The Forgotten Famous: A Tribute to Rififi

In a recent Editorial, published in the special ACS Medicinal Chemistry Letters issue “Highlighting Medicinal Chemistry in Italy”,¹ Maurizio Botta^† highlighted, starting from the second half of the last century, a number of outstanding success stories in the field of drug discovery and development by Italian universities, industries, and nonacademic research centers.

Auguste Le Breton, a French novelist published in 1953 “Du Rififi chez les hommes”, a detective fiction. A film noir adaptation of the same novel earned the American filmmaker Jules Dassin the award for best Director at the 1955 Cannes Film Festival.

A scientist of worldwide reputation, Piero Sensi and colleagues at the Lepetit Research Laboratories in Milan, isolated in 1959 the rifamycins, the Forgotten Famous, nicknamed “Rififi”.²

In 1963, Vladimir Prelog (1975 Nobel Prize in Chemistry) at ETH in Zurich succeeded in elucidating the structure of rifamycin B by chemical degradation and extensive use of ¹H NMR.

Rifamycin SV (Rifocin), the first rifamycin used clinically in 1963, was joined on the market by Rifampicin (Rifadin, Rifampin) in 1968, due to its improved bioavailability and greater activity against Gram-positive and Gram-negative bacteria, and especially against Mycobacterium tuberculosis.³ Rifampicin is still used as a first-line regimen against this agent, which is one of the top 10 causes of death and the leading cause from a single infectious agent (above all in opportunistic infections in AIDS).

In 1984, Mario Brufani at the University of Rome, together with colleagues at the Institute of Structural Chemistry “G. Giacomello” (now Institute of Crystallography) of the National Research Council of Italy - Rome, performed structure–activity relationship studies and characterized by X-ray crystallography and ¹H NMR and other spectroscopies the chemical structure of a new class of semisynthetic derivatives of rifamycin SV, including Rifaximin.⁴

Alfa Farmaceutici (now Alfasigma) in Bologna designed Rifaximin in collaboration with Mario Brufani, in order to achieve low gastrointestinal absorption, while retaining good antibacterial activity. In 1987, Alfa Farmaceutici successfully developed and brought to the Italian market Rifaximin (Normix), an effective and safe drug for the treatment of small intestine bacterial overgrowth. The US Food and Drug Administration approved Rifaximin as Xifaxan (Salix Pharmaceuticals) in 2004.

Rififi is still highly acclaimed by modern film critics as one of the greatest works in French film noir. Likewise, in light of the emerging multidimensional nature of Alzheimer’s Disease pathology, Rifaximin, for its unique properties of lowering blood ammonia levels by altering fecal flora, is currently being exploited (clinical trials - recruiting phase) along the brain–gut microbiota axis in Alzheimer’s Disease.⁵

Furthermore, the identification of Rifampicin resistance mutations in Mycobacterium tuberculosis calls for the urgent development of novel investigational rifamycins and new delivery systems.

Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.

Notes

^†We wish to express our profound sadness for the premature passing of Prof. Maurizio Botta, a scientist who contributed at the highest level to the scientific growth of medicinal chemistry in Italy, successfully promoting academia–industry partnerships. His smile, sharp wit, and intelligence will always be fondly remembered.