Boron as an element has occupied a prominent position in drug discovery and development

because of its distinctive characteristics such as:

 Vacant p orbital
 Nuclear fission induced by neutros.
 A tendency to form bondes with various biological targets.
 Metallomimetic proprieties
 Effective isostere
 Non-toxicity
Another important charactetistic is that we can produce less complex molecules that could
be easily produced in pharmaceutical industries at a lower cost than their carbon
counterparts.Currently there is a need to develop a new chemotheraupetic agents with
novel model of actions and boron-based heterocycles are exciting new compounds to
combat both the existing and new diseases.
Why is organoboron chemistry importante?
Because it can help us optimizising new synthehtic pathways and envolve new paradigs
for the development of potent therapeotuic agents.
 Bortexomib
 Tavaborole
 Crisaborole

Chemistry behind the organic boron chemistry.

Specially five and six membered heterocycles.
 Diazoborines: anti-bacteria potential
 Benxoxaboroles: anti-protozoal potential, malaria
 Oxadiazaboroles
 Oxazaborilidines
 Azabırines
Boron-based drugs demonstrate potent bioactivity with various molecular mechanisms.
Bortezomib and ixazomib are used to treat multiple myeloma and mantle cell lymphoma.
Brief biomedical information
They reversibly inhibit the 26S proteasome in mammalian cellsThe major function of
26S proteasome is to degrade ubiquitinated proteins and therefore maintain homeostasis
Bortezomib bind to β5 subunit while ixazomib bind to the 20 s catalytic subunit of the
chymotrysptin site of 26S proteasome in the cancer cell and inhibits the
targeted proteolysis thereby deregulating normal homeostatic mechanisms eventually leading
to cell death
vaborbactam and taniborbactam are used in combination with β-lactam antibiotics to
treat gram-negative infection They do not exhibit antibiotic activity on their own but they
help in potentiating the activity of β-lactam antibiotics .
.

The boron atom forms a reversible dative bond with the serine residue of the β-
lactamase enzyme thereby competitively inhibiting serine β-lactamases. This ultimately
prevents the hydrolysis of the β-lactam ring by β-lactamases consequently restoring the
activity of β-lactam antibiotics

Tavaborole is an antifungal drug approved for the treatment of onychomycosis and

other nail infections
Tavaborole inhibits protein synthesis by forming a covalent bond with LeuRS thereby
forming a covalent adduct with Ade 76 at the 3′ end of tRNA to the LeuRS editing site
ultimately blocking the catalytic turnover of leucine
Crisaborole is approved for the treatment of atopic dermatitis27. Although the exact
mechanism of action is not well defined, it belongs to the class of phosphodiesterase 4 (PDE-
4) inhibitors.

As a result, the levels of intracellular cyclic adenosine monophosphate (cAMP) are increased
which in turn downregulates inflammatory mediators (IL-4 and IL-13), tumor necrosis factor-
alpha (TNFα), and pro-inflammatory cytokines which are responsible for inflammation

2. Diazaborines
Over the past few decades, boron-nitrogen heterocycles
have surfaced as crucial scaffolds in drug discovery and
development. They are not only exhibit
remarkable pharmacokinetics but also demonstrate potent
extensive biological activities.

 Among all the boron-based compounds, the

therapeutic potential of diazaborines was studied
first They were primarily evaluated fortheir anti-
microbial potential, as many researchers
compared their internal hydrazone group to
the hydrazone of nitrofurantoin. Since then,
several scientists have been successfully exploring
this motif and investigating its Structure-Activity
relationship (SAR) and mode of action.

2.1. Antibacterial activity

 Grassberger and his co-workers prepared several fused five and six-membered
diazaborines and compared their SAR. They found that thieno fused diazaborines (1)
exhibited the most potent antibacterial activity.
  followed by benzo

 and then furan fused diazaborines

 literature demonstrated that the sulfonyl side chain

and boron atom were essential for this activity in N-
sulfonyl diazaborines and that these compounds
inhibit fatty acid synthesis by binding to
Enoyl reductase.

 2-Tosyl-benzodiazaborine (4) was found to be active

against Escherichia coli and Klebsiella pneumonia exhibiting MIC
values of 25 µg/mL and 3.1 µg/mL, respectively (Figure 6). In 1998,
de Boer et al. carried out crystallographic studies of diazaborines
and demonstrated that they bind competitively in the same site as
anticipated during catalysis
Kanichar et al. presented a series of diazaborine derivatives and screened
them for antibacterial activity against E. coli and Mycobacterium smegmatis
and found that nine compounds exhibited antibacterial activity with MICs of 2 to 16 µg/mL
against E. coli
two compounds (6 and 7, Figure 6) were found to be active against M. smegmatis with MICs
of 2 and 4 µg/mL, respectively61.
Jordan et al. pointed out that several diazaborine warheads retained their antibacterial activity
when the sulfonyl group was replaced by an amide or thioamide group62. Moreover, two
benzodiazaborine compounds (6 and 7) were found to have better activity than the sulfonyl
compound with a MIC of 16 µg/mL (E. coli), proving that acyl group can replace the
sulfonyl group in diazaborine heterocycles

In addition, compounds (8 and 9) were found to demonstrate moderate activity against E.

coli. Compound (8) exhibited promising activity against M. smegmatis with a MIC value of
4 µg/ mL.

 Scott et al. synthesized and characterized two

new thiosemicarbazones and three new benzodiazaborines
and tested them against the bacteria Bacillus
cereus and Pseudomonas aeruginosa and the
fungi Aspergillus niger and Saccharomyces cerevisiae.
 Among the prepared diazaborines, promising
activity was noticed for a few compounds
against Saccharomyces cerevisiae which
suggested the promise for the development of
new sulfur-based diazaborines antifungal agents.
Compound 13 displayed an IC50 value of 2.7 μM
against HNE and was non-toxic to control human
cell lines (CC50 greater than 100 against HEK
293 T)
  Serine protease inhibition is an important approach for the development of new anti-
inflammatory agents and Human Neutrophil elastase (HNE) has emerged as a
promising target for anti-inflammatory agents
 Antonia et al. synthesized a set of new diazaborine compounds in excellent yields in a
solitary step without requiring column purification and tested them against HNE

 Davis et al. identified two diazaborine based compounds (15 and 16) exhibiting
meaningful anti-TB activity among the prepared compounds against M.
tuberculosis strain H37Rv with a MIC of 8 µg/mL. The prime
candidates 17 (AN12855) and 18 (AN12541), displayed potent bactericidal activity .

 Pertschy et al. obtained unanticipated results when they tested diazaborine on yeast.
They found that diazaborine (4, Figure 8) demonstrated antifungal activity by
inhibiting the production of 27 s pre-rRNA thereby diminishing 60S subunits in the
cytoplasm and altering the distribution of fluorescent proteins towards the margin of
the nucleus.

Oxadiazaboroles
  contain a five-member ring with oxygen, boron, and two atoms of nitrogen.
 They symbolize a novel class of boron-containing compounds that are exceedingly
stable and water-soluble that researchers have been fruitfully exploring in the
development of new therapeutics.

Better results were obtained for disubstituted oxadiazaboroles than the other set of
compounds. Compounds (23, 24, and 25) were found to be active against C. albicans with
MICs between 0.08 and 0.75 µM, respectively.
compound (26) was found to have significant activity against Staphylococcus aureus with a
MIC of 0.06 µM
Employing the 2D statistical method, the correlation of pMIC (−log MIC) values of all the
compounds against the theoretical descriptors (lowest unoccupied molecular orbital;
ELUMO) and magnitude of the dipolar moment; µ) and σ (Hammett polar substituent
constant) gave two statistically significant 2D-QSAR models against Staphylococcus
aureus and C. albicans.

4. Oxazaborolidines
Publications indicate that oxazaborolidines, a novel class of boron-based heterocycles, exhibit
antibacterial activity. The first biological report on oxazaborolidines was by Jabbour et al. in
2004. They straightforwardly prepared the desired compounds by reacting ephedrine-
pseudo ephedrine with a boronic acid. These heterocycles were tested for antimicrobial
activity against Streptococcus mutans. All of the tested compounds displayed promising
antibacterial activity with MICs in the range of 0.53 to 6.75 µM. The prime compounds
(30 and 31).
5. Oxazoborolidine-ones
Although oxazoborolidine-ones are being used as catalysts for transforming various reactions,
medicinal chemists have recently studied their medicinal properties. A review of published
data indicates that many of these demonstrate anticancer activity against various cell lines.

A straightforward and high-yielding method for the preparation of

new diphenyl oxazoborolidine-ones was presented by Bejarano et al. by reacting substituted
alpha-amino acids and diphenyl boronic acids under alkaline pH.
A new method for the preparation of novel boroxazolidones and ketimines was reported by
Raunio et al. by reacting parent boroxazolidone with aromatic aldehydes in the presence of
Triazabicyclodecene (TBD). The desired compounds were screened for their cytotoxic
potential
6. Azaborines
 Azaborines are boron-based nitrogen heterocycles wherein the carbon–carbon doubled
bond is replaced by a B-N bond. Azaborines have gained a tremendous amount of
interest among the scientific fraternity because of B-N isosterism applications,
excellent pharmacokinetic profiles, and potent bioactivities
 nonsteroidal aminoboranes, by replacing C=C bond with B-N bond and investigated
their stability, estrogen receptor (ER) activity, and SAR. Compounds (40, 41, and 42)
were found to be potent estrogen receptor alpha (ERα) binding candidates with high
hydrolytic stability and efficacy.
  Similarly, Rombuts et al. unveiled new boron-based benzazaborinines by biosteric
replacement of naphthalene motif. The in vitro and in vivo profiles of these propanalol
analogues were comprehensively studied

 they were found to have remarkable bioavailability, Blood-brain barrier penetration

and non-toxic after subcutaneous administration in rats. This study solidifies the
importance of bioisosterism in drug discovery and development86.

 With the rise in resistant bacterial infections developing new antibiotics is the need of
the hour. In this context, Hanley et al. reported on CD437 analogs with promising
antibacterial activity but low aqueous solubility. To overcome this problem, they
synthesized new reteniod isosteres by using BN/CC isosterism.

7. Oxazaborines
 Oxazaborines are boron-based heterocycles typically consisting of six-membered
central aromatic ring bearing oxygen, nitrogen, and a boron atom. They are proving to
be a crucial motif in the design and development of novel NLRP3 inflammasome
inhibitors91. The current NLRP3 inflammasome inhibitors are expensive and non-
specific. This makes it ideal to develop cost-effective NLRP3
inflammasome inhibitors, which can directly target NLRP-IL1 pathway.
 SAR suggested that incorporation of steric and lipophilic substituents on the phenyl
rings weakened the biological activity while substitution of 4-F groups retained
 NLRP3 inhibitory activity, and any substitution on phenyl ring did not enhance the
activity.

8. Boronate esters
Kilic et al. reported a novel series of economical, straightforwardly-synthesizable and
adjustable boronate esters) and their analogous N-Heterocyclic Carbene (NHC)-
stabilized boronate esters. All the synthesized boronate esters were characterized
utilizing modern spectroscopic methods. In addition, their antimicrobial activity was
assessed against an array of bacterial and fungal pathogens. Interestingly, compound
(55) emerged as the best candidate with potent antimicrobial activity. It demonstrated
antibacterial activity with ZOI of 30.3 mm at 10 mg/ml against Enterobacter
aerogenes. Moreover, esters (56 and 57) exhibited enhanced antibacterial activity in
comparison to standard drugs; esters (56 and 57) demonstrated excellent antibacterial
activity at 10 mg/mL with a 36.3 mm zone of inhibition against S. aureus (Figure 14).
These compounds were also tested for anti-oxidant activity and the results suggested
that all the esters exhibit significant radical scavenging activity promising activity
when compared to reference compound
10. Miscellaneous boron based heterocycles
The application of boron-based compounds was relatively unexplored in the case
of neurodegenerative disorders. Therefore, a new class of boron-based heterocycles
was synthesized and evaluated. Importantly, Compound 114, (Figure 23) emerged as
the lead candidate exhibiting significant anti-oxidant and amyloid-β (Aβ) aggregation
inhibitory activity with an IC50 of 3.41 µM for self-induced Ab aggregation. At a
concentration of 20 µM, the synthesized oxaborinine derivative inhibited self-
induced Ab aggregation by 82.8% thereby proving to be potentially therapeutic for
the treatment of Alzheimer's disease151.
  e. As boron derivatives could smoothly pass the blood brain barrier, they may
be exceedingly important in combating brain cancer and neurodegenerative
diseases in future2.
 A new class of dioxaborepine derivatives was prepared and screened against
pathogenic Gram-positive bacteria, Gram-negative bacteria, and a fungal
strain. All the tested compounds depicted superior activity (MIC = 25–
50 μg/mL) against P. aeruginosa than other organisms. In particular,
Compounds 115 and 116; (Figure 23) were found to be the best antibacterial
candidates. The structural properties required for designing new potent
antimicrobial agents were obtained from QSAR studies
 Dioxazaborocanes are boronic adducts mostly used in chemical
transformations. They have received a considerable amount of attention for
their biological activity.

11. Future directions

Advances in boron chemistry have reinforced the therapeutic potential of boron-
based heterocycles in drug design. This article highlighted the current advances of
these boron derivatives exhibiting diverse pharmacological activities and
demonstrated their usefulness in the treatment of various diseases. Fascinatingly,
several boron-based therapeutics are currently in the drug discovery pipeline for
treating countless lethal diseases. Notably, as boron derivatives can effortlessly pass
the blood–brain barrier, they could be extremely valuable in combating brain cancer
and neurodegenerative diseases in the future. Undoubtedly, boron-based
heterocycles could be incorporated with other bioactive scaffolds to give potent
hybrid therapeutics displaying newer pharmacological activities with lesser side
effects. In addition, these compounds could also serve as leads for newer diagnostic
and imaging agents. It is expected that a new biological pathway would be discovered
and boron-based heterocycles will play a significant role in unveiling newer potent
therapeutics. We believe that more and more boron-based compounds with potent
activity and efficacy will unravel in the future and aid in the discovery and
development of newer pharmacological agents.