Perspective

pubs.acs.org/jmc

Data-Mining for Sulfur and Fluorine: An Evaluation of

Pharmaceuticals To Reveal Opportunities for Drug Design and
Discovery
Miniperspective
Elizabeth A. Ilardi, Edon Vitaku, and Jon T. Njardarson*
Department of Chemistry and Biochemistry, University of Arizona, 1306 E. University Boulevard, Tucson, Arizona 85721, United
States
*
S Supporting Information

ABSTRACT: Among carbon, hydrogen, oxygen, and nitrogen, sulfur and

fluorine are both leading constituents of the pharmaceuticals that comprise our
medicinal history. In efforts to stimulate the minds of both the general public
and expert scientist, statistics were collected from the trends associated with
therapeutics spanning 12 disease categories (a total of 1969 drugs) from our new
graphical montage compilation: disease focused pharmaceuticals posters. Each
poster is a vibrant display of a collection of pharmaceuticals (including structural
image, Food and Drug Administration (FDA) approval date, international
nonproprietary name (INN), initial market name, and a color-coded subclass of
function) organized chronologically and classified according to an association
with a particular clinical indication. Specifically, the evolution and structural
diversity of sulfur and the popular integration of fluorine into drugs introduced
over the past 50 years are evaluated. The presented qualitative conclusions in
this article aim to promote innovative insights into drug development.

P harmaceuticals have a profound effect on the overall well-

being of society. Each year, the pharmaceutical industry
produces a wealth of useful information characterizing the
drugs that have been developed. Conveniently, there exists
several drug databases that organize these descriptive proper-
ties, including data regarding drug structure, function,
pharmacology, pharmacokinetics, etc.1−3 Unfortunately, some
databases are minimal in scope or are difficult to navigate;
therefore, strategic analyses, such as the evaluation of
architectural or functional patterns that are present within
these sets of drugs, have been limited. The identification of
qualitative trends and patterns among all pharmaceuticals, or
data mining, is a profitable method to highlight new
opportunities for drug discovery.4 Statistics regarding functional
group, molecular composition, atom and substitution arrange-
ments, or target medical condition that characterizes each
structure can act as guides for the development of new
synthetic strategies, formulation of new drugs, and the
advancement of chemical education.5 This information can
also aid in identifying deficiencies within pharmacopoeia itself.
Images of molecular architectures serve as effective catalysts
that provoke serendipitous discovery. Over the years we have
learned that establishing a detailed knowledge of common
pharmaceutical structural motifs can reveal areas for the
development of new synthetic methodologies.6 Consequently,
our second-generation of graphical montages, the disease
focused pharmaceutical posters, harnesses the illustrative
language of organic chemistry to educate both the nonscientist
and the expert researcher (Table 1a).7 Our database consists of
thematic graphical timelines of the first formulations of drugs
approved by the United States Food and Drug Administration
introduced over the past century. Currently our collection
consists of 1969 compounds, and newly approved drugs will be
added annually. All therapeutics are grouped according to an
association with 12 disease categories (Anti-Infectives, Car-
diovascular, Alimentary Tract and Metabolism, Musculoskeletal
System, Oncological, Blood and Blood Forming Organs,
Endocrine System, Respiratory System, Dermatological, Nerv-
ous System, Sensory Organ, and Genitourinary and Sex
Hormone).8 Inspired by the educational success of our earlier
Top200 drug posters, each pharmaceutical is represented by its
structure, initial market name, INN, color-coded subclass of
function, and the initial date approved by the FDA.9−12 The
spartan descriptions enable a nonspecialist to obtain
information about organic architecture and utility without the
need of formal instruction. The database can continuously grow
as new drugs are approved annually. Perhaps the most
profitable facet of this compilation is that it can also perpetually
evolve. Uniquely themed posters can materialize based upon
Received: September 6, 2013
Published: October 8, 2013

© 2013 American Chemical Society 2832 dx.doi.org/10.1021/jm401375q | J. Med. Chem. 2014, 57, 2832−2842
Journal of Medicinal Chemistry Perspective

Table 1. (a, Left) Percent Composition of Small-Molecule, Combination, and Biological Pharmaceuticals in the 2011 Top200
Brand Name Drugs by U.S. Retail Sales and by Total U.S. Prescriptions, (b, Middle) Percent Composition of Drugs Containing
Sulfur or Fluorine (Excluding Biological Drugs) Using the Same Data Set, and (c, Right) Structures of Sulfur-Containing Drugs
in the Top 20 Drugs by U.S. Retail Sales and by Total U.S. Prescriptions in 2011.

Figure 1. Top200 pharmaceutical posters (produced annually) and disease focused pharmaceutical posters (12 primary posters, future montages
produced by demand).

drug similarities, parallels, or patterns contained within this
library of pharmaceuticals.
The subsequent analysis is intended to provide a practical
example of how simple data-mining can transform what may
seem like a daunting amount of information into a springboard
for inspiration, application, and/or further investigation using
supplementary resources. Of the principal elements that
comprise all drugs (carbon, hydrogen, oxygen, or nitrogen),
sulfur represents the fifth most prevalent element in overall
architectural representation and biological significance. Sulfur
compounds are in clinical use for variable medical conditions,
such as depression, arthritis, diabetes, cancer, and acquired
immune deficiency syndrome (AIDS) since the formal
establishment of the FDA in the early 20th century.13
Moreover, fluorine, the smallest halogen and most electro-
negative element, is a key constituent of about 20% of recently
approved pharmaceuticals.14 This Miniperspective investigates
select statistics associated with the incidence of sulfur and
fluorine in the molecular composition of small-molecule and
2833
combination drugs in our database. Following an initial
tabulation of the sulfur-containing and fluorinated pharmaceut-
icals in both of the Top200 brand name drugs by U.S. retail
sales in 2011 and Top200 brand name drugs by total U.S.
prescriptions in 2011, we then evaluated the overall diversity
and evolution of sulfur and fluorine in pharmaceuticals over
time (Figure 1).
The use of organosulfur compounds as medicinal remedies
dates back to the ancient Egyptians, who described a sulfuric
ointment with mild antiseptic effects. Similarly, the mytho-
logical writings of the ancient Greeks depicted injured warriors
healing in the sulfur-rich baths of Agamemnon. During the
Victorian era in Europe, people often used “brimstone and
treacle” as a laxative and tonic for children.15 In the 1920s,
“colloidal’” sulfur was regularly administered to patients
suffering from rheumatoid arthritis. Eventually, modern medical
applications of sulfur-containing compounds have grown to
include antibacterials, anti-inflammatories, dermatologics, and
cancer treatments.13 Considering the age of drug resistance and
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Journal of Medicinal Chemistry
Table 2. (a, Top) Percent Composition of Small-Molecule, Combination, and Biological Pharmaceuticals Introduced by Decade
and (b, Bottom) Percent Composition of Small-Molecule, Combination, and Biological Pharmaceuticals That Comprise Each
of the 12 Representative Disease Categories
the continual need for the development of medicinal therapies,
existing sulfur-containing compounds may provide leads to
forthcoming pharmaceuticals.
The medicinal impact of organosulfur compounds is
extraordinary. Inspection of the structures of compounds
within both of the Top200 brand name drugs by U.S. retail
sales (RS) in 2011 and Top200 brand name drugs by total U.S.
prescriptions (P) in 2011 revealed that 24.8% and 22.5% of
drugs (excluding biological drugs) contain this heteroatom.16 In
addition, 40% and 25% of the top 20 drugs by RS and P,
respectively, including Plavix (clopidogrel, no. 2 RS, no. 7 P,
thiophene), NexIUM (esomeprazole, no. 3 RS, no. 11 P,
sulfinyl), Seroquel (quetiapine, no. 6 RS, thiazepine), Singulair
(montelukast, no. 7 RS, no. 8 P, thioether), Crestor
(rosuvastatin, no. 8 RS, no. 10 P, sulfonamide), Cymbalta
(duloxetine, no. 9 RS, thiophene), Actos (pioglitazone, no. 13
RS, thiazolidinedione), Zyprexa, (olanzapine, no. 16 RS,
thiophene), and amoxicillin (no. 20 P, β-lactam) contain sulfur.
2834
Perspective
Noteworthy advances in the development of fluorinated
drugs as anesthetics, blood substitutes, antivirals, antifungals,
fluorinated steroids, anti-inflammatories, central nervous system
(CNS) medications, and anticancer therapies have been
accomplished within the past 10 years.17 However, to date,
the representation of fluorine is markedly less, existing in only
15% of the top 20 drugs, particularly, as a fluorinated aromatic:
Lipitor (atorvastatin, no. 1 RS, no. 5 P), Crestor (no. 8 RS, no.
10 P), and Lexapro (escitalopram, no. 18 RS, no. 16 P).
Conclusively, the percentage of sulfur-containing drugs exceeds
fluorinated compounds in both surveys.
Historically, small-molecule compounds range in architec-
tures from simple organic acyclics and heterocyclics to complex
peptides, carbohydrates, and natural products (Table 2).18
However, the first biological drug, a biosynthetic “human”
insulin trade-named Humulin, was developed by Genentech
and manufactured/marketed by Eli Lilly and Company. Since
its approval for therapeutic use in 1982, most of the
biopharmaceutical products derived from natural sources have
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Journal of Medicinal Chemistry Perspective

Table 3. (a, Left) Percent Composition of Sulfur-Containing and Fluorinated Pharmaceuticals per Decade within 12
Representative Disease Categoriesa and (b, Right) Fluorinated Pharmaceuticals Poster

a
The number above each bar reflects the combined total number of drugs approved during each decade (excluding biological drugs and oncological
combination therapies).

Table 4. Percent Composition of Sulfur-Containing and Fluorinated Pharmaceuticals That Comprise Each of the 12
Representative Disease Categoriesa

a
The number above each bar reflects the total number of drugs in each category (excluding biological drugs).

grown to include proteins, nucleic acids (deoxyribonucleic acid
(DNA), ribonucleic acid (RNA), or antisense oligonucleo-
tides), and living microorganisms (viruses and bacteria).19
Upon the basis of the results in Table 2, biologics, such as
synthetic insulin analogues, encompass a considerable percent-
age of drugs for the treatment of conditions dealing with blood
and blood forming organs. Indeed, the 146 representative
biologics (out of 1969 drugs) featured in the posters provide a
significant medicinal impact within other disease therapies
including rheumatology, oncology, cardiology, dermatology,
gastroenterology, and neurology. Although many contain sulfur,
primarily in the form of disulfides and amino acids,20 the focus
of the following analysis will concern the range of sulfur motifs
within small-molecule and combination drugs that have been
introduced since the early 1900s.
As evident by Table 3, the frequency of new fluorinated
drugs has been gradually rising since their first appearance in
the 1950s.21−26 However, sulfur continues to maintain its status
as the dominating heteroatom integrated into the set of 362
sulfur-containing FDA approved drugs (besides oxygen or
2835
nitrogen) through the present. Generally, advantages to the
carbon−fluorine bond include its metabolic stability and the
fact that fluorine acts as a bioisostere of the hydrogen atom.
The incorporation of fluorine generally increases a molecule’s
lipophilicity, facilitating bioavailability (as in minimizing the
potential cytochrome P450 enzymatic oxidation of proximate
functionalities), which in turn maximizes medicinal benefits at a
lower dosage.26 However, there is also a subset of molecules
where the introduction of fluorine can actually increase the
hydrophilicity of molecules, in which many of these had a
fluorine atom within 3 Å of an O atom.27 Currently, over 225
fluorinated small-molecule and combination pharmaceuticals
have been FDA approved exhibiting widespread biological
activity since 1955. The rise of fluorinated agents may be on the
horizon; nevertheless, sulfur continues to sustain its status as a
leading biologically relevant structural component. The
structural constraints of fluorine, as in the limitations associated
with valency, severely limit the development of varied drug
candidates.28,29
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Journal of Medicinal Chemistry Perspective

Figure 2. Structural diversity of sulfur-containing and fluorinated functional groups that describe the molecular architecture of the pharmaceuticals
within 12 representative disease categories.

Table 5. Percent Composition of Occurrences of Each Sulfur-Containing Functional Group (410 Instances in 369 Total Drugs)
That Describe Sulfur-Containing Pharmaceuticals within the 12 Representative Disease Categories (Excluding Biological
Drugs)

Of the 12 disease categories surveyed (Table 4), sulfur is
more heavily represented, prevailing in 10/12 groups, and
comprises >50% more drugs than fluorine in the Anti-Infectives
catagory and >60% in Cardiovascular and Musculoskeletal
categories. While sulfur clearly has the advantage of forming
more structurally diverse bonds, fluorinated compounds surpass
organosulfurs by nearly 30% for sensory organ therapies.
Perhaps this dominance can be attributed to the evolution of
analogues of synthetic fluorinated steroids, corticosteroids, and
prostanoids derived from their C−H precursors developed as
extremely potent ophthalmological and otological agents used
2836
to treat a variety of diseases. Still, the same fluorinated scaffold
has been established for dermatological treatments, which is
conceivably a factor that contributes to the equal distribution of
both sulfur and fluorine in this category. However, studies have
confirmed the development of many adverse effects of inhaled
corticosteroids or application of fluorinated therapies to the
face, including glaucoma.30,31 Therefore, even though a drug
scaffold may seem to recur throughout history, evidence of
unfavorable side effects reflects the continual need for skeletal
improvement. Although it appears that the distribution of sulfur
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Journal of Medicinal Chemistry
Table 6. Percent Composition of the Top Sulfur-Containing Functional Groups That Comprise Newly FDA Approved Drugs
per Decadea
a
The number on the top of each bar indicates the total number of sulfur functional groups in each category.
and fluorine is comparable in a few categories, the global range
of structure and function of sulfur compounds is far superior.
Elemental sulfur is nontoxic and essential for life. The human
body consists of nearly 0.25% sulfur, which is a crucial
component of many biological processes.32 As a third row
element with the capacity to expand its valence shell to form
more than four covalent bonds and to assume oxidation states
ranging from −2 to +6, sulfur can form a variety of molecular
arrangements, making it one of the most chemically versatile of
the early elements.33 A survey of the structures in our data set
determined that the architectures of sulfur-containing drugs can
be classified into 10 different categories of various permutations
of organosulfur derivatives including sulfonamide, sulfone,
sulfinyl, thioester, thioether, thiophene, thiazole, β-lactam,
thiazepine/thiazine, and thiadiazole, illustrated in Figure 2.34
Drugs consisting of minimally represented structural compo-
nents were characterized according to two additional functional
group classes, miscellaneous acyclic and miscellaneous cyclic.
Not surprisingly, over 10% of all compounds contain more than
one, or more than one type, of the listed functionalities.
Contrarily, fluorine is chemically restricted to bonding
predominantly35,36 with carbon, so the multiplicity of com-
pounds that can be generated is somewhat restricted.
The impact of the development of sulfur therapeutics was
instrumental to the evolution of the pharmaceutical industry.
Undoubtedly, several valuable lessons have been learned from
both the successes and failures of pioneering drugs, as well as
from the paths leading to their production. Table 5 reflects the
recurrence of a specific functional group in the set of sulfur-
containing drugs. Notably, over 25% of compounds contain a
sulfonamide substituent, present nearly 29% of the time. “Sulfa
drugs”, or synthetic substances derived from sulfanilamide (p-
aminobenzenesulfonamide), emerged as effective treatments for
bacterial infections and diabetes through the 1940s.37 In 1932,
Gerhard J. P. Domagk discovered that a prodrug derived from
sulfanilamide, trade-named Protonsil, had antagonistic proper-
2837
Perspective
ties against a wide range of bacteria. It was determined that the
sulfanilamide portion of the molecule was responsible for this
biological effect, acting as a bioisostere of carboxylic acid
groups. Sulfanilamide inhibited the action of the physiological
substance p-aminobenzoic acid (PABA) (required by bacteria
to synthesize folic acid), inspiring the theory for the mechanism
of action of drugs that is based on substance antagonism.38 In
the years following, manufacturers continued to produce
thousands of sulfa drug analogues, eventually leading to the
toxic preparation of “elixir sulfanilamide”, a medical disaster
that poisoned and killed over 100 people with diethylene glycol,
which was the cause of death. This event sparked the passage of
the Federal Food, Drug, and Cosmetic Act, which gave
authority to the FDA to oversee the safety of drugs and
production.39 Since sulfanilamide, more than 150 different
derivatives have appeared on the market, chemically modified
to achieve more effective antibacterial activity, wider spectrum
of microorganisms affected, or more prolonged action.
Sulfonamides also have an extensive biological profile, known
to exhibit antibacterial, hypoglycemic, diuretic, anticarbonic
anhydrase, antithyroid, anti-inflammatory, antihypertensive,
anticonvulsant, and anticancer properties. These compounds
are relatively inexpensive to produce and are still used in many
parts of the world to treat fungal diseases in combination with
other drugs synergistically.38 On the other hand, it is no secret
that several sulfonamide drug combinations or individual drugs
have been said to cause immune mediated allergic reac-
tions.40,41 However, reactions such as hypersensitivity or severe
skin rashes are now associated with the presence of an aniline
structure and have been incorrectly associated with solely
sulfonamide-containing drugs.42,43 In some cases, a person can
be desensitized to these adverse responses using a gradient
dosage.44 Currently, sulfa drugs are receiving renewed interest
for the treatment of infections caused by bacteria resistant to
other antibiotics.45
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Journal of Medicinal Chemistry
Table 7. Percent Composition of the Majority of Sulfur-Containing Functional Groups That Comprise Pharmaceuticals in Each
of the 12 Representative Disease Categoriesa
a
The number above each bar reflects the total number of sulfur-containing drugs in each category (excluding biological drugs).
Penicillins (penams), cephalosporins (cephems), and mono-
bactams constitute the broad class of β-lactam antibiotics, the
second most prevalent sulfur scaffold (10.5% representation).
In 1929, Alexander Fleming first isolated penicillin from the
fungal strain when he observed that bacterial cultures of
Staphylococcus in his laboratory were killed by a mold
contaminant, Penicillium notatum. The discovery of penicillin
was a breakthrough in modern medicinal chemistry, leading to
efficient mass production ($0.55/dose in 1946). In 1944, the
determination of penicillin’s crystal structure, the β-lactam ring
fused to a five-membered thiazolidine ring, by Dorothy
Hodgkin paved the way for the development of enhanced
antibiotics through structural modification.46−48 Today, amox-
icillin is still one of the most widely prescribed β-lactam
antibiotics since it initially entered the market in 1972. Twenty
years later, it was developed into a thriving combination drug
treatment for drug-resistant bacteria including clavulanic acid,
trade-named Augmentin (approved 1996). Furthermore,
cephalosporin analogues containing a β-lactam ring fused to a
six-membered dihydrothiazine ring exhibit more potent
antibacterial properties. Since the medicinal launch of cefalotin
in 1964, six generations of these agents have been synthesized
for clinical use.49 Monobactams, like aztreonam (Azactam,
approved 1986), are often used in the treatment of
meningitis.50
Thiazoles and thioethers are equally represented (both 8.8%)
as the third most exemplified constituent. Commercially
significant thiazoles include many nonsteroidal anti-inflamma-
tory drugs (NSAIDs) like the widely prescribed Mobic
(meloxicam) and are known to exhibit chemotherapeutic
effects.51 Pharmacologically, thioethers are linked to sulfinyls
and sulfones by their redox interconversion and exhibit
extensive biological activities.52
Several underrepresented sulfur-containing moieties have
emerged as promising structural components that can be
2838
Perspective
integrated into drugs that have yet to be marketed. In
particular, the incorporation of the sulfonamide RSO2NHR′
is a strategic approach to designing compounds with limited
CNS penetration.45 Recently, isothioureas and related com-
pounds have been found to be inhibitors of the aspartyl
protease β-secretase, which is known to play a role in
Alzheimer’s disease.53 The chemically stable sulfoximine
functionality retains many favorable medicinal properties but
has been significantly overlooked as a feature of potential
clinical candidates.54 In addition, the strongly electron-with-
drawing and chemically inert pentafluorosulfanyl (SF5)
substituent possesses a greater lipophilicity than CF3 and is
metabolically stable.36,37,55,56 Further investigation of such
minimally explored discoveries in sulfur (or fluorine) chemistry
can only enhance drug design and development.
From a historical perspective, sulfonamides have been a
leading constituent in new drugs since the first appearance in
the 1930s, occupying six different decades over the past 100
years (Table 6). Introduced in 1959, hydrochlorothiazide, a
sulfonamide-based diuretic is a component of nearly 7% of all
small-molecule and combination drugs, has been derivatized
into several multifunctional analogs, and remains a successful
additive used today.57 Interestingly, the prominence of β-
lactams has declined, while pharmaceuticals containing
thiazoles are resurfacing since the 1940s and 1950s. Over the
past 30 years, thioethers and thiophenes have also emerged as
key functional group substituents.
Evidently, the inclusion of sulfur into new drugs became
increasingly popular prior to the 2000s. During the 1990s,
sulfur-containing drugs for the treatment of half of the disease
categories (Dermatological, Endocrine System, Genitourinary
and Sex Hormones, Nervous System, Respiratory System, and
Sensory Organ) reached an all-time high. Similarly, sulfur-
containing drugs in the Anti-Infectives and Cardiovascular
categories peaked in the 1980s. On the other hand, the
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Journal of Medicinal Chemistry
Figure 3. (A) Representative sulfur pharmaceuticals introduced during each decade over the past century. (B) Evolution of sulfur and fluorine
pharmaceuticals. (C) Past and present sulfur−fluorine overlap.
frequency of compounds in the Alimentary Tract and
Metabolism category and the Blood and Blood Forming
Organ category was greatest in the 2000s. Additionally, sulfur
incorporation into products of the Musculoskeletal and
Oncological category is becoming more common in recent
years.
The overall frequency of sulfur substituent and representa-
tion within each disease category is fairly synchronous.
Predictably, sulfonamides are a primary structural feature
incorporated into 11/12 disease categories, with the only
exception being the Respiratory System (Table 7). They also
dominate half of them, in particular, Cardiovascular (75.4%),
Sensory Organ (41.7%), Blood and Blood Forming Organ
(35.3%), Musculoskeletal (34.8%), Alimentary Tract and
Metabolism (31.0%), and Endocrine System (28.6%) drugs.
Overall, thiophenes are the second most versatile architectural
constituent (8/12 categories), although they are lower in
occurrence as opposed to thiazoles and thioethers, represented
in 5/12 and 4/12 categories, respectively. Thiazepines/
2839
Perspective
thiazines follow accordingly in quantity and functional
capability, most prevalently in Nervous System (31.7%) and
Respiratory System (20.0%) compounds. Although the β-
lactam is the second most represented moiety in the total
number of sulfur-containing pharmaceuticals, it seems that they
are most functionally useful as Anti-Infectives and Respiratory
System drugs. Sulfinyl groups are significant in Alimentary
Tract and Metabolism (21.4%) and Musculoskeletal (17.4%)
drugs, including many that are also Top200 drugs. Thiadiazoles
are most common in Sensory Organ (16.7%) drugs; however,
they maintain a widespread biological activity profile.58,59 The
sulfone is an underrepresented functional group, but a
therapeutic example exists in 50% of disease categories. The
least exemplified functionality, the thioester, is present in the
many analogues of fluticasone, a potent Respiratory System
drug. In particular, thioesters are inherently reactive as acylating
agents and are potential metabolites of carboxylic acids in vivo
which can be converted to acyl-coenzyme A esters.60
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Journal of Medicinal Chemistry
Acyclic and cyclic sulfur constituents describe 17.3% of
pharmaceuticals. Particularly, sulfonic acid derivatives, for
example, the heparin analogues,61 are in highest frequency
within the miscellaneous-acyclic group, primarily existing as a
constituent in drugs within 10/12 disease categories (excluding
Nervous System and Dermatological drugs). In the late 1990s,
thiazolidinediones, the most represented of the miscellaneous-
cyclic group, were introduced into drugs as components of
antidiabetic agents for Alimentary Tract and Metabolism and
Endocrine System treatments.62,63
The beauty of organic structural imagery often probes
curiosity. Upon visual inspection of our extensive data set, it is
no surprise that many functionally and architecturally
captivating pharmaceutical agents incorporate a form of sulfur
(Figure 3A). For example, thiopental, a general anesthetic drug,
is nearly 80 years old and still in use. In fact, a quick
investigation of this compound (using supplementary sources)
reveals that it holds a place on The World Health
Organization’s “Lists of Essential Medicines”, a list of the
basic medical requirements to establish a fundamental health-
care system.64 It is intriguing that a small sulfinyl compound
like dimethyl sulfoxide (DMSO) (Rimso-50, approved 1978)
has an extensive medicinal utility scope still in use.65
Interestingly, a rare gold thiolate complex trade-named Ridaura
(auranofin) initially entered the market in 1986 to treat
rheumatoid arthritis.66 The dermatological Altabax (retapamu-
lin, approved 2007) was the first drug of a new class of modern
antibiotics to be approved for human use since the discovery of
its parent-compound pleuromutilin in 1950.67 Recently, Teflaro
(ceftaroline, approved 2010), an advanced generation cepha-
losporin prodrug incorporating several forms of sulfur
(isothiazole, β-lactam, thioether, and thiazole in conjunction
with a phosphamic acid, oxime, and a pyridine ring), was
approved for the treatment of pneumonia and bacterial skin
infections.68,69
The posters also enable any viewer to observe the evolution
of structure and function of drugs over time. For example,
antipsychotic treatments of schizophrenia have evolved from
promazine,70 consisting of a thiazine adduct, into the inclusion
of a more complex isothiazole containing motif, Latuda
(lurasidone).71 Similarly, the previously popular volatile
anesthetic haloethane has since been replaced by the highly
fluorinated Ultane (sevoflurane) (Figure 3B).72
In 1959, two pyscholeptic Nervous System compounds,
fluphenazine and trifluoperazine, were the first approved drugs
to incorporate both a form of sulfur and fluorine within their
molecular skeletons. Presently, the sulfur−fluorine overlap has
expanded to 36 small-molecule and combination pharmaceut-
icals spanning 10 disease categories (apart from Sensory Organ
category and Genitourinary and Sex Hormones category). With
the exception of the miscellaneous-acyclic and thiadiazole
compounds, all forms of sulfur are represented in conjunction
with fluorinated motifs. Although no discernible patterns reveal
functional group compatibility trends between sulfur and
fluorine motifs, trifluorinated aromatics exist in the highest
frequency in combination with the majority of sulfur moieties.
In 2012, Xtandi (enzalutamide) was FDA approved for the
treatment of castration-resistant prostate cancer, capitalizing on
the dual functionality of sulfur (thioamide) and fluorine
(fluorinated aromatic) for its biological efficacy (Figure 3C).73
Considering the overall functional competence of drugs,
there is no doubt that sulfur will continue to be a leading
constituent of novel pharmaceuticals. From a synthetic
2840
Perspective
chemistry perspective, the number of unearthed opportunities
to develop new methodologies using this medicinal anthology
as inspiration is both advantageous and imminent. In the future,
we aim to continue to evolve new transformations using sulfur
as the central element.6,74 Currently, a new sulfur-themed
pharmaceutical poster has been added to our collection and is
available on the Internet.7
In conclusion, we presented a concise analysis of the
presence of sulfur and fluorine within an extensive set of
marketed drugs (1969, total) spanning 100+ years of our
medicinal history. The statistics regarding the percent
composition and functional group representation of both
elements in reference to decade and disease category reflect just
one demonstration of the magnitude of correlations, whether
positive or negative, that can be derived from this data set. The
emphasis on minimalism as a part of our graphical design
philosophy significantly contributed to the overall ease of our
statistical assembly. It is notable that people of different
educational backgrounds can effortlessly perform this data-
mining technique to varying degrees, appealing to the scholastic
desires of both the general public and the expert. The
information contained within this poster collection can also
incite supplementary exploration using alternative sources.
Future investigations will inevitably expose new avenues for the
advancement of life sciences including combinatorial chemistry
and drug design.
■
*
ASSOCIATED CONTENT
S Supporting Information
Tables listing the initial market name, INN, function, rank, and
sulfur and fluorine functional group presence for the Top200
drugs by U.S. Retail Sales and Total Prescriptions in 2011;
tables listing the initial market name, FDA approval year,
subclass of function, and sulfur and fluorine functional group
type for 1969 pharmaceuticals (FDA approved from the 1900
through 2012) in 12 disease categories, where drugs are
categorized according to (1) small-molecule, combination, and
biological drugs, (2) sulfur and fluorine functional group
presence, and (3) sulfur functional group by decade and by
disease category. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
AUTHOR INFORMATION
Corresponding Author
*Phone: 607-227-9347. E-mail: njardars@email.arizona.edu.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
Biographies
Elizabeth A. Ilardi received a B.S. in Chemistry at The College of
William and Mary, VA, and a Ph.D. in Organic Chemistry under the
supervision of Dr. Armen Zakarian at University of California, Santa
Barbara. Inspired by her passion for science, she chose to continue
postdoctoral research in Organic Synthesis at The University of
Arizona.
Edon Vitaku completed a B.S. in Chemistry at Idaho State University
in 2010. He is currently a Ph.D. candidate at the University of Arizona.
The focus of his research studies includes the development of novel
dx.doi.org/10.1021/jm401375q | J. Med. Chem. 2014, 57, 2832−2842
Journal of Medicinal Chemistry
oxidative dearomatization strategies to be applied towards the
synthesis of natural products.
Jon T. Njardarson received his Ph.D. at Yale University, CT, in 2001
with Professor John L. Wood. Following postdoctoral training with
Professor Samuel J. Danishefsky at The Memorial Sloan-Kettering
Cancer Center, NY, he started his independent career in 2004 at
Cornell University, NY. In 2010, Professor Njardarson moved his
research group to The University of Arizona.
■
ACKNOWLEDGMENTS
We thank the National Science Foundation (NSF Grant
CHE1266365) for research support.
■
ABBREVIATIONS USED
AIDS, acquired immune deficiency syndrome; CNS, central
nervous system; DMSO, dimethyl sulfoxide; DNA, deoxy-
ribonucleic acid; FDA, Food and Drug Administration; INN,
international nonproprietary name; PABA, p-aminobenzoic
acid; RNA, ribonucleic acid
■
REFERENCES
(1) Knox, C.; Law, V.; Jewison, T.; Liu, P.; Ly, S.; Frolkis, A.; Pon, A.;
Banco, K.; Mak, C.; Neveu, V.; Djoumbou, Y.; Eisner, R.; Guo, A. C.;
Wishart, D. S. DrugBank 3.0: A Comprehensive Resource for “Omics”
Research on Drugs. Nucleic Acids Res. 2011, 39, D1035−D1041.
(2) Thomson Reuters Integrity. http://integrity.prous.com (2013).
(3) About GOSTAR. http://gostardb.com/gostar/doc/
HyperlinkDownloadPDF.pdf (accessed August 2013).
(4) Ranjan, J. Data Mining in Pharma Sector: Benefits. Int. J. Health
Care Qual. Assur. 2009, 22, 82−92.
(5) For a recent example of mining a drug database, see the
following: Giordanetto, F.; Kihlberg, J. Macrocyclic Drugs and Clinical
Candidates: What Can Medicinal Chemists Learn from Their
Properties?. J. Med. Chem. [Online early access]. DOI: 10.1021/
jm400887j. Published Online: Aug 28, 2013.
(6) For a representative example, see the following: Rogers, E.; Araki,
H.; Batory, L. A.; McInnis, C. E.; Njardarson, J. T. Highly Selective
Copper-Catalyzed Ring Expansion of Vinyl Thiiranes: Application to
Synthesis of Biotin and the Heterocyclic Core of Plavix. J. Am. Chem.
Soc. 2007, 129, 2768−2769.
(7) Our Top200 drug posters and disease focused pharmaceutical
posters (including two additional themes: fluorinated pharmaceuticals
and sulfur-containing pharmaceuticals) can be found at the Njardarson
research group Web site: http://www.cbc.arizona.edu/njardarson/
group/.
(8) Ilardi, E. A.; Vitaku, E.; Njardarson, J. T. An In-Pharm-Ative
Educational Poster Anthology Highlighting the Therapeutic Agents
That Chronicle Our Medicinal History. J. Chem. Educ. 2013, 90,
1403−1405.
(9) The data presented in our Disease Focused Pharmaceutical
Posters were collected and confirmed using several sources; see
Supporting Information.
(10) Drug Information Online. http://www.drugs.com/ (accessed
November 2011).
(11) CenterWatch: FDA Approved Drugs. http://centerwatch.com/
drug-information/ (2013).
(12) Approved Drug Products with Therapeutic Evaluations (Orange
Book), 33rd, ed.; U.S. Department of Health and Human Services, U.S.
Food and Drug Administration: Rockville, MD, 2013.
(13) Acton, A. Q., Ed. Sulfur Compounds: Advances in Research and
Application; ScholarlyEditions: Atlanta, GA, 2012.
(14) Emsley, J. Nature’s Building Blocks: An A−Z Guide to the
Elements; Oxford University Press: Oxford, U.K., 2011.
(15) For information regarding the historical medicinal uses of sulfur,
see the following: Rapp, , G. R. Archaeo-Mineralology; Springer-Verlag:
Berlin, Germany, 2009,.
2841
Perspective
(16) Data reflecting the top 200 rankings was collected from http://
www.pharmacytimes.com/publications/issue/2012/July2012/Top-
200-Drugs-of-2011 (2012).
(17) Filler, R.; Saha, R. Fluorine in Medicinal Chemistry: A Century
of Progress and a 60-Year Retrospective of Selected Highlights. Future
Med. Chem. 2009, 1, 771−791.
(18) For information on the use of biological drugs in the
pharmaceutical industry, see the following: Evens, R. P, Ed. Drug
and Biological Development: From Molecule to Product and Beyond;
Springer Science + Business Media, LLC: New York, NY, 2007.
(19) Greenstein, B.; Brook, D. A. Biological Therapeutics;
Pharmaceutical Press: London, U.K., 2011.
(20) For a recent review of sulfur-containing amino acids in
pharmacology, see the following: Cordomi, A.; Gómez-Tamayo, J.
−C.; Gigoux, V.; Fourmy, D. Sulfur-Containing Amino Acids in
7TMRs: Molecular Gears for Pharmacology and Function. Trends
Pharmacol. Sci. 2013, 34, 320−331.
(21) Müller, K.; Faeh, C.; Diederich, F. Fluorine in Pharmaceuticals:
Looking Beyond Intuition. Science 2007, 317, 1881−1886.
(22) Kirk, K. L. Fluorine in Medicinal Chemistry: Recent
Therapeutic Applications of Fluorinated Small Molecules. J. Fluorine
Chem. 2006, 127, 1013−1039.
(23) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Fluorine in
Medicinal Chemistry. Chem. Soc. Rev. 2008, 37, 320−330.
(24) (a) Hagmann, W. L. The Many Roles for Fluorine in Medicinal
Chemistry. J. Med. Chem. 2008, 51, 4359−4369. (b) Ramachandran, P.
V. Welcome to “Fluorine in Medicinal Chemistry”. Future Med. Chem.
2009, 1, 771−772.
(25) O’Hagan, D. Fluorine in Health Care: Organofluorine
Containing Blockbuster Drugs. J. Fluorine Chem. 2010, 131, 1071−
1081.
(26) Ojima, I., Ed. Fluorine in Medicinal Chemistry and Chemical
Biology; John Wiley & Sons: Chichester, U.K., 2009.
(27) Böhm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.;
Müller, K.; Obst-Sander, U.; Stahl, M. Fluorine in Medicinal
Chemistry. ChemBioChem 2004, 5, 637−643.
(28) For information regarding structure and function of fluorine in
pharmaceuticals, see the following: Bégué, P., Bonnet-Delpon, D., Eds.
Bioorganic and Medicinal Chemistry of Fluorine; John Wiley & Sons,
Inc.: Hoboken, NJ, 2008.
(29) For information about newly developed fluorinated derivatives,
see the following: Manteau, B.; Pazenok, S.; Vors, J.-P.; Leroux, F. R.
New Trends in Chemistry of alpha-Fluorinated Ethers, Thioethers,
Amines and Phosphines. J. Fluorine Chem. 2010, 131, 140−158.
(30) Representative examples of adverse affects of fluorinated
steroids and corticosteroids: Burry, J. N. Topical Drug Addiction,
Adverse Effects of Fluorinated Corticosteroid Creams and Ointments.
Med. J. Aust. 1973, 1, 393−396.
(31) Kligman, A. M.; Leyden, J. J. Adverse Effects of Fluorinated
Steroids Applied to the Face. JAMA, J. Am. Med. Assoc. 1974, 60−62.
(32) Spina, D. Drugs for the Treatment of Pulmonary Diseases. In
Biological Interactions of Sulfur Compounds; Mitchell, S., Ed.; Cam-
bridge University Press: Cambridge, U.K., 2003.
(33) Oae, S.; Okuyama, T., Eds. Organic Sulfur Chemistry: Biochemical
Aspects; CRC Press, Inc.: Boca Raton, FL, 1992.
(34) Cremlyn, R. J., Ed. An Introduction to Organosulfur Chemistry;
John Wiley & Sons: Chichester, U.K., 1996.
(35) The SF5 moiety is beginning to attract the attention of
medicinal chemists. The σ/π plot was first published in the following:
Craig, P. N. Interdependence between Physical Parameters and
Selection of Substituent Groups for Correlation Studies. J. Med. Chem.
1971, 14, 680−684.
(36) For a recent review of the SF5 moiety that includes applications
in drug design, see the following: Altomonte, S.; Zanda, M. Synthetic
Chemistry and Biological Activity of Pentafluorosulphanyl (SF5)
Organic Molecules. J. Fluorine Chem. 2012, 143, 57−93.
(37) Gaudillière, J.-P. The First Miracle Drugs: How the Sulfa Drugs
Transformed Medicine (Review). Bull. Hist. Med. 2009, 83, 218−220.
dx.doi.org/10.1021/jm401375q | J. Med. Chem. 2014, 57, 2832−2842
Journal of Medicinal Chemistry Perspective

(38) Anderson, R.; Groundwater, P.; Todd, A.; Worsley, A. J. (61) Golan, D. E., Tashjian, A. H., Armstron, E. J., Armstron, A. W.,
Antibacterial Agents: Chemistry, Mode of Action, Mechanisms of Eds. Principles of Pharmacology: The Pathophysiologic Basis of Drug
Resistance, and Clinical Applications; John Wiley & Sons, Ltd.: Therapy, 3rd ed.; Lippincott Williams & Wilkins, a Wolters Kluwer
Chichester, U.K., 2012. Business: Philadelphia, PA, 2012.
(39) U.S. Food and Drug Administration. Sulfanilamide Disaster. (62) Jain, A. K.; Vaidya, A.; Ravichandran, V.; Kashaw, S. K.; Agrawal,
http://www.fda.gov/AboutFDA/WhatWeDo/History/ R.-K. Recent Developments and Biological Activities of Thiazolidinone
ProductRegulation/SulfanilamideDisaster/ (accessed March 2013). Derivatives: A Review. Bioorg. Med. Chem. 2012, 20, 3378−3395.
(40) Rogers, K., Ed. Medicine and Healers through History; Britannica (63) Levine, R. R., Walsh, C. T., Shwartz-Bloom, R. D., Eds.
Educational Publishing: New York, NY, 2011. Pharmacology Drug Actions and Reactions, 6th ed.; Parthenon
(41) Rudy, E. Sulfa Allergy”Distinguishing between Sulfonamide Publishing Group: New York, NY, 2000.
and Sulfite Sensitivities. Drug Ther. Top. 2004, 33, 21−26. (64) For the most recent World Health Organization Lists of
(42) Smith, D. A.; Jones, R. M. The Sulfonamide Group as a Essential Medicines, see the following: http://www.who.int/
Structural Alert: A Distorted Story? Curr. Opin. Drug Discovery Dev. medicines/publications/essentialmedicines/en/ (2013).
2008, 11, 72−79. (65) Walker, M., Ed. DMSO Nature’s Healer; Avery: New York, NY,
(43) For more information, see the following: Knowles, S.; Shapiro, 1993.
L. E.; Shear, N. H. Reactive Metabolites and Adverse Drug Reactions. (66) Jones, C. J.; Thornback, J. R. Medicinal Applications of
Clin. Rev. Allergy Immunol. 2001, 24, 239−247. Coordination Chemistry; The Royal Society of Chemistry: Cambridge,
(44) Shoaib, S.; Shah, A.; Rivera, G.; Ashfaq, M. Recent Advances in U.K., 2007.
Medicinal Chemistry of Sulfonamides. Rational Design as Anti- (67) Jones, R. N.; Fritsche, T. R.; Sader, H. S.; Ross, J. E. Activity of
Retapamulin (SB-275833), a Novel Pleuromutilin, against Selected
Tumoral, Anti-Bacterial and Anti-Inflammatory Agents. Mini-Rev. Med.
Resistant Gram-Positive Cocci. Antimicrob. Agents Chemother. 2006,
Chem. 2013, 13, 70−86.
50, 2583−2586.
(45) For mechanistic studies of sulfa drugs, see the following: Haruki,
(68) The phosphamic acid substituent of ceftaroline was designed to
H.; Pedersen, M. G.; Gorsko, K. I.; Pojer, F.; Johnsson, K.
be removed in vivo.
Tetrahydrobiopterin Biosynthesis as an Off-Target of Sulfa Drugs. (69) Kollef, M. H. New Antimicrobial Agents for Methicillin-
Science 2013, 340, 987−991. Resistant Staphyloccoccus aureus. Crit. Care Resusc. 2009, 11, 282−286.
(46) The medicinal history of β-lactam antibiotics has been (70) Promazine is no longer approved for human use in the United
extensively reviewed. Hunter, P. A.; Darby, G. K.; Russell, N. J. Fifty States.
Years of Antimicrobials: Past Perspective and Future Trends; Press (71) For information regarding lurasidone, see the following: Caccia,
Syndicate of the University of Cambridge: New York, NY, 1995. S.; Pasina, L.; Nobili, A. Critical Appraisal of Lurasidone in the
(47) Tames, R. Penicillin: A Breakthrough in Medicine; Heinemann Management of Schizophrenia. Neuropsychiatr. Dis. Treat. 2012, 8,
Library: Chicago, IL, 2006. 155−168.
(48) Beta-Lactam Antibiotics: Penicillin, Ampicillin, Beta-Lactamase, (72) Smith, I.; Nathanson, M.; White, P. F. SevofluraneA Long-
Amoxicillin, Beta-Lactam Antibiotic, History of Penicillin, Flucloxacillin; Awaited Volatile Anaesthetic. Br. J. Anaesth. 1996, 76, 435−445.
General Books LLC, 2010. (73) For medical information regarding Xtandi, see http://xtandihcp.
(49) Greenwood, D., Finch, R., Davey, P., Wilcox, M., Eds. com/ (accessed Jun 2013).
Antimicrobial Chemotherapy, 5th ed.; Oxford University Press, Inc.: (74) For an example of our recent endeavors in sulfur chemistry, see
New York, NY, 2007. the following: Li, F.; Calabrese, D.; Brichacek, M.; Lin, I.; Njardarson,
(50) Duma, R. J. Aztreonam, the First Monobactam. Ann. Intern. J. T. Efficient Synthesis of Thiopyrans Using Sulfur-Enabled Anionic
Med. 1987, 106, 766−767. Cascade. Angew. Chem., Int. Ed. 2012, 51, 1938−1941.
(51) Loughlin, K. R., Generali, J., Eds. Prescription Drugs: Alternative
Uses, Alternative Cures: Over 1,500 New Uses for FDA-Approved Drugs;
The Philip Leif Group, Inc.: New York, NY, 2006.
(52) Damani, L. A., Ed. Sulphur Containing Drugs and Related Organic
Compounds; Ellis Horwood Limited: Chichester, U.K., 1989.
(53) For a recent example, see the following: Stamford, A.;
Strickland, C. Inhibitors of BACE for Treating Alzheimer’s Disease:
A Fragment-Based Drug Discovery Story. Curr. Opin. Chem. Biol.
2013, 17, 320−328.
(54) Lücking, U. Sulfoximines: A Neglected Opportunity in
Medicinal Chemistry. Angew. Chem., Int. Ed. 2013, 52, 9399−9408.
(55) Welch, J. T.; Lim, D. S. The Synthesis and Biological Activity of
Pentafluorosulfanyl Analogs of Fluoxetine, Fenfluramine, And
Norfenfluramine. Bioorg. Med. Chem. 2007, 15, 6659−6666.
(56) Wipf, P.; Mo, T.; Geib, S. J.; Caridha, D.; Dow, G. S.; Gerena,
L.; Roncal, N.; Milner, E. E. Synthesis and Biological Evaluation of the
First Pentafluorosulfanyl Analogs of Mefloquine. Org. Biomol. Chem.
2009, 7, 4163−4165.
(57) Acton, A. Q. Advances in Chlorothiazide Research and
Application; ScholarlyEditions: Atlanta, GA, 2012.
(58) Siddiqui, N.; Ahuja, P.; Ahsan, W.; Pandeya, S. N.; Alam, M. S.
Thiadiazoles: Progress Report on Biological Activities. J. Chem. Pharm.
Res. 2009, 1, 19−30.
(59) Li, Y.; Geng, J.; Liu, Y.; Yu, S.; Zhao, G. ThiadiazoleA
Promising Structure in Medicinal Chemistry. ChemMedChem 2013, 8,
27−41.
(60) Grillo, M. P. Drug-S-acyl-glutathione Thioesters: Synthesis,
Bioanalytical Properties, Chemical Reactivity, Biological Formation
and Degradation. Curr. Drug Metab. 2011, 12, 229−224.

2842 dx.doi.org/10.1021/jm401375q | J. Med. Chem. 2014, 57, 2832−2842