的作用。所有高科技特性，如氟化、7位哌嗪环的存在以及分子的立体异构现象，都仅仅是早期几代萘啶酸类似物所具有的特征的组合。尽管每摩尔已经达到了几乎前所未有的效力水平，同时具备有效的广谱抗菌活性和可接受的药代动力学性质，但所有这些进展都是在对这些药物如何作用于敏感细菌缺乏适当了解的情况下取得的，并且仍在这样的情况下进行。这种知识的缺乏，再加上我们几乎完全不知道抗菌活性与对人类可能产生的影响之间的关系，目前是合理开发真正优化的4-喹诺酮类药物的一个障碍。
