Origins of the Quinolone Class of Antibacterials: An Expanded “Discovery Story”

Abstract

Published descriptions of the specific lines of research leading to the discovery of therapeutically important medicines, especially major new class medicines, have long provided value to the biopharmaceutical community as models of success, often influencing the strategies and methods of subsequent drug research. Quinolone antibacterials represent one of medicine's most important classes of anti-infective agents; yet in contrast to many other classes of anti-infectives, astonishingly few details concerning the origin of the class or the rationale leading to the selection of the first clinical agent, nalidixic acid, were ever published by the discoverers. Moreover, earlier disclosures of an independent discovery of the quinolone class of antibacterials have been almost entirely overlooked by the scientific literature. This review brings together all the available information from primary literature sources relating to both discoveries and provides for the first time a much fuller, if still partially speculative, story of the earliest years of this important class of drugs.

Endless resistance. Endless antibiotics?

“…The fluoroquinolones are an important example of exceptionally useful antibacterials having (for the most part) origins in the synthetic realm. 53,54 The second realm is the antibiotics discovered by Nature, as exemplified by the incredible array of natural products found during the “Golden Age” of antibiotic isolation and thereafter. 55 The interface between the two realms comprises the structures synthetically elaborated from the antibiotics of Nature.…”

Case Files of the University of California, San Francisco Medical Toxicology Fellowship: Seizures and a Persistent Anion Gap Metabolic Acidosis

“…Nalidixic acid was the first quinolone antibiotic available, introduced in the USA in 1964 [18]. It is rarely used in the USA today; however, reports of overdose include altered mental status, seizure, coma, and metabolic acidosis [19,20].…”

Design, Synthesis and In Vitro Anti‐mycobacterial Activities of 8‐OMe Ciprofloxacin‐1H‐1,2,3‐triazole‐isatin‐(thio) Semicarbazide/Oxime Hybrids

“…The structure-activity relationship indicated that the incorporation of the OMe group at C-8 position of quinolone core has resulted in a greater binding affinity to the topoisomerase IV enzyme, and 8-OCH 3 FQs derivatives with N1-cyclopropyl substitution are much more potent against drug-resistant MTB than the corresponding 8-H analogs [7]. Moreover, the capacity of FQs to form hydrogen bond may favor their anti-TB activities because of the ability to bond the active site.…”

“…It is notable that 8-OCH 3 ciprofloxacin (8-OCH 3 CPFX, Fig. 1) exhibited excellent biological activities [8], and some of 8-OCH 3 CPFX derivatives showed promising anti-TB activities [9]. Therefore, CPFX is a useful chemotype to searching new anti-TB agents.…”