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Current Medicinal Chemistry, XXXX, XX, XX-XX 1

MINI-REVIEW ARTICLE

Hybrids Diazine: Recent Advancements in Modern Antimicrobial

Therapy

Violeta Mangalagiu2, Ramona Danac1, Dumitrela Diaconu2,*, Gheorghita Zbancioc1 and

Ionel I. Mangalagiu1,2,*
1
Faculty of Chemistry, Alexandru Ioan Cuza University of Iasi, Bd. Carol 11, Iasi, 700506, Romania;
2
Institute of Interdisciplinary Research – CERNESIM Center, Alexandru Ioan Cuza University of Iasi, Bd.
Carol 11, Iasi, 700506, Romania

ARTICLE HISTORY
Received: November 01, 2022
Revised: February 21, 2023
Accepted: February 24, 2023
DOI:
10.2174/0929867330666230418104409
Keywords: Diazine hybrids, antimicrobial, pyridazine, pyrimidine, pyrazine, fused diazine.
Abstract: Nowadays, antimicrobial therapies have become a very challenging issue be-
cause of a large diversity of reasons such as antimicrobial resistance, over consumption
and misuse of antimicrobial agents, etc. A modern, actual and very useful approach in an-
timicrobial therapy is represented by the use of hybrid drugs, especially combined five
and six-membered ring azaheterocycles. In this review, we present an overview of the re-
cent advanced data from the last five years in the field of hybrid diazine compounds with
antimicrobial activity. In this respect, we highlight here essential data concerning the syn-
thesis and antimicrobial activity of the main classes of diazine hybrids: pyridazine, pyrim-
idine, pyrazine, and their fused derivatives.

1. INTRODUCTION During the last decades, infectious diseases caused

by microorganisms represent a major challenge to mod-
Diazines derivatives, namely pyridazine (1,2-
ern society, especially because of antimicrobial re-
diazine), pyrimidine (1,3-diazine), pyrazine (1,4-
sistance, overconsumption and misuse of antimicrobial
diazine) and their fused derivatives have demonstrated
agents, the toxicity of drugs, high prices, etc. [1, 6-15].
fascinating potential applications in different fields of
As a result, there is a big demand from society and the
economic activity, especially in medicine and pharma-
pharmaceutical industry for new drugs with better anti-
cy, opto-electronics, agriculture, etc. [1-5]. In medici-
microbial activity, better specificity, lower toxicity, bet-
nal chemistry, diazines are invaluable privileged scaf-
ter and enhanced properties generally. Despite the fact
folds being the core part of most existing drugs on the
that annually thousands of new antimicrobial com-
market, playing a crucial role in modern therapy. Many
pounds are synthesized by scientists to fulfill society’s
drugs and compounds containing pyridazine, pyrimi-
demand, obtaining new drugs with antimicrobial activity
dine, pyrazine, and their fused derivatives have been
remains a big challenge in medicinal chemistry. One of
demonstrated to possess versatile biological activities,
the most promising methods for obtaining antimicrobial
which include antibacterial, antifungal, antitubercular,
compounds is molecular hybridisation, which consists of
antimalarial, antileishmanial, antiviral, anti-HIV, anti-
combining two or more drug pharmacophores with dif-
cancer, antihypertensive, diuretics, antiaggregative,
ferent biological activities via a flexible linker resulting
antiplatelet, cardiotonic, antidepressant, anxiolytics,
in a single chemical entity, more flexible and with a
antiseizure, analgesic, hypnotic sedatives, anti neuro-
higher molecular weight, Scheme 2 [7, 20].
degenerative, antiallergic, etc. [1,6-19]. Some repre-
sentative examples of drugs on the market with diazine The resulting hybrid molecules have certain ad-
skeletons are presented in Scheme 1. vantages but also some drawbacks. The resulting hy-
brid compounds have some undeniable better proper-
*Address correspondence to this author at the Faculty of Chemistry,
Alexandru Ioan Cuza University of Iasi, Bd. Carol 11, Iasi, 700506, Roma- ties compared with initial parent drugs, usually pos-
nia; E-mail: ionelm@uaic.ro sessing better biological activity and specificity, lower

0929-8673/XX $65.00+.00 © XXXX Bentham Science Publishers

2 Current Medicinal Chemistry, XXXX, Vol. XX, No. XX
Scheme 1. Representative drugs with diazine skeletons on the market.
drug-drug interactions, lower toxicity, and side effects,
etc., generally a consistent improvement of pharmaco-
dynamic, pharmacokinetic, and toxicologic properties
of the potential hybrid drug candidates. On the other
hand, the resulting hybrid could also have some draw-
backs. A more flexible structure may reduce target
binding efficiency while having a higher molecular
weight could negatively impact both oral bioavailabil-
ity and the ability to penetrate the cellular membrane.
The greatest majority of the existing drugs from the
market contain in their structure a nitrogen heterocycle,
some of them being with a hybrid structure (Scheme 1),
which justifies the demand of the pharmaceutical in-
dustry for such drugs with nitrogen hybrid heterocycle
skeleton. As a matter of fact, most of the hybrid drugs
belong to five-member ring azaheterocycles (especially
azole and diazole) and six-member ring azaheterocy-
cles (especially azine and diazine) or a combination of
these two classes, some representative examples being
depicted in Scheme 1.
In this review, we present an overview of the recent
advanced related to the synthesis and antimicrobial ac-
tivity of hybrid six-member ring azaheterocycles with
two nitrogen atoms (diazine) derivatives. The review is
divided into three main sections, according to the na-
ture of the heterocycle. The first section is dealing with
hybrid pyridazine and phthalazine, the second one with
hybrid pyrimidine and quinazoline, and the third one
with hybrid pyrazine.
Mangalagiu et al.
Scheme 2. Molecular hybridisation approach.
2. DISCUSSION
2.1. Hybrid Six-member Ring Pyridazine and
Phthalazine
Recently Radwan et al. [21] have performed a study
concerning the in vitro antimicrobial activities of some
newly hybrid isoxazolo-pyridazine derivatives. The
synthesis starts with the N-alkylation reaction of ami-
no-isoxazole derivatives followed by condensation and
cyclo condensation of the intermediary, when the de-
sired hybrid isoxazolo-pyridazine 1a, b are obtained,
Scheme 3.
The synthesized hybrid isoxazolo-pyridazine 1a, b
were tested for their antibacterial activity against
Gram-positive strains (three strains: Staphylococcus
aureus, Bacillus subtilis, Enterococcus faecalis) and
Gram-negative (three strains: Escherichia coli, Pseu-
domonas aeruginosa, Staphylococcus typhi) and for
their antifungal activity (two strains: Candida albicans,
Aspergillus niger) by MIC assay. The tested hybrids
Hybrids Diazine in Modern Antimicrobial Therapy
Scheme 3. Reaction pathway to obtain isoxazolo-pyridazine hybrids 1a,b.
Scheme 4. Reaction pathway to obtain benzimidazole-pyridazine 2a and benzimidazole-phthalazine 2b,c.
proved to have very good antibacterial activity against
all tested strains. The most potent hybrid was proved to
be 1a, being more active against E. faecalis (9.5 fold),
S. aureus (5.1 fold), S. typhi (4.1 fold), A. niger (2.1
fold), C. albicans (1.8 fold), and having equipotent ac-
tivity towards B. subtilis, comparative with the control
drug ampicillin respectively clotrimazole.
Deshpande et al. [22] synthesized new hybrids of
benzimidazole-pyridazine and benzimidazole-
phthalazine derivatives and studied their antimicrobial
activities. The synthesis is straight, involving a cy-
clocondensation reaction of the benzimidazole hydra-
zide derivatives with succinic, phthalic, and tetrachlo-
rophthalic anhydrides, when the corresponding hybrids
benzimidazole-pyridazine 2a and benzimidazole-
phthalazine 2b,c are obtained, Scheme 4.
The synthesized hybrids were tested for their anti-
bacterial, antifungal, and antitubercular activity. The
antibacterial assay was performed against Gram-
positive strains (Staphylococcus aureus, Enterococcus
faecalis) and Gram-negative (Escherichia coli,
Klebsiella pneumoniae) while the antifungal assay was
performed against Candida albicans and Aspergillus
niger, by MIC assay. The tested hybrids proved to have
very good antibacterial activity against E. faecalis, su-
perior to the control drug ciprofloxacin. The activity
against all the others strains was moderate to weak.
Aricu et al. [23] have performed a study concerning
the in vitro antimicrobial activities of some new hybrid
Current Medicinal Chemistry, XXXX, Vol. XX, No. XX 3
terpene-pyridazine derivatives. The reaction pathway
involves an N-alkylation reaction of the pyridazine de-
rivatives with bromide-terpene derivatives 3a-b, when
the corresponding hybrid terpene-pyridazine 4a-d are
obtained, Scheme 5.
The synthesized hybrids were tested for their anti-
bacterial (Gram-positive strain Bacillus polymyxa and
Gram-negative strain Pseudomonas aeruginosa) and
antifungal (five strains: Aspergillus flavus, Fusarium
solani, Penicillium chrysogenum, Penicillium fre-
quentans, Alternaria alternata) activity, by MIC assay.
The tested hybrids proved to have very good antifungal
and antibacterial activity against all tested strains, one
compound (namely, 4d) being extremely active, and
highly superior to the control drug caspofungin respec-
tively kanamycin.
Mourad et al. [24] synthesized a library of oxadia-
zole-phthalazine 4-7 and pyrazolo-phthalazine 8-11
hybrids and studied their antibacterial activities. The
key intermediary in the synthesis is hydrazine-
phthalazine I which treated with the corresponding re-
agents leads to the desired products, Scheme 6.
The synthesized hybrids were tested for their anti-
bacterial activity against two Gram-positive bacteria
(Bacillus subtilis and Staphylococcus aureus) and two
Gram-negative bacteria (Pseudomonas aeruginosa and
Escherichia coli). All tested hybrids manifested a
strong antibacterial activity against Gram-positive bac-
teria, in many cases superior to control amoxicillin.
4 Current Medicinal Chemistry, XXXX, Vol. XX, No. XX
Scheme 5. Reaction pathway to obtain terpene-pyridazine 4a-d.
Scheme 6. Reaction pathway to obtain oxadiazole-phthalazine 4-7 and pyrazole-phthalazine 8-11 hybrids.
The activity against Gram-negative bacteria was ne-
glectable.
Zaheer et al. [25] synthesized a series of hybrid
quinoline-phthalazine derivatives and studied their an-
timicrobial activities. The synthesis involves a direct
and efficient strategy, a one-pot four-component reac-
tion when the corresponding hybrid quinoline-
phthalazine 12a-fand 13a-f are obtained, Scheme 7.
The synthesized hybrids were tested for anti-biofilm
activity against the bacteria Pseudomonas aeruginosa
and fungus Candida albicans, by MIC method. The
most promising compounds against the tested strains
have proved to be 12a and 12f, which manifest an an-
timicrobial activity superior to control ciprofloxacin,
respectively, fluconazole.
2.2. Hybrid Six-member Ring Pyrimidine and
Quinazoline
Vlasov et al. [26] have studied the antimicrobial ac-
tivities of some new hybrid imidazopyridine-
Mangalagiu et al.
pyrimidine derivatives. The reaction pathway involves
an initial alkylation of aminopyridine which are leading
to salt 14, followed by a cyclization reaction of salt 14
when the hybrid imidazopyridine-pyrimidine 15 is ob-
tained. The alkylation of 15 with 2-
chloroarylacetamides leads to another hybrid, the im-
idazopyridine-pyrimidine derivative 16a,b, Scheme 8.
The synthesized compounds were tested for their
antibacterial activity against Gram-negative and Gram-
positive bacterial stains. The obtained results reveal a
moderate activity of the compounds against the tested
bacterial strains.
In a subsequent paper, Vlasov et al. [27] have studied
the antimicrobial activities of a new class of hybrid ben-
zimidazole-pyrimidine derivatives. The reaction pathway
involves a cyclocondensation reaction of functionalized
thieno-pyrimidine when the hybrid imidazopyridine-
pyrimidine 17 is obtained. The alkylation of 17 with 2-
chloroarylacetamides leads to another hybrid, the imidaz-
opyridine-pyrimidine derivative 18a-l, Scheme 9.
Hybrids Diazine in Modern Antimicrobial Therapy Current Medicinal Chemistry, XXXX, Vol. XX, No. XX 5

Scheme 7. Reaction pathway to obtain quinoline-phthalazine 12a-f and 13a-f.

Scheme 8. Reaction pathway to obtain hybrid imidazopyridine-pyrimidine 14-16.

Scheme 9. Reaction pathway to obtain hybridimidazopyridine-pyrimidine 17 and 18a-l.

Scheme 10. Reaction pathway to obtain hybrid piperidine- or oxazine- pyrimidine 19a,b.

The synthesized hybrids were tested for their anti-
bacterial and antifungal activity. The antibacterial as-
say was performed against Gram-positive strains
(Staphylococcus aureus, Bacillus subtilis) and Gram-
negative (Escherichia coli, Pseudomonas aeruginosa,
Proteus vulgaris) while the antifungal assay was per-
formed against Candida albicans. The tested hybrids
proved to have very good antibacterial activity against
Gram-positive strains and moderate against Gram-
negative strains. The hybrid 18d proved to have the
best antibacterial activity. The antifungal activity was
moderate to weak.
Tolba et al. [28] have performed a study concerning
the antimicrobial and anticancer activities of some hy-
brid piperidine- and oxazine- pyrimidine derivatives.
The reaction pathway involves an alkylation of piperi-
dine or oxazine heterocycles, the desired hybrids 19a,b
being obtained, Scheme 10.
The synthesized compounds were tested for their
antibacterial activity against Gram-positive (Bacillus
cereus, Staphylococcus aureus) and Gram-negative
(Pseudomonas aeruginosa, Escherichia coli) strains.
The obtained results reveal a good activity of com-
pound 19b against tested bacterial strains, in the range
of control drug nitrofurantoin.
El-Dash et al. [29] synthetised a new class of hybrid
thiazole-pyrimidine derivatives and studied their anti-
microbial activities. The reaction pathway involves
alkylation of the pyrimidine derivative with
6 Current Medicinal Chemistry, XXXX, Vol. XX, No. XX
Scheme 11. Reaction pathway to obtain hybrid thiazole-pyrimidine 20a-j.
Scheme 12. Reaction pathway to obtain hybrid imidazothieno-pyrimidine 21-27.
2-chloroarylacetamides, leading to the desired hybrids,
the thiazole-pyrimidine derivative 20a-j, Scheme 11.
The synthesized hybrids were tested for their anti-
bacterial and antifungal activity. The antibacterial as-
say was performed against Gram-positive (Staphylo-
coccus aureus, Streptococcus pneumoniae) and Gram-
negative (Escherichia coli, Salmonella Typhimurium)
strains while the antifungal assay was performed
against Candida albicans. The tested hybrids have no
bacterial activity. Only one hybrid compound (20d) has
moderate antifungal activity, slightly weaker compared
to nystatin as the standard antifungal drug.
Othman et al. [30] synthesized a library of hybrid
imidazothieno-pyrimidine derivatives and studied their
antimicrobial activities. The starting hybrid imidaz-
othieno-pyrimidine 21a,b was obtained by alkylation
of pyrimidine derivative with 2-chloroacetyl deriva-
tives, Scheme 12.
The intermediary hybrid 21a,b is then transformed
in other pyrimidine hybrids, pyrimidine 22-27, Scheme
12. The synthesized hybrids were tested for their anti-
bacterial (two strains, Bacillus cereus and Klebsiella
pneumoniae) and antifungal (two strains, Aspergillus
Mangalagiu et al.
flavus and Aspergillus ochraceus) activity, by inhibi-
tion zone diameter and minimum inhibitory concentra-
tion. The tested hybrids have good to moderate activity,
with one hybrid compound (26) having excellent ac-
tivity against Klebsiella pneumoniae, superior to the
control drug chloramphenicol.
Sanad et al. [31] synthesised a library of hybrid
fused thiazole-pyrimidine derivatives and studied their
antimicrobial activities. Initially, they synthesised the
hybrid starting derivatives 28-30, which underwent
different chemical transformations leading to the de-
sired hybrids, the fused thiazole-pyrimidine derivative
31-36, Scheme 13.
The synthesized hybrids were tested for their anti-
bacterial activity. The antibacterial assay was per-
formed against Gram-positive (Staphylococcus aureus,
Streptococcus mutans) and Gram-negative (Escherich-
ia coli, Klebsiella pneumonia) strains. The tested hy-
brids proved to have good antibacterial activity against
both Gram-positive and Gram-negative strains. The
hybrid 36a has shown the best antibacterial activity
against all bacteria, with MIC value in the range of 4-
15 µg/mL, superior to control drugs (ampicillin for
Gram-positive, gentamicin for Gram-negative).
Hybrids Diazine in Modern Antimicrobial Therapy
Scheme 13. Reaction pathway to obtain hybrid fused thiazole-pyrimidine 28-36.
Scheme 14. Reaction pathway to obtain hybrid thiadiazole-pyrimidine 37 and 38.
El-Naggar et al. [32] synthesized a library of hybrid
thiadiazole-pyrimidine derivatives and studied their
antimicrobial and anticancer activities. To obtain the
desired compounds, the thiadiazole thiosemicarbazide
intermediary was treated with bis-methylthiomethylene
barbituric acid or malonic acid, when the hybrid thiadi-
azole-pyrimidine derivative 37, 38 was obtained,
Scheme 14.
Some other thiadiazole-pyrimidine hybrids were ob-
tained by using a similar strategy, Scheme 15.
The synthesized hybrids were tested for their anti-
bacterial and antifungal activity. The antibacterial as-
say was performed against Gram-positive (Staphylo-
coccus aureus, Bacillus subtilis) and Gram-negative
(Escherichia coli, Pseudomonas aeruginosa) strains
while the antifungal assay was performed against Can-
dida albicans and Aspergillus niger. Some of the tested
Current Medicinal Chemistry, XXXX, Vol. XX, No. XX 7
hybrids (namely, 38 and 40) have very good antibacte-
rial and antifungal activity, comparable to the control
drugs amoxicillin, respectively, fluconazole.
Šlachtová et al. [33] synthesised a new class of hy-
brid thiazole-pyrimidine derivatives 49a-f, 50a-n and
studied their antimicrobial activities. The synthesis was
performed in the solid phase on resin, involving immo-
bilization of amino acids on the resin, different reac-
tions of protection, deprotections, hydrolysis, etc., as it
is depicted in Scheme 16.
The synthesized hybrids were tested for their anti-
bacterial (Staphylococcus aureus, Pseudomonas aeru-
ginosa, Escherichia coli and Enterococcus faecalis),
antifungal (Candida albicans and Aspergillus niger)
and antitubercular (Mycobacterium tuberculosis
H37Rv) activity. In all cases, the tested hybrids have a
neglectable antimicrobial activity.
8 Current Medicinal Chemistry, XXXX, Vol. XX, No. XX Mangalagiu et al.

Scheme 15. Reaction pathway to obtain hybrid thiadiazole-pyrimidine 39-48.

Scheme 16. Reaction pathway to obtain hybrid thiazole-pyrimidine 49a-f and 50a-n.

Shiva Raju et al. [34] synthesised a library of 24
hybrid triazolo-pyrimidine derivatives 51a-x and stud-
ied their antitubercular activities. The reaction pathway
is straight, involving an N-alkylation of the pyrrolo-
pyrimidine derivative followed by the click reaction of
the intermediary, Scheme 17.
The synthesized triazolo-pyrimidine hybrids were
tested for their antitubercular activity. The antitubercu-
lar assays reveal that most of the hybrids have good
antitubercular activity, two hybrids (51q and 51r) be-
ing very promising, the minimum inhibitory concentra-
tion having the value of 0.78 µg/mL, superior to the
control drugs ethambutol and ciprofloxacin.
Hybrids Diazine in Modern Antimicrobial Therapy
Scheme 17. Reaction pathway to obtain hybrid triazolo-pyrimidine 51a-x.
Scheme 18. Reaction pathway to obtain hybrid piperazino-pyrimidine 52a-x.
Vekariya et al. [35] synthesized a series of hybrid
piperazino-pyrimidine derivatives and studied their
antibacterial, antifungal, antitubercular, and antimalari-
al activities. The reaction pathway involves a cy-
clocondensation than an N-alkylation of piperazine,
followed by a reaction with isothiocyanates of the in-
termediary when the desired hybrid piperazino-
pyrimidine derivatives 52a-x are obtained, Scheme 18.
The synthesized piperazino-pyrimidine hybrids
were tested for their antibacterial (four strains, Staphy-
lococcus aureus, Pseudomonas aeruginosa, Escherich-
ia coli, Staphylococcus pyogenes), antifungal (three
strains, Candida albicans, Aspergillus niger and As-
pergillus chrysogenum), antitubercular and antimalarial
activities. The antibacterial assay reveals that four
compounds (namely, 52j, 52n, 52r, and 52s) have ex-
cellent antibacterial activity against the tested bacterial
strains. A special mention for the hybrid 52s has to be
pointed out, which was found to be the most potent
Current Medicinal Chemistry, XXXX, Vol. XX, No. XX 9
against all bacterial strains except Escherichia coli,
with an activity superior to all three standard drugs
used in the assay, ampicillin, ciprofloxacin, and chlo-
ramphenicol. Four other hybrids (namely, 52e, 52f,
52r, and 52s) have excellent antifungal activity against
the fungus Candida albicans, superior to the standard
drug Griseofulvin. Two hybrids, namely, 52r and 52s,
have excellent antimalarial activity against Plasmodi-
um faliciparum, with an IC50 of 0.09 µg/mL respective-
ly 0.07 µg/mL, superior to control standard drugs, qui-
nine, and chloroquine. The antitubercular activity was
neglectable.
Bhatia et al. [36] synthesized a library of pyrimido-
pyrimidine hybrids and studied their antimicrobial ac-
tivity. The synthesis is straight (in one step), involving
the reaction of pyrimidine derivative with 1,4-
bis(bromomethyl)benzene, when the desired pyrimido-
pyrimidine hybrids 53a-j are obtained, Scheme 19.
10 Current Medicinal Chemistry, XXXX, Vol. XX, No. XX Mangalagiu et al.

Scheme 19. Reaction pathway to obtain hybrid pyrimido-pyrimidine 53a-j.

Scheme 20. Reaction pathway to obtain hybrid pyrimido-pyrimidine 54a-j.

Scheme 21. Reaction pathway to obtain hybrid coumarin-pyrimidine 55a-j.

The synthesized hybrids were tested for their anti-
bacterial (four strains, Staphylococcus aureus, Pseu-
domonas aeruginosa, Escherichia coli, Bacillus sub-
tilis) and antifungal (two strains, Cladosporium ox-
ysporum and Candida albicans) activity, by inhibition
zone diameter and minimum inhibitory concentration.
The tested hybrids have good to moderate activity, and
three hybrids (53b,c,d), had excellent antifungal activi-
ty against both strains superior to the control drug flu-
conazole.
In another paper, Bhatia et al. [37] synthesized a
new series of pyrimido-pyrimidine hybrids and studied
their antimicrobial activity. The reaction pathway was
similar to that described above, involving the reaction
of pyrimidine derivative with 1,4-bis(bromomethyl)
acetylene, when the desired pyrimido-pyrimidine hy-
brids 54a-j are obtained, Scheme 20.
The synthesized hybrids were tested for their anti-
bacterial (four strains, Staphylococcus aureus, Pseu-
domonas aeruginosa, Escherichia coli, Bacillus sub-
tilis) and antifungal (two strains, Cladosporium ox-
ysporum, and Candida albicans) activity, by inhibition
zone diameter and minimum inhibitory concentration.
Some of the tested hybrids have good to moderate ac-
tivity, with hybrid 54b having an excellent antifungal
activity (against both tested strains and superior to the
control drug fluconazole) while hybrid 54j has excel-
lent antibacterial activity (against all tested bacterial
strains and superior to control drug ciprofloxacine).
Naik et al. [38] synthesized a new class of hybrid
coumarin-pyrimidine derivatives and studied their an-
timicrobial and anticancer activities. The reaction
pathway involves the reaction of chalcone derivatives
with isonicotinamidine hydrochloride, leading to the
desired hybrids, the coumarin-pyrimidine derivative
55a-j, Scheme 21.
The synthesized hybrids were tested for their anti-
microbial and anticancer activity. The antibacterial as-
say was performed against Gram-positive strains
(Staphylococcus aureus, Bacillus subtilis) and Gram-
negative (Escherichia coli, Pseudomonas aeruginosa)
strains, while the antifungal assay was performed
against Candida albicans, Aspergillus flavus, Tricho-
derma harzianum and Penicillium chrysogenum. Two
hybrids (55f and 55h) manifest a powerful antibacterial
activity against all bacterial strains, while the other five
Hybrids Diazine in Modern Antimicrobial Therapy Current Medicinal Chemistry, XXXX, Vol. XX, No. XX 11

Scheme 22. Reaction pathway to obtain hybrid coumarin-pyrimidine 57-63.

Scheme 23. Reaction pathway to obtain hybrid triazolo-pyrimidine 64a-j.

Scheme 24. Reaction pathway to obtain hybrid imidazole-pyrimidine 65a-k.

(55b, 55c, 55d, 55f, and 55h) hybrids manifest a very
strong antifungal activity against all fungus strains.
Some of the hybrids manifest significant anticancer
activity.
Mourad et al. [39] synthesized a library of hybrid
coumarin-pyrimidine derivatives and studied their an-
timicrobial activities. The reaction pathway involves
the reaction of coumarin intermediary derivative 56
with different reagents, which are leading to the desired
coumarin-pyrimidine hybrids 57-63, Scheme 22.
The obtained hybrids were tested for their antibacte-
rial activity against Gram-positive strains (Staphylo-
coccus aureus, Bacillus subtilis) and Gram-negative
strains (Escherichia coli, Staphylococcus enteritis).
The obtained results reveal that the hybrids have a
modest antibacterial activity.
Kaoukabi et al. [40] synthesized a new class of tria-
zolo-pyrimidine derivatives and studied their antiviral
activity. The reaction pathway is straight, involving a
click reaction of the pyrimidine intermediary with the
corresponding azide, leading to the desired triazolo-
pyrimidine hybrid 64a-f, Scheme 23.
The synthesized hybrids were evaluated for their an-
tiviral activity. Some of the tested compounds (64c,
64d, 64f, 64g) exhibited a strong antiviral activity, with
an EC50 in the range of 3-10 µM.
Chikkula et al. [41] synthesized a library of imidaz-
ole-pyrimidine derivatives and studied their antibacte-
rial, antifungal, analgesic, and anti-inflammatory ac-
tivities. The reaction pathway is straight, involving a
cyclocondensation reaction of imidazole intermediary
with the corresponding reagent, leading to the desired
imidazole-pyrimidine hybrid 65a-k, Scheme 24.
12 Current Medicinal Chemistry, XXXX, Vol. XX, No. XX
Scheme 25. Reaction pathway to obtain terpene-pyrazine 67 and terpene-pyrimidine 66, 68, and 69.
Scheme 26. Reaction pathway to obtain hybrid benzimidazole-quinazoline 69a-j and 70a-d.
The obtained hybrids were tested for their antibacte-
rial activity against Gram-positive and Gram-negative
strains (B. cereus, S. aureus, M. luteus, S. epidermidis,
K. pneumoniae, P. aeruginosa, E. coli) and for antifun-
gal activity against A. fumigatus and A. niger strains.
The obtained results reveal that the hybrids have mod-
est antibacterial and antifungal activity.
Kuchkova et al. [42] synthesized a series of hybrids
of terpene-pyrimidine and terpene-pyrazine derivatives
and studied their antimicrobial activity. The reaction
pathway involves an N-acylation reaction of the amino-
diazine (pyrimidine or pyrazine) derivatives with the
corresponding acyl chloride terpene, when the corre-
sponding hybrids terpene-pyrimidine 66 and terpene-
pyrazine 67 are obtained, Scheme 25. In the case of 2-
aminopyridine derivative, the reaction occurs different-
ly, a mixture of hybrid mono-terpene-pyrimidine 68
and bis-terpene-pyrimidine 69 being obtained, Scheme
25.
Mangalagiu et al.
The synthesized hybrids 66-69 were tested for their
antibacterial activity against Gram-positive strains
(Staphylococcus aureus, Sarciria lutea, Bacillus cere-
us, Bacillus subtilis), Gram-negative strains (Esche-
richia coli, Pseudomonas aeruginosa) and for antifun-
gal activity against fungal strains Candida albicans,
Candida glabrata and Candida sake. The tested hy-
brids proved to have very good antibacterial activity
against two Gram-positive bacterial strains (S. aures
and B. cereus) and were neglectable to all the other
microbial strains.
Malasala et al. [43] synthesized a library of
benzimidazole-quinazoline derivatives and studied
their antimicrobial activities. The reaction pathway is
straight, involving a cyclo condensation reaction of the
o-phenylenediamine derivative with the corresponding
quinazoline, leading to the desired benzimidazole-
quinazoline hybrid 69a-j, Scheme 25. In another reac-
tion sequence, the benzimidazole-quinazoline hybrid
Hybrids Diazine in Modern Antimicrobial Therapy Current Medicinal Chemistry, XXXX, Vol. XX, No. XX 13

Scheme 27. Reaction pathway to obtain hybrid morpholine-quinazoline 71a-u and 72a-p.

Scheme 28. Reaction pathway to obtain hybrid triazole-quinazoline 73a-j.

70a-d was obtained by acylation of 5-amino-
benzimidazole derivatives with the corresponding
quinazoline, Scheme 26.
The obtained hybrids were tested for their antibacte-
rial activity against Staphylococcus aureus strains (in-
cluding methicillin and vancomycin-resistant S. aure-
us) and for antitubercular activity against
Mycobacterium tuberculosis strains. Nine of the tested
hybrids (69a, 69b, 69c, 69d, 69f, 69g, 69h, 69i, and
70c) have a very powerful antimicrobial activity with
MICs in the range of 4–64 µg/mL.
Gu et al. [44] synthesized a library of hybrid
morpholine-quinazoline derivatives and studied their
antimicrobial activities. A first series was synthesized
starting with the reaction of quinazoline derivatives
with morpholine, followed by hydrolysis and N-
acylation, when the desired hybrid morpholine-
quinazoline 71a-u are obtained, Scheme 26. A second
series is obtained starting from quinazoline derivatives
with dimethyl morpholine, followed by hydrolysis and
N-acylation, when the desired hybrid morpholine-
quinazoline 72a-p are obtained, Scheme 27.
The obtained hybrids were tested for their antibacte-
rial activity against the drug-resistant Escherichia coli
strain expressing AcrB which is indicated as (+)AcrB.
Eight compounds from the first series of hybrids (71b,
71d, 71f, 71h, 71j, 71l, 71m, and 71p) were found to
have MIC values reduced by 8 folds comparative with
the control drugs chloramphenicol and erythromycin.
14 Current Medicinal Chemistry, XXXX, Vol. XX, No. XX Mangalagiu et al.

Scheme 29. Reaction pathway to obtain hybrid benzofuran-quinazoline hybrids 74a-i to 76a-i and imidazole-benzofuran-
quinazoline 77a-i.

From the second series of hybrids, eleven com-
pounds (72a, 72b, 72c, 72e, 72g, 72h, 72i, 72k, 72m,
72o, and 72p) were found to have MIC values reduced
by 19 folds compared with the control drugs chloram-
phenicol and erythromycin.
Maddali et al. [45] synthesized a library of triazole-
quinazoline derivatives and studied their antibacterial,
antifungal, and antitubercular activities. The reaction
pathway involves a click cyclocondensation reaction
followed by another cyclocondensation of the interme-
diary, when the desired triazole-quinazoline hybrids
73a-j are obtained, Scheme 28.
The obtained hybrids were tested for their antibacte-
rial activity against five bacterial strains (Staphylococ-
cus aureus, Bacillus subtilis, Escherichia coli, Pseu-
domonas aeruginosa, Klebsiella pneumoniae) and for
antitubercular activity against Mycobacterium
tuberculosis strain. Four of the tested hybrids (73a,
73e, 73h, and 73j) have very good antibacterial activity
with a diameter of the inhibition zone in the range of
19 to 33 mm. As far as antitubercular activity, five of
the tested hybrids (73b, 73d, 73e, 73i, and 73j) have
very good activity with a MIC in the range of 7 to 11
µg/mL, compared to the reference drug rifampicin.
Asadi et al. [46] synthesized a library of hybrid ben-
zofuran- and imidazole-benzofuran- quinazoline deriva-
tives and studied their antimicrobial activities. The reac-
tion pathway starts from quinazoline and benzofuran
derivatives and involves a suite of typical organic chem-
istry reactions: N-alkylation, reduction, chlorination, and
quaternization when the desired benzofuran-quinazoline
hybrids 74a-i to 76a-i and imidazole-benzofuran-
quinazoline 77a-i are obtained Scheme 29.
The obtained hybrids were tested for their antimi-
crobial activity against Gram-positive bacteria (three
strains, Staphylococcus aureus, Bacillus subtilis, Lis-
teria monocitogenes) and Gram-negative bacteria
(three strains, Escherichia coli, Pseudomonas aeru-
ginosa, Salmonella entritidis) and to fungus Candida
albicans. All hybrid imidazole-benzofuran-quinazoline
77a-i manifested significant activity against Gram-
positive and Gram-negative bacteria. One compound,
namely, 74e, has excellent antibacterial activity in the
range of the control drug ciprofloxacin. The antifungal
activity is neglectable.
2.3. Hybrid Six-member Ring Pyrazine
The literature survey indicates that in the period
taken into consideration for this review, the last five
years, there were not too many contributions to the
field of hybrid 1,4-diazine. However, this aspect does
not influence with anything the importance of pyrazine
hybrids in medicinal chemistry.
Bhandare et al. [47] synthesized a library of hy-
bridpyrimidine-pyrazine derivatives and studied their
antimicrobial and anticancer activities. The reaction
pathway involves two steps, a condensation reaction of
acetyl-pyrazine followed by a cyclocondensation reac-
tion of the resulting chalcone-pyrazine derivative with
guanine when the desired pyrimidine-pyrazine hybrids
78a-s are obtained, Scheme 30.
The synthesized hybrids were tested for their anti-
microbial activity against Gram-positive bacteria
(Staphylococcus aureus, Bacillus subtilis), Gram-
negative bacteria: (Escherichia coli, Pseudomonas ae-
ruginosa) and fungus Aspergillus niger and Candida
tropicalis. Some of the hybrids manifest significant
activity against Gram-positive and Gram-negative bac-
teria as well as fungi. Three compounds, namely, 78d,
78i, and 78j, have excellent antibacterial activity with
MIC in the range of 50 µM, superior to the control drug
ciprofloxacin (MIC = 145 µM for Gram-positive bacte-
ria respectively MIC = 75 µM for Gram-negative).
Moreover, three compounds, namely. 78i, 78j, and
78k, have very good antifungal activity with MIC in
the range of 50 µM, superior to the control drug flu-
conazole (MIC = 80 µM).
Shaik et al. [48] synthesized a library of hybrid ben-
zothiazepines-pyrazine derivatives and studied their
Hybrids Diazine in Modern Antimicrobial Therapy Current Medicinal Chemistry, XXXX, Vol. XX, No. XX 15

Scheme 30. Reaction pathway to obtain hybrid pyrimidine-pyrazine78a-s.

Scheme 31. Reaction pathway to obtain hybrid benzothiazepines-pyrazine 79a-t.

Scheme 32. Reaction pathway to obtain hybrid sulfonamide-pyrazine 80a-n and 81a-n.

antimicrobial activities. The reaction pathway involves
two steps, a condensation reaction of acetyl-pyrazine
followed by a cyclocondensation reaction of the result-
ing chalcone-pyrazine derivative with 2-aminothio-
phenol, when the desired benzothiazepines-pyrazine
hybrid 79a-t is obtained, Scheme 31.
The obtained hybrids were tested for their antibacte-
rial activity (against Gram-positive bacteria Staphylo-
coccus aureus, Bacillus subtilis and Gram-negative
bacteria Escherichia coli, Pseudomonas aeruginosa),
antifungal activity (against Aspergillus niger and Can-
dida tropicalis) and antitubercular activity (against My-
cobacterium tuberculosis). Some of the hybrids mani-
fest significant antimicrobial activity. The hybrid 79f
has excellent antibacterial activity with a MIC of 38
µM, superior to the control drug ciprofloxacin (MIC =
145 µM for Gram-positive bacteria, respectively, MIC
= 72µM for Gram-negative). Two hybrid derivatives,
namely, 79f and 79p, have very good antifungal
16 Current Medicinal Chemistry, XXXX, Vol. XX, No. XX
Scheme 33. Reaction pathway to obtain hybrid quinoline-pyrazine82a-h.
activity with MIC of 19µM, respectively, MIC of 44
µM, superior to the control drug fluconazole (MIC of
84 µM, respectively, MIC of 63 µM). The antitubercu-
lar assay revealed that one hybrid, namely, 79m, had a
good antitubercular activity with a MIC of 18 µM, su-
perior to the control drug pyrazinamide (MIC = 412
µM).
Bouz et al. [49] synthesized a series of hybrid sul-
fonamide-pyrazine derivatives and studied their an-
titubercular activities. The reaction pathway involves
one step, an acylation reaction of amino-pyrazine with
sulfonyl chloride, when the desired sulfonamide-
pyrazine hybrids 80a-n and 81a-n are obtained,
Scheme 32.
The obtained hybrids were tested for their antituber-
cular activity against Mycobacterium tuberculosis, My-
cobacterium kansasii, and Mycobacterium avium. The
antitubercular assay revealed that only two hybrids,
namely, 80d and 81d, have good antitubercular activity
against M. tuberculosis with a MIC of 6.25 µg/mL.
Panda et al. [50] synthesized a library of hybrid
quinoline-pyrazine derivatives and studied their anti-
microbial activities. The reaction pathways involve one
step, an acylation reaction of fluoroquinolone deriva-
tives with benzotriazole-pyrazine, when the desired
quinoline-pyrazine hybrids 82a-h are obtained, Scheme
33.
The obtained hybrids were tested for their antibacte-
rial activity against Gram-positive bacteria (Staphylo-
coccus aureus and Streptococcus pyogenes) and Gram-
negative bacteria (Salmonella typhi, Pseudomonas ae-
ruginosa). Some of the hybrids manifest significant
antibacterial activity. The hybrid 82h has excellent an-
tibacterial activity against the Gram-positive bacterial
strains (MIC of 74.6 µM against S. aureus and MIC of
149.3 µM against S. pyogenes), superior to the control
drug norfloxacin 1 and ciprofloxacin 2 (MIC = 3914.3
µM, 3772.4 µM; 1957.2 µM, 3772.4 µM for drug1 and
Mangalagiu et al.
2 against S. aureus and S. pyogenes). Against Gram-
negative bacterial strains, the hybrids have a modest
antibacterial activity.
CONCLUSION
In conclusion, we report herein the latest recent ad-
vancements concerning the synthesis and antimicrobial
properties of hybrid diazine derivatives. The hybrid
pyridazine, pyrimidine, pyrazine, and their fused deriv-
atives have invaluable importance in modern antimi-
crobial therapy, the results presented in this review in-
dicate that they have a large variety of antimicrobial
activities, including antibacterial, antifungal, antimy-
cobacterial, antileishmanial, antimalarial, antiviral, etc.
Moreover, the hybrids diazine combined especially
with a five-member ring azaheterocycle are leading to
compounds of great interest in antimicrobial drug dis-
covery, such approach being a very promising pathway
in the continued struggle with drug resistance, multi-
drug resistance, and extensively-drug-resistance phe-
nomena to microbial pathogens.
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
This work was supported by a grant from the Ro-
manian Ministry of Education and Research, CNCS -
UEFISCDI, project number PN-III-P4-ID-PCE-2020-
0371, PNCDI III. This work was co-funded by the
European Social Fund, through Operational Pro-
gramme Human Capital 2014-2020, project number
POCU/993/6/13/153322, project title Educational and
training support for Ph.D. students and young research-
ers in preparation for insertion into the labor market.
CONFLICT OF INTEREST
Dr. Mangalagiu Ionel I is on the Editorial Advisory
Board of the journal CMC.
Hybrids Diazine in Modern Antimicrobial Therapy
ACKNOWLEDGEMENTS
The authors are thankful to the Romanian Ministry
of Research, Innovation and Digitization, within Pro-
gram 1—Development of the national RD system,
Subprogram 1.2—Institutional Performance—RDI ex-
cellence funding projects, Contract no.
11PFE/30.12.2021 and project POC/448/1/1 Research
Centre with Integrated Techniques for Atmospheric
Aerosol Investigation in Romania-RECENT AIR
(grant agreement MySMIS no. 127324) and CERNES-
IM Center, within the Institute for Interdisciplinary Re-
search at the Alexandru Ioan Cuza University of Iasi,
for infrastructure used.
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