The number of articles published on tetracycline drugs has reached the threshold of 50,000 papers since 1948. Over the last 10 years, technological fields are emerging in bacteriology and cellular physiology of eukaryotic cells. However, chemical mechanisms of tetracyclines are not completely understood in terms of their function in human cells and, to this day, no (Q)SAR model is validated without doubts. Tetracyclines were first discovered by Dr. Benjamin Dugger of Lederle Laboratories in the mid 1940s as the fermentation product of an unusual golden-colored soil bacterium aptly named Streptomyces aureofacians [1]. Tetracyclines (TCs) are a class of antibiotics able to inhibit protein synthesis in gram positive and gram negative bacteria by preventing the attachment of aminoacyl-tRNA to the ribosomal acceptor (A) site [2]. This mechanism has been confirmed by X-ray crystallography [3]. TCs bind specifically to the bacterial ribosome and not specifically with eukaryotic ribosomes. TCs belong to a notable class of biologically active and commercially valuable compounds. This fact may be simply illustrated by mentioning the most important clinical application of TCs, their employment as broad antimicrobial-spectrum antibiotics for human and veterinary use [4]. While they were initially developed as antibiotics, they also hold promise as non-antibiotic compounds for future study and use. Tetracyclines, as dynamics entities, possess unique chemical and biological characteristics that may explain their ability to interact with so many different cellular targets, receptors and cellular properties [5]. The discovery of new uses for tetracyclines and their novel biological properties against both prokaryotes and eukaryotes is currently under investigation by numerous scientists throughout the world. TCs as drugs show only few side effects: one is chelation of calcium and subsequent intercalation in bones and teeth while the other is somewhat like photosensitizing drugs, given their phototoxic action on keratinocytes and fibroblasts. The mechanisms of phototoxicity in vitro and in vivo are not yet entirely clear [6].

The therapeutic uses are as follows: antibacterial and non-antibacterial. In the literature, these uses fall into five main categories, namely: (I) newer and more potent tetracyclines used in anitibacterial resistance [7], (II) the nonantibacterial uses of tetracyclines targeted toward inflammation [8] and arthritis [9,10,11,12]; (III) in neurology: (a) In tissue destructive diseases acting like antifibrilogenics [13]; (b) Inhibiting caspase-1 and caspase-3 expression in Hungtington’s disease [14]; (c) Ischemia [15]; (d) Parkinson’s [16] and other neurodegeneration diseases; (IV) antiviral and anticancer [17,18,19]; (V) Tet repressor controlled gene switch [20].

Historically, tetracyclines are considered First generation if they are obtained by biosynthesis such as: Tetracycline, Chlortetecycline, Oxytetracycline, Demeclocycline. Second generation if they are derivatives of semi-synthesis such as: Doxycycline, Lymecycline, Meclocycline, Methacycline, Minocycline, Rolitetracycline. Third generation if they are obtained from total synthesis such as: Tigecycline. However, some researchers consider Tigecycline to be distinct from other tetracyclines drugs and are considered as a new family of antibacterials called Glycylcyclines.

The present paper introduces a new schematic point of view about the denomination and the classification of Tetracycline-Structure-Based drugs. In the years to come, new TCs, which now are advanced in the clinical trials (Phase III of Pharmaceutical Trials Protocol), will be available in therapy. TCs obtained via total synthesis, such as Tigecycline, are considered members of the Third generation if they show wide spectrum activities (both Gram⁺ and Gram⁻) Aminomethylcycline derivatives are considered in the same way as Glycylcycline (Scheme 1). In the last five years, thousands of medicinal chemists around the world have synthesized, tested and patented more than 310 tetracycline similar compounds, in particular in the USA [36]. Harvard University [37] and Tetraphase [38] made available pentacycline antibacterials (a structural modification of Doxycycline with five rings), azatetracycline and flurocycline (heteroatoms insert into the D ring, as show in Figure 1) and alkylaminotetracycline antibacterials.

All these compounds are the “logical results of modification around the four rings of tetracyclines that historically started with the master work of Golub and McNamara [39,40] when, thirty years ago, the first eight compounds called chemically modified tetracyclines (CMTs) were introduced in the literature. In 1983, Golub and McNamara [39,40] introduced a new concept concerning the therapeutic usefulness of tetracyclines. They proposed two main ideas. First, tetracyclines, but not other antibiotics, can inhibit the activity of collagenase—a specific collagenolytic metallo-neutral protease produced by host tissues which has repeatedly been implicated in periodontal destruction. Second, this newly discovered property of the drugs could provide a novel approach to the treatment of diseases, such as periodontal diseases, but also certain medical disorders (e.g., non-infected corneal ulcers), which involve excessive collagen destruction. In these cases, TCs appear to inhibit collagenase activity by a mechanism unrelated to the drug’s antibacterial efficacy. In fact, all CMTs have been modified by the removal of the dimethylamino group from the C4 position on the A ring. To better classify the new compounds it is very important to understand which chemical properties make it possible for tetracycline-structure-based drugs to act as a “chameleonic” entity. As discussed in the previous paragraph, TCs can be considered as wide-spectrum antibiotics versus bacteria, fungi, virus and cancer cells. In this view TCs can be considered an optimum example of multi target drugs and the first well documented in the literature. Moreover, Doxorubicin and all the other anthracyclines are structurally correlated to tetracyclines and it is appropriate to classify them both in the same scheme because of their chemical similarities, chemical physics properties and their use as anti-cancer drugs.

In this work a new framework is introduced for the classification of old and novel TCs and their Structure Activity Relationship. The possibility to open access of large chemical data base has changed enormous. All data reporting in this paper has been verified and compared with the National Health Institution Public Library (Bethesda, MD) using PubChem Project. The computational analysis has been performed on a data set of 1325 TCs with a similarity score of 90%, starting from more than 322,000 compounds recorded in PubChem (this paper is in preparation). From that set were chosen the best in class TCs with a similarity score major of 95% (Scheme 1). For each TC selected, PubChem shows at least 112 tautomers and conformers structure with “rule of five” data. The new classification proposed is based on a medicinal chemistry approach due to the complexity of the novel TCs drugs, e.g.,: Chemical modified tetracycline (CMT), Anthracycline drugs (Doxorubicin) and structurally-correlated-tetracycline (Pentacyclin, Glycylcyclin, Flurocyclin, Aminomethylcyclin and Azatetracylin).

The role of lipophilicity of TCs is the main factor to explain the biological potency and dynamics of this old family of drugs. It is important to understand the conformational flexibility and the affinity of TCs of metals ions due to the several functional groups present in the molecular skeleton to obtain a significant SAR study. After more than 60 years of scientific investigation, TCs are considered a master example of the pleitropic family of compounds with promising therapeutic properties. Due to the wide use in therapy and their low toxicity, TCs can be considered the first Multi-Target Drugs fully and well discussed in the history of pharmacology.

Newer and more potent antibacterial compounds can be expected to fight the tetracycline-resistant pathogens. New, third-generation derivatives have been designated to be more potent, especially against bacteria possessing ribosomal protection and efflux mechanisms. TCs have increased in potency over time compared to other structural classes of antibiotics. TCs have shown a complex mechanism of action towards various targets due to their conformations under physiological conditions. Such conformations, depending on pH and metal ion concentrations, allow TCs to act in a “chameleonic-like” manner in a large number of diseases. As already suggested, the future of TCs will have increased utility as one of the best anti-inflammatory drugs.