Hydrazides as powerful tools in medicinal chemistry: synthesis, reactivity, and biological applications

Academic Edi o s:
Michail Ch is odoulou and
Cons an inos A hanassopoulos
Recei ed: 11 May 2025
Re ised: 20 June 2025
Accep ed: 30 June 2025
Published: 3 July 2025
Ci a ion: Teixei a, S.; Cas anhei a,
E.M.S.; Ca alho, M.A. Hyd azides as
Powe ul Tools in Medicinal
Chemis y: Syn hesis, Reac i i y, and
Biological Applica ions. Molecules
2025,30, 2852. h ps://doi.o g/
10.3390/molecules30132852
Copy igh : © 2025 by he au ho s.
Licensee MDPI, Basel, Swi ze land.
This a icle is an open access a icle
dis ibu ed unde he e ms and
condi ions o he C ea i e Commons
A ibu ion (CC BY) license
(h ps://c ea i ecommons.o g/
licenses/by/4.0/).
Re iew
Hyd azides as Powe ul Tools in Medicinal Chemis y:
Syn hesis, Reac i i y, and Biological Applica ions
So ia Teixei a 1,2 , Elisabe e M. S. Cas anhei a 2and M. Alice Ca alho 1,*
1Cen e o Chemis y o Uni e si y o Minho (CQ-UM), Campus de Gual a , 4710-057 B aga, Po ugal;
[email p o ec ed]
2Cen e o Physics o Minho and Po o Uni e si ies (CF-UM-UP), Uni e si y o Minho, Campus de Gual a ,
4710-057 B aga, Po ugal; [email p o ec ed]
*Co espondence: [email p o ec ed]
Abs ac
The inc ease in d ug esis ance and he high oxici y o cu en d ugs ha e inspi ed he
scien i ic communi y o de elop new d ugs o a ious diseases. Hyd azides ha e become
an a ac i e unc ional g oup o easily ob ain a ple ho a o no el compounds wi h a b oad
ange o biological ac i i ies. This e iew, which con ains s udies in he li e a u e om
he p e ious i e yea s, ocuses on he syn hesis me hods and biological applica ions o
hyd azides and hei de i a i es. He e, he de ails o he expe imen al eac ion condi ions
used o he syn hesis o hyd azides and hei de i a i es (hyd azide–hyd azones and
he e ocycle de i a i es) a e p esen ed, as well as he pu i ica ion me hods and he biological
ac i i y o he syn hesized compounds.
Keywo ds: hyd azides; hyd azide de i a i es; syn hesis; bioac i e hyd azide de i a i es
1. In oduc ion
Acco ding o he Wo ld Heal h O ganiza ion [
1
], diabe es, ca dio ascula (ischemic
hea disease and s oke), espi a o y (ch onic obs uc i e pulmona y disease and espi a-
o y in ec ions), cance s, and Alzheime ’s and demen ia diseases a e some o he leading
causes o dea h wo ldwide. Besides hese diseases, mala ia, ube culosis, HIV/AIDS, and
ci hosis o he li e a e among he leading causes o dea h in low-income coun ies. The
main obs acles o ea ing/e adica ing hese diseases include he inc ease in d ug esis ance
o cu en d ugs [2–9] and he high oxici y o he d ugs used in he ea men s [2,10–12].
Nowadays, many e o s ha e been made o de elop no el and sa e he apeu ic
al e na i es. The scien i ic communi y has been sea ching o new compounds wi h educed
oxici y and imp o ed biological e icacy, o e en po en ial p obes o bioimaging in disease
diagnosis [13].
Hyd azides a e a class o o ganic compounds wi h he unc ional g oup R-CON-R
1
N-
R
2
R
3
[
14
]. I is an ex emely impo an g oup in o ganic chemis y, being an e ec i e
subs a e in bo h domains o chemical eac ions and medicinal chemis y [15,16].
Since he 20 h cen u y, se e al hyd azides such as isoniazid 1(isonico inic acid hy-
d azide) [
9
,
17
,
18
], p-aminosalicylic acid hyd azide 2[
19
], on u ace am hyd azide 3[
20
,
21
],
isoca boxazide 4[
22
], ip oniazid 6[
23
], nialamide 7[
11
] and bense azide 5[
24
] ha e been
in oduced o he apeu ic pu poses, as an i ube culosis, an i i al, an icon ulsan , neu-
os imula o , an idep essi e (monoamine oxidase inhibi o ), and an i-Pa kinson agen s
(Figu e 1).
Molecules 2025,30, 2852 h ps://doi.o g/10.3390/molecules30132852
Molecules 2025,30, 2852 2 o 71
Figu e 1. Examples o hyd azides and hei he apeu ic applica ions.
O e ime, hyd azides 8we e ound o be g ea p ecu so s o o he bioac i e com-
pounds such as hyd azine–hyd azones 9[
25
,
26
]. Hyd azides 8we e also employed as build-
ing block syn hons o di e en classes o he e ocycles, like py olones 10 [
27
,
28
], py azoles
11 [
29
,
30
], oxadiazoles 12 [
31
], hiadiazoles 13 [
30
,
32
], iazoles 14 [
30
], by cycliza ion o
cycloaddi ion eac ions wi h o he eagen s [
28
,
33
] (Figu e 2). These hyd azide de i a i es
simila ly e ealed a wide ange o biological ac i i ies, including an i umo [
34
–
37
], an imi-
c obial [
38
], an i ungal [
39
], an imala ial [
2
], an ileishmanial [
40
], an i-in lamma o y [
41
],
an idiabe ic [
42
,
43
] and an ioxidan [
44
] p ope ies. They also showed he bicide ac i i y o
we e used as dyes [45,46].
Figu e 2. Linea and he e ocyclic compounds syn hesized om hyd azides.
Molecules 2025,30, 2852 3 o 71
A e iew desc ibing he syn hesis o hyd azides and he e ocyclic ings om hy-
d azides was published in 2014 by Majumda e al. [
47
]. In 2018, Hosseini e al. [
32
]
epo ed a compila ion o he syn hesis o he e ocycles om cyanoace ohyd azides. Also,
in 2021, Mali e al. [
48
] b ie ly epo ed he impo ance o he hyd azides and hei de i a-
i es (speci ically hyd azide–hyd azones) as bioac i e compounds o e he yea s.
This e iew p esen s a comp ehensi e compila ion and desc ip ion o he me hods
used o syn hesize hyd azides in he las 5 yea s, hei use as p ecu so s o syn hons o
gene a e new de i a i es, and hei main biological applica ions.
Mo eo e , h oughou he e iew, ables will be p o ided summa izing he expe i-
men al condi ions o he syn hesis and pu i ica ion o hyd azides and hei de i a i es.
2. Hyd azides
2.1. Syn hesis o Hyd azides
The i s exis ing hyd azides, speci ically o mic and ace ic acid hyd azides, we e
p oduced by Ku zius in 1895 [
49
]. Cu en ly, many hyd azides wi h alkyl, a yl, and
he e oa yl subs i uen s a e being syn hesized o o e come d ug esis ance and oxic-
i y. Hyd azides 8(Scheme 1) a e con en ionally syn hesized om compounds 16, such
as
es e s [2,13,26,34–41,43,44,50–95], anhyd ides [96], and acyl chlo ides [2,97,98],
o o h-
e s [
99
–
103
] ha possess a good lea ing g oup, and hyd azine. When i is no possible
o ha e compounds 16 a ailable, he lea ing g oup is p oduced om he acid de i a i e
15 [
82
,
85
,
88
,
96
]. Acco ding o he eac ion condi ions ou lined in Table 1, he expe imen al
eac ion condi ions o gene a e hyd azide 8 om p ecu so 16 do no di e much, and
usually, he eac ion akes place in an alcohol sol en , a oom empe a u e, o unde
e lux. The eac ions did no las mo e han 24 h, and gene ally, p oduc 8was pu i ied by
ec ys alliza ion o by column ch oma og aphy. Hyd azides 8a o 8abb we e ob ained in
low o excellen yields (26–98%) om es e s (17a–17aaw), anhyd ides (18), acyl chlo ides
(19a–c), o o he s (20–23).
Scheme 1. Rep esen a i e scheme o hyd azide syn hesis.
Besides he egula unc ional g oups, Zhao e al. [
99
] ob ained he hyd azide 8aay om
ac i a ed in e media y 20 by eac ion wi h hyd azine hyd a e (Scheme 2). The acid de i a i e
8abc was ob ained om 8aay by eac ion wi h sodium hyd oxide in aqueous me hanol.
Scheme 2. Syn hesis o hyd azide 8abc. (a) H
2
NNH
2·
H
2
O, E
3
N, Na
2
SO
4
, CHCl
3
, 35
◦
C; (b) NaOH,
MeOH/H2O, . .
Molecules 2025,30, 2852 4 o 71
Singh e al. [
104
] ob ained hyd azides ia he ansamida ion o N-Boc, N-ni oso, and
N- osyl amides wi h hyd azine hyd a e, a oom empe a u e, in 76–94% yields (Scheme 3).
Scheme 3. Syn hesis o hyd azides 8 by ansamida ion; (a)
2
HNNH
2
(2-3 eq), DCM, . .,
30 min–2 h;
when R
2
= Boc and R
3
= Me, o R
1
= Alk, DBU (1 eq) is also used; (b) 25 (3 eq), DCM, . ., 1 h;
(c) 2HNNH2(3 eq), DCM, . ., 1 h.
Table 1. Reac ion condi ions o he syn hesis and pu i ica ion o hyd azides om es e s, anhyd ides,
acyl chlo ides, and o he s.
Re . S a ing Ma e ial Expe imen al Condi ions Pu i ica ion P ocess Hyd azide
Compounds (η%)
[50]
17a
Hyd azine hyd a e (1.2 eq)
E OH
75–80 ◦C
2 h
Silica gel column
ch oma og aphy
8a X=N,O;R=Alk
(70–95%)
[51]
17b
Hyd azine hyd a e
(10 eq)
MeOH
Re lux
3 h
-
8b
[26]
17c
Hyd azine hyd a e (n.s.)
E OH o MeOH
85 ◦C
6 h
Rec ys alliza ion
om aqueous
e hanol o me hanol
8c (88%)
[26]
17d
Hyd azine hyd a e (n.s.)
E OH o MeOH
85 ◦C
6 h
Rec ys alliza ion
om aqueous
e hanol o me hanol
8d (54%)
Molecules 2025,30, 2852 5 o 71
Table 1. Con .
Re . S a ing Ma e ial Expe imen al Condi ions Pu i ica ion P ocess Hyd azide
Compounds (η%)
[26]
17e
Hyd azine hyd a e (n.s.)
E OH o MeOH
85 ◦C
6 h
Rec ys alliza ion
om aqueous
e hanol o me hanol
8e (75%)
[26]
17
Hyd azine hyd a e (n.s.)
E OH o MeOH
85 ◦C
6 h
Rec ys alliza ion
om aqueous
e hanol o me hanol
8 (83%)
[55]
17g
Hyd azine hyd a e (10 eq
added d opwise)
MeOH
Re lux
2 h
-
8g (80%)
[56]
17g
Hyd azine hyd a e
(9 eq added d opwise)
MeOH
Re lux
2 h
Silica gel column
ch oma og aphy
8g (55%)
[57]
17h
Hyd azine hyd a e (80%)
(20.6 eq)
Nea
Re lux
n.s.
-
8h (96%)
[43]
17i
Hyd azine 80% (n.s.)
E OH
Re lux
6h
n.s.
8i (50%)
[43]
17j
Hyd azine 80% (n.s.)
E OH
Re lux
6 h
n.s.
8j (57%)
[43]
17k
Hyd azine 80% (n.s.)
E OH
Re lux
6 h
n.s.
8k (47%)
[13]
17l
Hyd azine hyd a e (1.7 eq)
MeOH
Re lux
4.5 h
Rec ys alliza ion
om me hanol
8l (63%)
[34]
17m
Hyd azine hyd a e (n.s.)
E OH
Re lux
8–10 h
n.s.
8m R = H, B (n.s.)

Molecules 2025,30, 2852 6 o 71
Table 1. Con .
Re . S a ing Ma e ial Expe imen al Condi ions Pu i ica ion P ocess Hyd azide Compounds
(η%)
[38]
17n
Hyd azine hyd a e (1.1 eq)
E OH
Re lux
3 h
Rec ys alliza ion
om e hanol
8n (75%)
[40]
17o R2= H, R3= H
17p R2= Cl, R3= H
17q R2= H, R3= Cl
Hyd azine hyd a e 80%
(n.s.)
E OH
Re lux
3 h
n.s. 8o R2= H, R3= H
8p R2= Cl, R3= H
8q R2= H, R3= Cl
(n.s.)
[53]
17
Hyd azine hyd a e (1 eq)
Anhyd ous E OH
~0 ◦C
30 min
Rec ys alliza ion
om e hanol 8 (73%)
[54]
17s
Hyd azine hyd a e (n.s.)
MeOH
Re lux
6 h
Rec ys alliza ion
om e hanol
8s (n.s.)
[39]
17
Hyd azine monohyd a e (8
eq)
E OH
Ice ba h
30 min
-
8 (n.s.)
[59]
17u
Hyd azine hyd a e (2 eq)
E OH
Re lux
8 h
-
8u (91%)
[105]
17
17w
Hyd azine hyd a e (1.1 eq)
MeOH
Py idine (ca .)
Re lux
6–7 h
Rec ys alliza ion
om me hanol
8
8w
(n.s)
[61]
17x
Hyd azine hyd a e (2 eq)
E OH
Re lux
4 h
-
8x (n.s.)
[62]
17y
Hyd azine hyd a e 80% (~8
eq, d opwise)
E OH
95–100 ◦C
12 h
Rec ys alliza ion
om e hanol
8y (89%)
Molecules 2025,30, 2852 7 o 71
Table 1. Con .
Re . S a ing Ma e ial Expe imen al Condi ions Pu i ica ion P ocess Hyd azide Compounds
(η%)
[36]
17z
Hyd azine hyd a e (n.s.)
E OH
80–90 ◦C
8 h
-
8z (n.s.)
[41]
17aa
Hyd azine hyd a e 85%
(~6.5 eq)
MeOH
Re lux
8 h
-
8aa R = Me, OMe
(82–92%)
[63]
17ab
Hyd azine hyd a e (~10 eq)
MeOH
Re lux
5 h
Rec ys alliza ion
om me hanol
8ab (37%)
[64]
17ac
Hyd azine hyd a e (n.s.)
E OH
Re lux
6 h
-
8ac (78%)
[35]
17ad
Hyd azine (4 eq)
E OH
Re lux
5 h
Rec ys alliza ion
om e hanol
8ad (73%)
[65]
17ae
Hyd azine hyd a e (6 eq.)
E OH
30 ◦C
1 h
Rec ys alliza ion
om e hanol
8ae (26%)
[66]
17a
Hyd azine hyd a e 80% (31
eq)
E OH
Re lux
8 h
Rec ys alliza ion
om e hanol
8a (n.s.)
[67]
17ag
Hyd azide hyd a e (4.6 eq)
E OH
Re lux
3 h
Rec ys alliza ion
om e hanol
8ag (78%)
[68]
17ah
Hyd azine hyd a e 80% (31
eq)
E OH
Re lux
4 h
Rec ys alliza ion
om e hanol
8ah (70%)
[43]
17ai
Hyd azine hyd a e 80% (15
eq)
E OH
Re lux
8 h
Rec ys alliza ion
om e hanol
8ai (63%)
Molecules 2025,30, 2852 8 o 71
Table 1. Con .
Re . S a ing Ma e ial Expe imen al Condi ions Pu i ica ion P ocess Hyd azide Compounds
(η%)
[43]
17aj
Hyd azine 80% (n.s.)
E OH
Re lux
6 h
n.s. 8aj R′= Alk, Halide
(39–54%)
[43]
17ak
Hyd azine 80% (n.s.)
E OH
Re lux
6 h
n.s.
8ak (46%)
[43]
17al
Hyd azine 80% (n.s.)
E OH
Re lux
6 h
n.s.
8al (57%)
[43]
17am
Hyd azine 80% (n.s.)
E OH
Re lux
6 h
n.s.
8am (56%)
[72]
17ao
Hyd azine hyd a e (~3 eq)
E OH
Re lux
12 h
-
8ao (n.s.)
[73]
17ap
Hyd azine hyd a e (2 eq)
E OH
Re lux
8 h
-
8ap (80%)
[75]
17aq
Hyd azine hyd a e 85% (3
eq)
E OH
. .
4 h
Rec ys alliza ion
om isop opyl
alcohol
8aq (67%)
[76]
17a
Hyd azine hyd a e 99% (1
eq)
E OH
Re lux
6 h
Rec ys alliza ion
om e hanol
8a R1= H, Cl, CH3
(67–73%)
[77]
17as
Hyd azine hyd a e (1.5 eq)
E OH
Re lux
4 h
Rec ys alliza ion
om e hanol
8as (90%)
[78]
17a
Hyd azine hyd a e (1.02 eq)
E OH
Re lux
3 h
Rec ys alliza ion
om e hanol o
me hanol
8a (89–97%)
Molecules 2025,30, 2852 9 o 71
Table 1. Con .
Re . S a ing Ma e ial Expe imen al Condi ions Pu i ica ion P ocess Hyd azide
Compounds (η%)
[79]
17au
Hyd azine hyd a e (20 eq)
E OH
Re lux
4 h
Rec ys alliza ion
om e hanol
8au (61%)
[37]
17a
Hyd azine hyd a e 80% (3
eq)
E OH
Re lux
3 h
Rec ys alliza ion
om e hanol/DMF
8 (90%)
[80]
17ac
Hyd azine monohyd a e (1
eq)
E OH
Re lux
4 h
Rec ys alliza ion
om dioxane
8ac(90%)
[81]
17w
Hyd azine hyd a e (4 eq)
E OH
Re lux
6 h
-
8aw X = N, CH
(48–55%)
[82]
17x
Hyd azine (1 eq)
E OH
Re lux
3 h
-
8ax(94%)
[83]
17ay R = 4-F-C6H4,
17az R =
4-CH3–C6H4
17aaa R =
2-Cl,4-Cl-C6H3
Hyd azine hyd a e (n.s.)
E OH
Re lux
n.s.
n.s.
8ay R = 4-F-C6H4,
8az R = 4-CH3–C6H4
8aaaR =
2-Cl,4-Cl-C6H3
(n.s.)
[84]
17aab
Hyd azine hyd a e (10 eq)
E OH
Re lux
7 h
-
8aab (80%)
[2]17aac R = 2- u yl
17aad R =
3,4,5-(MeO)3C6H2
17aai R =
3,4-(MeO)2C6H3
Hyd azine hyd a e (n.s.)
-
Re lux
n.s.
-
8aac R = 2- u yl
8aad R =
3,4,5-(MeO)3C6H2
8aai R =
3,4-(MeO)2C6H3
(n.s.)
[85]
17al
Hyd azine hyd a e (~11 eq)
E OH
. .
3–4 h
-
8al (98%)
Molecules 2025,30, 2852 16 o 71
Scheme 9. Syn hesis o hyd azides 47 and moclobemide: (a) oluene, 456 nm, , 16 h; (b) DCM, . .,
20 h; (c) i. MsCl, DCM, E 3N, DMAP, . ., 24 h; ii. mo pholine, 100 ◦C, 6 h.
Scheme 10. Syn hesis o compounds 50; (a) E
3
N (0.5–3.5 eq), CH
3
CN, . ., 30 min–15 h; (b) E
3
N
(3.5 eq), H2O, CH3CN, . ., 24 h.
2.2. Biological Ac i i y o Hyd azides
The compounds p esen ed in Figu e 3showed an icance ac i i y agains a ious can-
ce cell lines. Hyd azide 8ac showed good an icance ac i i y agains MCF-7 b eas cance
and HepG2 hepa ocellula ca cinoma cell lines wi h IC
50
= 8.1
µ
M and
IC50 = 28.6 µM,
espec i ely [
64
]. Hyd azides 8aap.1 and 29c.1 also displayed an icance ac i i y owa ds
he MCF-7 cance cell line wi h IC
50
alues o 2.37 and 1.83
µ
M, espec i ely [
92
]. Besides
ha , Sab y e al. [
92
] epo ed ha hese hyd azides showed a s ong dual inhibi ion ac i i y
o EGFR/HER2 kinase wi h IC
50
alues o 0.153
µ
M (EGFR) and 0.108
µ
M (HER2) o 29c.1
and 0.122
µ
M (EGFR) and 0.108
µ
M (HER2) o 8aap.1. In
in i o
s udies in Swiss albino
mice mamma y glands, compounds 8aap.1 and 29c.1 showed umo olume educ ions by
65.3 and 76.5%, espec i ely, a 10 mg/kg.
De i a i es 29a.1 and 29a.2, epo ed by Ramí ez e al. [
106
], we e also es ed agains
he MCF-7 cance cell line. Compounds 29a.1 and 29a.2 p esen ed IC
50
alues o 15.41 and
12.99
µ
M, espec i ely. In addi ion, de i a i es 29a.3 and 29a.2 we e ac i e agains he A549
cell line (lung cance ) wi h IC50 alues o 37.17 and 31.02 µM, espec i ely [106].
Hyd azides 8ad and 29b.1, epo ed by Abdel ehim e al. [
35
] and Han e al. [
107
],
p esen ed ac i i y agains he HCT-116 colo ec al cance cell line wi h IC
50
alues o
8.44 µg/mL
and 2.02
µ
M (Figu e 3). Compound 29b.1 also showed ac i i y agains PC-3
(p os a ic adenoca cinoma), A549 (lung cance ), and MDA-MB-231 ( iple-nega i e b eas
cance ) cance cell lines, wi h IC
50
alues o 1.95, 1.62, and 1.55
µ
M. I also showed po en
inhibi o y ac i i ies agains phospha idylinosi ol 4,5-bisphospha e 3-kinase ca aly ic sub-

Molecules 2025,30, 2852 17 o 71
uni alpha iso o m (PI3K
α
) wi h an IC
50
= 0.46 nM and mammalian a ge ing o apamycin
(mTOR) wi h an IC50 = 12 nM [107].
Figu e 3. Hyd azides wi h an icance ac i i y.
Hyd azide 8b (Figu e 4) was e alua ed o i s an ibac e ial and an i ungal ac i i ies. I
showed a s ong an ibac e ial and an i ungal ac i i y, wi h inhibi ion zones o 29, 30, 28
and 16 mm agains Bacillus sub ilis,Esche ichia coli,Candida albicans and Aspe gillus nige ,
espec i ely [
51
]. Compounds 8c–8 also exhibi ed ac i i y agains E. coli,B. sub ils, and
Asp. nige s ains, p esen ing inhibi ion zones a ying be ween 2 and 5 mm [26].
Compounds 28 (Figu e 4) we e e alua ed as ungicides [
109
]. Compounds 28a.1–
28a.5 exhibi ed g ow h inhibi ion ac i i y agains Bo yosphae ia do hidea,Rhizoc onia solani,
and Gibbe ella zeae wi h EC
50
alues wi hin he 10.0–0.306
µ
g/mL ange, which we e
highe ac i i y han hose o he comme cial ag ochemicals azoxys obin, boscalid, and
luxapy oxad [109].
Disubs i u ed hyd azides 29 we e es ed as an imala ial agen s. Compounds 29a.4
and 29a.5 (Figu e 5) showed an imala ial ac i i y wi h IC
50
alues o 0.65 and 0.64
µ
M,
espec i ely [106].
Hyd azides p esen in Figu e 6we e e alua ed as an i i als. Compound 8abc showed
an i i al ac i i y agains in luenza A as a Neu aminidase inhibi o agains H5N1 and H1N1
sub ypes wi h IC
50
alues o 26.8 nM and 11.9 nM, espec i ely [
99
]. Mo eo e , hyd azide
8aax.1 was p esen ed as a g ea immunomodula o , p esen ing 80% p o ec ion agains he
highly pa hogenic a ian in luenza i us (H5N8) [28].
Myelope oxidase plays a key ole in he human an imic obial sys em by oxidizing i al
molecules o mic oo ganisms in phagolysosomes h ough he p oduc ion o hypochlo ous
acid. I has been associa ed wi h in lamma o y diseases such as enal inju y, mul iple
scle osis, and ca dio ascula and neu odegene a i e diseases. Saylam e al. [
65
] epo ed
compound 8ae (Figu e 7) as an excellen myelope oxidase inhibi o wi h an
IC50 = 0.393 µM,
which is compa able o he s anda d d ug 4-aminobenzoic acid hyd azide.
Molecules 2025,30, 2852 18 o 71
Figu e 4. Hyd azides wi h an ibac e ial and an i ungal ac i i y.
Figu e 5. Hyd azides wi h an ipa asi ic ac i i y.
Figu e 6. Hyd azides wi h an i i al ac i i y.
Figu e 7. Myelope oxidase inhibi o .
Molecules 2025,30, 2852 19 o 71
3. Hyd azide De i a i es
3.1. Hyd azide–Hyd azones
3.1.1. Syn hesis o Hyd azide–Hyd azones
Hyd azide–hyd azone de i a i es a e among he mos equen ly syn hesized and
epo ed hyd azide de i a i es in he li e a u e. These compounds s and ou in o ganic
and medicinal chemis y since hey ha e exhibi ed a wide ange o biological ac i i ies
and ha e been used as impo an in e media es in he syn hesis o he e ocycle ings om
hyd azides. The hyd azide–hyd azone moie y con ains he unc ional g oup -CO-NH-
N=CR
1
R
2
, which is a combina ion o he hyd azide and imine g oups. The imine g oup
con e s E/Z isome ism and pho och omism in bo h solu ion and he solid s a e [
55
,
97
].
Mo eo e , he -NH- and C=O g oups allow he compounds o ha e he capabili y o binding
o anions/ca ions and biomolecules; he coexis ence o imine and ca bonyl g oups allows
hem o es ablish me allo-assemblies [55].
In he pas ew yea s, hyd azides ha e been ex ensi ely used o syn hesize se e al
hyd azide–hyd azone de i a i es, as po en ial agg ega ion-induced emission luminogens
(AIEgens), p obes, o an icance , an imic obial, an i ungal, an i ube culosis, an imala ial, an-
i i al, and an ioxidan agen s. Some de i a i es exe hei ac i i y h ough he inhibi ion o
speci ic enzymes such as ace ylcholines e ase, bu y ylcholines e ase,
α
-glucosidase, and o he s.
Hyd azide–hyd azones 52 a e syn hesized om he eac ion be ween a hyd azide and an
aldehyde/ke one [
13
,
34
,
37
,
38
,
43
,
53
,
54
,
56
,
57
,
66
–
68
,
71
–
73
,
75
–
79
,
95
–
98
,
101
,
117
–
127
] (Scheme 11).
Acco ding o he s udies in his e iew, hese eac ions, in gene al, occu in alcohols (e hanol o
me hanol) and a high empe a u es (Table 3). The eac ions occu ed wi hou o wi h acid ca al-
ysis, such as ace ic
acid [34,43,54,66,71,73,76,77,79,95,96,117,119,121,123,127]
o p-TsOH [
55
,
56
],
and in hese cases, he eac ions may occu a oom [
55
,
56
,
79
,
117
] o high empe a-
u es [
34
,
38
,
43
,
54
,
66
,
68
,
71
–
73
,
76
,
77
,
95
,
96
,
119
,
121
,
123
,
127
]. Hyd azide–hyd azone de i a-
i es we e ob ained in low o excellen yields.
As men ioned ea lie , some hyd azides a e comme cially a ailable. Howe e , o he s
a e syn hesized by he scien i ic communi y o o igina e he equi ed compounds. He e,
hyd azide–hyd azones syn hesized om alkyl, a yl, o he e oa yl hyd azides as s a ing
ma e ials, p oduced o no by he au ho s, will be p esen ed. The biological ac i i y o he
gene a ed compounds will also be e iewed.
Scheme 11. Rep esen a i e scheme o hyd azide–hyd azones syn hesis.
Table 3. Reac ion condi ions o he syn hesis and pu i ica ion o hyd azide–hyd azones.
Re . S a ing Ma e ial Expe imen al Condi ions Pu i ica ion P ocess Hyd azone Compounds (η%)
[124]
8abd (1 eq)
E OH, e lux, 2 h
Rec ys alliza ion om
e hanol
52a (71%)
Molecules 2025,30, 2852 20 o 71
Table 3. Con .
Re . S a ing Ma e ial Expe imen al Condi ions Pu i ica ion P ocess Hyd azone Compounds (η%)
[97]
8aaw
RCHO (1.25 eq)
MeCN:CHCl
3
(1:1), HOAc (0.9 eq),
65 ◦C, 24 h
R = A
Silica gel column
ch oma og aphy
52b R = A (72–94%)
[68]
8ah
RCHO (1.1 eq)
E OH, glacial CH3COOH (d ops),
e lux, 8 h
R = A
Rec ys alliza ion om
e hanol
52c R = A (56–95%)
[96]
MeO
MeO
NHNH2
O
OMe
OMe
R1
8aau
(1 eq)
MeOH, CH3COOH (ca .), e lux,
1h
Flash column
ch oma og aphy
52d (63–85%)
[72]
8as
RCHO (1 eq), E OH, pipe idine
(0.3 eq), e lux, 2 h
R = A
-
52e R = A (n.s.)
[77]
8ao
RCHO (1 eq), E OH, CH3COOH
(d ops), e lux, 6–8 h
R = A
Rec ys alliza ion om
e hanol
52 R = A (85–92%)
[57]
8h
RCHO (1 eq)
E OH, e lux
R = A
-
52g R = A (26–55%)
[57]
8h
MeCOR (1 eq)
E OH, e lux
R = A
-
52h R = A (15–61%)
[75]
8aq
MeCOR1(n.s.)
E OH, e lux, 1 h
Rec ys alliza ion om
E OH, n-BuOH, o i-P OH
52j (61–89%)
[73]
8ap
MeCOR (1 eq), CH3COOH (17 eq),
E OH, e lux, 6–8 h
R = A
Rec ys alliza ion om
ace ic acid
52k R = A (85–95%)
Molecules 2025,30, 2852 21 o 71
Table 3. Con .
Re . S a ing Ma e ial Expe imen al Condi ions Pu i ica ion P ocess Hyd azone Compounds (η%)
[101]
8aba.1
(1 eq)
dioxane, e lux, 30 min
Rec ys alliza ion om
e hanol/dioxane mix u e
(1:1) o dioxane
52l (77%)
[76]
8a
R2CHO (1 eq)
E OH, CH
3
COOH (ca .), e lux, 6 h
R2= A
Rec ys alliza ion om
e hanol
52m R2= A (41–60%)
[76]
8a
MeCOR (1 eq)
E OH, CH
3
COOH (ca .), e lux, 6 h
R = A
Rec ys alliza ion om
e hanol
52n R = A (46–62%)
[117]
8abe R1= H
8ab R1= CH3
(1 eq)
E OH, CH3COOH (0.9 eq), . .
Rec ys alliza ion om
dichlo ome hane/e hanol
(1:2)
52o (40–84%)
[43]
8ai–8am
(an ano in)
E OH, CH3COOH, 50 ◦C, 2h
Silica gel column
ch oma og aphy
52p (73–89%)
[55]
8g
RCHO (1 eq)
MeOH, p-TsOH (ca .), . ., 2 h
R = A
Silica gel column
ch oma og aphy
52q R = A (90–95%)

Molecules 2025,30, 2852 22 o 71
Table 3. Con .
Re . S a ing Ma e ial Expe imen al Condi ions Pu i ica ion P ocess Hyd azone Compounds (η%)
[56]
8g
RCHO (n.s.)
MeOH, p-TsOH (ca .), . .,
o e nigh
R = A
Silica gel column
ch oma og aphy
52q R = A (60–79%)
[95]
8aa
RCHO (1.1 eq)
E OH, CH3COOH ( ew d ops),
e lux, 12 h
R = A
Rec ys alliza ion om
e hanol
52s R = A (68–90%)
[66]
8a
RCHO (1.1 eq)
E OH, CH3COOH ( ew d ops),
e lux, 8 h
R = A
Rec ys alliza ion om
e hanol
52 R = A (55–80%)
[67]
8ag
RCHO (1.1 eq)
E OH, e lux, 3 h
R = A
Rec ys alliza ion om
e hanol
N
H
O
N R
I
B
52u R = A (24–90%)
[118]
8abj R = 2-HO
8a R = 4-HO
R2CHO (0.99 eq)
E OH o i-P OH, 60 ◦C, 0.5–6 h
R2= A
Rec ys alliza ion om
i-P OH
52 R = 2-HO, 4-HO; R2= A
(66–92%)
[38]
O
NHNH2
I
OH
8n
RCHO (1.1 eq)
E OH, e lux, 3–35 min
R = He A
Rec ys alliza ion om
e hanol
52w R = He A (18–97%)
[43]
8j,8k
(n.s.)
E OH, CH3COOH, 50 ◦C, 2h
Silica gel column
ch oma og aphy
52p (73–89%)
[13]
8l
2,4-(HO)2C6H3CHO (1 eq)
MeOH, e lux, 6 h -
52y (84%)
[34]
8m
1. (1 eq)
CH3COOH (28 eq), 90 ◦C, 6 h
2. NaHCO3
Rec ys alliza ion om
e hanol
52z R, R1, R2= alkyl o halide
(86–90%)
Molecules 2025,30, 2852 23 o 71
Table 3. Con .
Re . S a ing Ma e ial Expe imen al Condi ions Pu i ica ion P ocess Hyd azone Compounds (η%)
[98]
8aax
RCHO (1 eq), E OH, 78 ◦C, 4 h
R = A
Rec ys alliza ion om
ace oni ile o 70%
e hanol
52aa R = A (50–86%)
[37]
8a
RCHO (2.1 eq)
E OH/DMF, e lux, 5 h
R = A
Rec ys alliza ion om
DMF/e hanol
52ab R = A (72–80%)
[119]
1X=N,Y=CH
8abg.1 X=CH,Y=N
8abg.2 X=N+-O−,Y=CH
8abg.3 X=CH,Y=N+-O−
(n.s)
E OH o CH3COOH, e lux
n.s.
52ac (46–65%)
[119]
(n.s)
E OH o CH3COOH, e lux
R1, R2= alkyl
n.s.
52ad R1, R2= alkyl (72–95%)
[53]
8
RCHO (1.1 eq), E OH, e lux, 2 h
R = A
Rec ys alliza ion om
e hanol
52ae R = A (10–93%)
[120]
1X=N,Y=CH
8abg.1 X=CH,Y=N (1 eq)
E OH, e lux, 5 h
Silica gel column
ch oma og aphy
52a R=R=H,OCH3, F, Cl
(89–94%)
[43]
8al E OH,
CH3COOH, 50 ◦C, 2 h
Silica gel column
ch oma og aphy
52p.12
[54]
8s
R1COR2(1 eq)
E OH, ace ic acid (~0.2 eq), e lux,
8 h
-
52ag R1= A , R2= H o alkyl
(62–92%)
Molecules 2025,30, 2852 24 o 71
Table 3. Con .
Re . S a ing Ma e ial Expe imen al Condi ions Pu i ica ion P ocess Hyd azone Compounds (η%)
[121]
1X=N,Y=CH
8abh X, Y = C-B , C-Cl, CH, N,
C-Me, C-NO2(1 eq)
E OH, CH
3
COOH (ca .), e lux, 3 h
Rec ys alliza ion om
e hanol
52ah (60–80%)
[122]
8abi (1 eq)
MeOH, e lux
Rec ys alliza ion om
me hanol
52ai (78–95%)
[123]
1(1 eq)
MeOH, CH
3
COOH (d ops), e lux,
2 h
Rec ys alliza ion om
e hanol
52aj R1= A (75–87%)
[78]
8a (n.s.), 25 min
-
52ak R = A (93%)
[79]
8au
4-HOC6H4CHO (1 eq)
E OH, CH3COOH (d ops), . ., 30
min
Rec ys alliza ion om
e hanol
52al (23%)
[125]
8abh
RCHO (1 eq), E OH, e lux, 1–2h
R = He A
Rec ys alliza ion om
e hanol/wa e o e hanol 52an R = He A
(82–95%)
[126]
1(1 eq),
MeOH, A (g), e lux, 3–60 h;
Y1: CHO, Z: H, Ph, cyclopen yl
Rec ys alliza ion om a
mix u e o
chlo o o m/e he o silica
gel column
ch oma og aphy
52ao (40–86%)
Y2: CONH=CHPy; Z: H, Ph,
cyclopen yl
[126]
1(1 eq),
MeOH, A (g), . ., 18–48 h
Y1: CHO, Z: H, Ph, cyclopen yl
Rec ys alliza ion om a
mix u e o
chlo o o m/e he o silica
gel column
ch oma og aphy 52ap (78–81%)
Y2: CONH=CHPy; Z: H, Ph,
cyclopen yl
[127]
8abh
(1 eq), E OH,
CH3COOH (0.8 eq), e lux, 4–7 h
R1= Me o Ph; R2= Me o H; R3=
Me o OC2H5
Rec ys alliza ion om
e hanol
52aq (73%)
n.s.—no speci ied by he au ho s.
Molecules 2025,30, 2852 25 o 71
3.1.2. Biological Ac i i y o Hyd azide–Hyd azones
The new hyd azide–hyd azone de i a i es ep esen ed in Figu e 8we e e alua ed as
an icance agen s. Compounds 52a,52c.1,52d.1, and 52e.1 showed good ac i i y agains
human b eas cance cell lines, speci ically agains he MCF7 line, wi h IC
50
alues o
7.38, 59.81, 3.49, and 14.6
µ
M, espec i ely [
68
,
72
,
96
,
124
]. Mo eo e , compound 52c.1 also
showed p omising an icance ac i i y, wi h IC
50
= 22.42
µ
M, agains he human b eas
cance cell line MDA-MB-231. Compound 52c.1 was es ed
in i o
and dec eased he umo
olume in bo h low (60 mg/kg) and high (120 mg/kg) doses in mice [
68
]. Besides he
ac i i y agains b eas cance , compound 52a showed ac i i y agains he HepG2 cance
cell line wi h IC
50
= 8.79
µ
M [
124
]. In addi ion, de i a i es 52d we e also es ed agains
HCT-116 and SK-MEL-28 (melanoma) cance cell lines. Compound 52d.1 displayed he
highes ac i i y wi h IC
50
alues o 6.82 and 10.39
µ
M, espec i ely, wi h no ele an oxici y
on non-malignan HaCaT (human ke a inocy e) cells [96].
Acco ding o Halil e al. [
97
], na u al compounds wi h bioac i e p ope ies, when
combined wi h hyd azides, can lead o new ac i e compounds wi h inc eased ac i i y.
Hence, Halil e al. [
97
] syn hesized molecules wi h s uc u e 52b (Figu e 8) s a ing om
he na u al p oduc oleanolic acid. The
in i o
an icance ac i i y was s udied on he A549
(adenoca cinomic human al eola basal epi helial) cell line. O he hi een compounds
syn hesized, compound 52b.1 showed he bes ac i i y wi h IC
50
= 0.08
µ
M and low
cy o oxici y on he BEAS-2B cells (human non- umo igenic lung epi helial cells).
The an icance ac i i y o comb e as a in–oxindole 52d, py imidine de i a i es 52e,
and iazoles 52 (Figu e 8) was also e alua ed agains he A549 cell line. Compounds
52d.1 and 52e.1 we e p omising an icance agen s wi h IC
50
alues o 1.26 and 11.3
µ
M,
espec i ely [
72
,
77
,
96
]. Fu he mo e, Abba e al. [
72
] iden i ied he de i a i e 52e.1 as a
po en compound agains DU145 (p os a e cance ) using HeLa (ce ical cance ) cell lines
wi h IC50 alues o 13.4 and 9.1 µM, espec i ely [72].
Acco ding o Almehmadi e al. [
77
], molecules 52 e ealed an an icance capaci y,
p esen ing a g ow h inhibi ion anging om 55 o 90% a 400
µ
g/mL agains he A549
cell line.
Han e al. [
95
] desc ibed de i a i es 52s.1 and 52s.2 wi h high an icance ac i -
i y agains he human colo ec al adenoca cinoma (Colo-205) cell line (
IC50 = 50.0
and
20.5 µM, espec i ely
). On he o he hand, compounds 52s.3, 52s.4, 52s.5, 52 .1, and 52 .2
displayed he g ea an icance ac i i y agains he li e hepa ocellula ca cinoma HepG2
cell line wi h IC
50
= 30.5, 35.9, 20.8, 42.4, and 37.4
µ
M, espec i ely [
66
]. De i a i es 52 .1
and 52 .2, epo ed by Han e al. [
66
] (Figu e 8) exhibi ed lowe ac i i y han de i a i es 52s.
Among he hi een di e en hyd azones 52u, desc ibed by Popiołek e al. [
67
], compound
52u.1 exhibi ed he bes cy o oxici y wi h IC
50
= 33.45 and 11.94
µ
M agains hepa ocellula
ca cinoma (HepG2) and enal adenoca cinoma (769-P) cell lines, espec i ely, and addi ion-
ally showed high selec i i y, wi h low cy o oxici y agains he no mal Ve o cell line, wi h
IC50 = 320.54 µM.
Among indole de i a i es 52z [
34
], compound 52z.1 was he mos ac i e agains he
A549 lung adenoca cinoma cell line wi h IC
50
= 0.793
µ
M. This compound also showed
g ea ac i i y agains ce ical HeLa and b eas MCF-7 cance cells wi h IC
50
= 1.69 and
1.19
µ
M. The au ho s s udied he mechanisms o ac ion o compound 52z.1 ega ding
di e en signaling pa hways igge ed in HeLa and MCF-7 cells, and i was e i ied ha
his compound induced cell apop osis h ough he gene a ion o eac i e oxygen species
and ac i a ion o many signal ansduc ion pa hways [34].
Molecules 2025,30, 2852 32 o 71
when placed in he p esence o human se um albumin (HSA), hey disassemble and display
an e iden luo escence signal.
Figu e 15. Hyd azide–hyd azone as po en ial p obes.
Compounds 52aj,52ak, and 52al (Figu e 16) we e es ed as po en ial an ioxi-
dan s [
78
,
79
,
123
]. Among he wel e de i a i es 52aj es ed
in i o
, compound 52aj.1
showed he bes ac i i y acco ding o he DPPH me hod (SC
50
= 0.03 mg/mL) [
123
].
Howe e , compound 52ak showed an ioxidan ac i i y
in i o
in a s acco ding o Abdel-
hamid e al. [
78
]. Amongs he quinoline hyd azide–hyd azone de i a i es syn hesized by
Cahyana e al. [
79
], compound 52al showed he bes an ioxidan ac i i y by DPPH assay
wi h IC50 = 843.52 ppm, ye his was weak compa ed o asco bic acid wi h IC50 = 11 ppm.
Figu e 16. Hyd azide–hyd azone wi h an ioxidan ac i i y.
Apa om hei biological impo ance, hyd azide–hyd azone compounds a e occa-
sionally men ioned in he ollowing poin s as use ul in e media e syn hons o he syn hesis
o some he e ocyclic ings [40,47].
3.2. He e ocycles om Hyd azides
Hyd azides a e widely used as syn hons in he syn hesis o a a ie y o he e ocycles
ia elec ophilic eac ions. A e he cycliza ion p ocess, he di e en he e ocycles can
also be u he modi ied o no o ob ain compounds wi h biological ac i i y. Wi hin he
he e ocycles gene a ed om hyd azides, i has become possible o iden i y he syn hesis o
py olones, py azoles, oxadiazoles, hiadiazoles, iazoles, and iazepinones in he ecen
li e a u e, which will be discussed in he ollowing sec ions. The biological ac i i y o he
syn hesized compounds will also be p esen ed.
3.2.1. Py olones
Syn hesis o Py olones
Py olones a e i e-membe ed he e ocyclic lac ams ecognized as impo an sca -
olds whose o igin may be na u al o syn he ic, wi h a wide a ie y o pha macological
ac i i ies [
133
,
134
]. These compounds can p esen an icance [
27
,
135
–
137
], an imala -
ial [
138
], an i-in lamma o y [
139
], an i i al [
28
], and an ioxidan ac i i ies [
140
]. In 2015,
Pelkey e al. [
141
] epo ed di e en me hods, including one-componen in amolecula o
wo-componen in e molecula cycliza ion app oaches o py olone syn hesis ha we e
epo ed h ough he end o 2014.

Molecules 2025,30, 2852 33 o 71
Acco ding o he li e a u e men ioned in Table 4, om 2019 o 2024,
[27,28,101,137,140],
py olones 53 and 54 can be o med om he eac ion o hyd azides (compounds 8aax o
8aba) and elec ophiles (e.g., acyl chlo ides o aldehydes) (Scheme 12) [
27
,
28
,
101
,
137
,
140
].
The eac ions wi h acyl chlo ides occu ed unde e lux [
27
,
28
,
140
] o a oom empe a-
u e [
28
,
137
], and in some cases, a base [
28
] was used. When he eac ion occu ed wi h
aldehydes [
28
,
101
,
140
], he eac ions we e pe o med ia he ca alysis o ace ic acid, in
e hanol, unde e lux condi ions. The p oduc s we e gene ally ob ained in good yields.
Table 4. Reac ion condi ions o he syn hesis and pu i ica ion o py olones om hyd azides.
Re . Hyd azide Expe imen al Condi ions Pu i ica ion P ocess Final Compounds (η%)
[27]
8aba.2
(n.s)
Benzene, e lux
n.s.
53a (78%)
[137]
8aba.2
(1 eq, d opwise)
DMF, . ., 4 h
Rec ys alliza ion om
e hanol
53b (78%)
[28]
8aax.1
(1 eq)
E 3N, dioxane, . ., 1 h
Rec ys alliza ion om
e hanol
53c (86%)
[28]
8aax.1
PhCOCl (1 eq)
Benzene, e lux, 1 h
Rec ys alliza ion om
e hanol
53d (68%)
[140]
8aax.2
CH3COOCOCH3(10.5 eq), . .,
1 h
Rec ys alliza ion om
benzene
53e (65%)
[140]
8aax.2
CH3COOCOCH3(10.5 eq),
e lux, 4 h
Rec ys alliza ion om
pe oleum e he (60–80)
53 (60%)
[140]
8aax.2
PhCOCl, benzene, e lux, 3 h Rec ys alliza ion om
benzene
53g (60%)
Molecules 2025,30, 2852 34 o 71
Table 4. Con .
Re . Hyd azide Expe imen al Condi ions Pu i ica ion P ocess Final Compounds (η%)
[140]
8aax.2
RCHO (1 eq), E OH,
CH3COOH, e lux, 3 h
Rec ys alliza ion om
dioxane
54c (80%)
[28]
8aax.1
(1 eq),
CH
3
COOH, e hanol, e lux, 1 h
Rec ys alliza ion om
e hanol/dioxane
mix u e (1:1)
54a (87%)
[101]
8aba.2
RCHO (1 eq)
E OH, CH
3
COOH (ca .), e lux,
1 h
Rec ys alliza ion om
e hanol/dioxane
mix u e
54b (80–84%)
n.s.—no speci ied by he au ho s.
Scheme 12. Rep esen a i e scheme o py olone syn hesis om hyd azides.
Biological Ac i i y o Py olone De i a i es
The py olone de i a i e 53a exhibi ed g ea
in i o
an icance ac i i y agains HCT-
116 and MCF-7 cell lines, wi h IC
50
= 7.49 and 8.51
µ
M [
27
], espec i ely (Figu e 17). Also,
compound 53b showed IC50 = 46.3 µg/mL agains HePG2 cell lines [137].
Molecules 2025,30, 2852 35 o 71
Figu e 17. Py olones wi h an icance ac i i y.
Compounds 53c and 53d, epo ed by El-Helw e al. [
28
], showed a high pe cen age o
p o ec ion agains he pa hogenic a ian in luenza i us (H5N8) [
28
], highe han 80% o
immunomodula o s. Mo sy e al. [
101
] epo ed on compounds 54b.2 and 54b.3, which
exhibi ed an i i al ac i i y wi h 100% p o ec ion agains Newcas le disease i us (Figu e 18).
Figu e 18. Py olones wi h an i i al ac i i y.
Mo eo e , Yousse e al. [
140
] used he phosphomolybdenum me hod o de e mine
he an ioxidan capaci y o compounds 53e–gand 54c (Figu e 19). The compounds showed
good o mode a e an ioxidan capaci y, p esen ing 163.0 o 262.27 mg o acid asco bic
equi alen s pe g am (AEE/g) o d y compound.
Figu e 19. Py olones wi h an ioxidan ac i i y.
Molecules 2025,30, 2852 36 o 71
3.2.2. Py azoles
Syn hesis o Py azoles
Py azole de i a i es a e i e-membe ed N-he e ocycle compounds wi h wo adjacen
ni ogen a oms (1,2-posi ions) [
29
]. Unsubs i u ed py azole is a plana s uc u e wi h h ee
possible au ome ic o ms (55-A,55-B, and 55-C), as ep esen ed in Figu e 20.Howe e , i
can also exis as a dime (55-D), in concen a ed solu ion, ia hyd ogen bonding [142].
Figu e 20. Tau ome ic s uc u es and dime o py azole.
In he azole amily, py azole de i a i es a e one o he mos s udied compounds, wi h
a wide ange o chemical and biological p ope ies [
29
,
143
,
144
]. In clinical use, imon-
aban , sildena il, omepizole, celecoxib, and uxoli inib a e some o he py azole-based
d ugs [
142
]. In he li e a u e, py azoles ha e been desc ibed as an imic obial [
128
,
145
,
146
],
an i-in lamma o y [147,148], and an icance agen s [149–151].
Hassani e al. [
29
] and Ríos e al. [
143
] compiled he wo ks epo ing he syn hesis
o py azole de i a i es be ween 2013 and 2023 and be ween 2017 and 2022, espec i ely.
Py azoles we e ob ained om he eac ion be ween hyd azine and a ca bon uni , such as
1,3-dica bonyl,
α
,
β
-unsa u a ed ca bonyl compounds, ace ylenic ke ones, o
β
-enaminones
o simila compounds.
Al hough py azoles a e usually ob ained om hyd azine, in his e iew, we p esen
hyd azides as p ecu so s o py azoles, dihyd opy azoles, o py azolidine-diones (
Table 5
).
The syn hesis o hese compounds occu ed be ween hyd azides 8and se e al ca -
bonyl/ni ile compounds as ep esen ed in Scheme 13. Py azoles 63 o 66 we e ob ained in
e hanol, unde e lux, in he p esence o no o an o ganic base [
80
,
146
]. Dihyd opy azoles
67–70 [
80
,
128
,
146
] o py azolidine-diones 71 [
80
] we e gene a ed om hyd azides and
ca bonyl/ni ile compounds in he p esence o a s ong ino ganic base, in e hanol o DMF,
a oom empe a u e o unde e lux. The p oduc s we e usually ob ained wi h good
yields [80].
Table 5. Reac ion condi ions o he syn hesis and pu i ica ion o py azoles, dihyd opy azoles, and
py azolidine-dione om hyd azides.
Re . S a ing Ma e ial Expe imen al Condi ions Pu i ica ion P ocess Py azole Compounds
(η%)
[80]
8ac
CH2(COOC2H5)2
C2H5ONa/E OH
Re lux, 14–17 h
Rec ys alliza ion om
dioxane
71a (90%)
[80]
8ac
CH3COCH2COOC2H5
DMF
K2CO3
Re lux, 12–15 h
Rec ys alliza ion om
me hanol
69a (85%)
Molecules 2025,30, 2852 37 o 71
Table 5. Con .
Re . S a ing Ma e ial Expe imen al Condi ions Pu i ica ion P ocess Py azole Compounds
(η%)
[80]
8ac
CNCH2COOE
DMF
K2CO3
Re lux, 14–17 h
Rec ys alliza ion om
me hanol
68a (77%)
[80]
8ac
CNCH2COPh
E OH
Re lux, 6–9 h
Rec ys alliza ion om
dioxane
65a (72%)
[80]
8ac
CH3COCH2COCH3
E OH
Pipe idine (ca .)
Re lux, 10–15 h
Rec ys alliza ion om
me hanol
64a (95%)
[80]
8ac
CNCH2CN
E OH
Pipe idine (ca .)
Re lux, 20–25 h
Rec ys alliza ion om
DMF
66a (70%)
[128]
1
NaOH/E OH
. . 8–9 min
Rec ys alliza ion om
me hanol
67a (82–88%)
[128]
8abg.1
NaOH/E OH
. . 8–9 min
Rec ys alliza ion om
me hanol
67b (82–87%)
[146]
8abk
CH3COCH2COOC2H5
DMF/E OH
CH3COOH
Re lux, 5 h
Column
ch oma og aphy
70a (62–67%)
[146]
8abk
CH3COCH2COCH3
DMF/E OH
CH3COOH
Re lux
8 h
Column
ch oma og aphy
64b (61–72%)

Molecules 2025,30, 2852 38 o 71
Scheme 13. Rep esen a i e scheme o py azoles, dihyd opy azoles, and py azolidine-dione syn hesis
om hyd azides.
Also, ecen ly, A dakani e al. [
145
] epo ed he syn hesis o dihyd opy azole 72 by
he eac ion o subs i u ed hyd azide 28c wi h alkyl isocyanides and dialkyl ace ylenedica -
boxyla es a oom empe a u e, in 72–84% yields (Scheme 14).
Scheme 14. Syn hesis o dihyd opy azole de i a i es 48: (a) ace one, –5 ◦C, 10 min, . ., 24 h.
Biological Ac i i y o Dihyd opy azole and Py azole De i a i es
Compounds 67a,b(Figu e 21) we e sc eened o hei
in i o
an ibac e ial and an i-
ungal ac i i ies. Compound 67a.2, wi h an MIC = 100
µ
g/mL agains G am-posi i e B.
sub ilis and a s onge MIC = 50
µ
g/mL agains C. e ani, was equipo en o mo e po en
han he e e ence d ugs ampicillin (MIC 250
µ
g/mL) and cip o loxacin (MIC
100 µg/mL
).
Molecules 2025,30, 2852 39 o 71
Compound 67a.4 was mo e po en han ampicillin agains S. au eus (MIC 62.5
µ
g/mL). In
gene al, compounds 67a, wi h isoniazid moie ies, we e mo e e ec i e agains all mic oo -
ganisms han hose wi h nico inic hyd azide de i a i es 67b (Figu e 21) [128].
Figu e 21. Py azole de i a i es wi h an ibac e ial, an i ungal, o an icance ac i i ies.
Compounds 70a and 64b (Figu e 21) demons a ed e ec i e an ibac e ial ac i i y
agains S aphylococcus au eus,Bacillus sub ilis,E. coli, and Pseudomonas ae uginosa, wi h MIC
alues anging om 8 o 16
µ
g/mL, and good cy o oxici y
in i o
agains wo human
cance cells, HCT-116 (colon) and HL-60 (leukemia), hough i was less han he s anda d
5- luo ou acil [146].
3.2.3. Oxadiazoles
Syn hesis o Oxadiazole De i a i es
Oxadiazoles a e one o he mos aluable i e-membe ed he e ocycles, holding one
oxygen and wo ni ogen a oms, wi h an ex ensi e spec um o applica ions [
31
]. F om
he oxadiazole isome s o 1,2,3-oxadiazole 73, 1,2,4-oxadiazole 74, 1,2,5-oxadiazole 75, and
1,3,4-oxadiazole 76, p esen ed in Figu e 22, 1,3,4-oxadiazole 76 s ands among he mos
s udied and used, due o i s b oad ac i i y spec um [
152
,
153
]. This isome appea s in
some a ailable d ugs, such as Zibo en an, Fu amizole, Ral eg a i , and Nesapidil [
83
],
bu ecen ly, new de i a i es ha e been shown o ha e biological ac i i ies, including
an icance [
82
], an ibac e ial, an i ungal [
154
], an imala ial [
2
], an ileishmanial [
40
], an i u-
be cula [
81
], an i i al [
28
], an i-in lamma o y [
41
,
85
], an ioxidan [
105
], and insec icidal
ac i i ies [103].
Figu e 22. S uc u es o oxadiazole isome s.
Sha ma e al. [
31
] collec ed and discussed he syn hesis o 1,3,4-oxadiazoles in he pas
15 yea s. The au ho s discussed dehyd ogena i e cycliza ion o 1,2-diacylhyd azines wi h
phospho us oxychlo ide (POCl
3
), phospho ic acid (H
3
PO
4
), and hionyl chlo ide (SOCl
2
);
oxida i e cycliza ion o hyd azide–hyd azones; and deca boxyla i e cycliza ion.
Molecules 2025,30, 2852 40 o 71
He e, we epo he use o hyd azides in he syn hesis o 1,3,4-oxadiazoles. Acco ding
o Table 6, 1,3,4-oxadiazoles can be syn hesized om he eac ion be ween a hyd azide
and ca bon elec ophilic eagen s such as aldehydes, oxalyl chlo ides, ca boxylic acids,
o ca bon disul ide, as ep esen ed in Scheme 15. Some 2,3-dihyd o-1,3,4-oxadiazol-2-yl
de i a i es 78 ha e been syn hesized om hyd azides 8, wi h hyd azide–hyd azones 52
as in e media es [
40
,
82
,
154
]. This me hod s a s wi h he eac ion o hyd azide and an
aldehyde, and hen he eac ion ollows in he p esence o ace ic anhyd ide unde e lux.
The oxadiazoles 78 ob ained by his me hod we e gene ally ob ained in low o excellen
yields. On he o he hand, Paidi e al. [
153
] epo ed he syn hesis o 2,5-disubs i u ed
1,3,4-oxadiazoles 77 ia one-po NaOCl-media ed oxida i e cycliza ion om hyd azide–
hyd azones 52, gene a ed in si u om hyd azides 8and aldehydes (Scheme 15). The bes
condi ions epo ed by Paidi e al. [
153
] included hyd azide 8in he p esence o aldehydes
and -BuOH, unde e lux, ollowed by a eac ion wi h 10–12% aqueous NaOCl a oom
empe a u e. These eac ion condi ions we e applied o hyd azides and aldehydes wi h
bo h elec on-dona ing and elec on-wi hd awing g oups, and he desi ed p oduc s 77
we e ob ained in mode a e o excellen yields. Compounds 77 we e also gene a ed di ec ly
om 8by eac ion wi h ace ic anhyd ide [80].
Table 6. Reac ion condi ions o he syn hesis and pu i ica ion o 1,3,4-oxadiazoles and hei de i a i es.
Re . S a ing Ma e ial Expe imen al Condi ions Pu i ica ion P ocess Oxadiazole Compounds (n%)
[154]
8abl
1. RCHO
E OH, e lux, 3 h
2. Ac2O (32 eq), e lux, 3 h
Rec ys alliza ion om
e hanol/ace one (3:1 / )
mix u e
78a R = A (22–76%)
[82]
8ax
1. RCOR1
70 ◦C, 2 h
2. Ac2O (10.5 eq), e lux, 8 h
Rec ys alliza ion om
e hanol
78b R = A , R1= H, CH3(n.s.)
[40]
8o R2= H, R3=H
8p R2= Cl, R3= H
8q R2= H, R3= Cl
1.
E OH, CH3COOH (ca .)
80 ◦C, 3 h
2. Ac2O (10.5 eq), 155 ◦C, 90 min
Flash ch oma og aphy
78c R
1
= CH
3
, H, F; Y = CH, N;
R2and R3= H, Cl (40–71%)
[153]
8R1= Alk, A
1. R2CHO, -BuOH, e lux, 2–3 h
2. NaOCl, . ., 1–2 h Column ch oma og aphy
77 R1= Alk, A ; R2= Alk, A
(50–93%)
[80]
8ac
Ac2O, 10–15 min, E ONa, 6–8 h; Rec ys alliza ion om
e hanol
77a (88%)
[80]
8ac
Ac2O, e lux, 25–30 h Rec ys alliza ion om
me hanol
77b
Molecules 2025,30, 2852 41 o 71
Table 6. Con .
Re . S a ing Ma e ial Expe imen al Condi ions Pu i ica ion P ocess Oxadiazole Compounds (n%)
[84]
8aab
R-X-CO2H (1 eq)
POCl3(5 eq), 50 ◦C, 4 h
X-R = CH2O-A , CH2-A o A
Rec ys alliza ion om
e hanol
77c X-R = CH2O-A , CH2-A
o A (46–66%)
[152]
1Y=No 8o Y = CH (1 eq)
POCl3(48 eq), e lux, 9 h
Rec ys alliza ion om an
app op ia e sol en
77d X = S, SO
2
; R = H, CH
3
, Cl;
Y = N, CH
(59–70%)
[83]
8o R=C6H5
8ay R = 4-F-C6H4
8az R = 4-CH3–C6H4
8aaa R = 2-Cl,4-Cl-C6H3
(1 eq), POCl3(n.s.),
e lux
6–7 h
Rec ys alliza ion om
isop opanol
77e R = A (80–88%)
77e.1 R=C6H5
77e.2 R = 4-F-C6H4
77e.3 R = 4-CH3–C6H4
77e.4 R = 2-Cl,4-Cl-C6H3
[2]
8R1= H, CH3, F (1 eq), POCl3(53
eq)
60–70 ◦C
Rec ys alliza ion om
me hanol
77 R = A yl, He A ;
R1= H, CH3, F (80–89%)
[59]
8u
R1CO2H (1 eq), POCl3(6.7 eq),
e lux, 6–8 h
Rec ys alliza ion om
me hanol
77g R1= A (78–90%)
[105]
8
(0.5 eq)
POCl3ul asonica ion (35 kHz)
35–60 min
Rec ys alliza ion om
2-p opanol
77h (80–92%)
[105]
8w
(0.5 eq)
POCl3(53 eq)
ul asonica ion (35 kHz) 35–50 min
Rec ys alliza ion om
2-p opanol
77i (87–91%)
[81]
1X=No 8o X = CH
1. CH2Cl2, 0◦C
ClCOCOOE (1.1 eq)
E 3N
. ., 8 h
2. p-TosCl (1 eq)
. ., 4 h
Rec ys alliza ion om
e hanol
79a X = N o CH (87, 83%)
Molecules 2025,30, 2852 48 o 71
Figu e 24. 1,3,4-oxadiazole-2- hiol de i a i es wi h an icance and/o an ibac e ial ac i i ies.
Compound 78a.1 (Figu e 25) showed p omising ac i i y agains S aphylococcus epide -
midis wi h an MIC = 0.48
µ
g/mL, as well as low cy o oxici y agains he L929 no mal cell
line [154].
Figu e 25. 1,3,4-oxadiazoles as an ibac e ial and an i ungal agen s.
Long e al. [
39
] designed, syn hesized, and e alua ed oxadiazole de i a i es 85
(
Figu e 25
) o hei an i ungal, an ioomyce e, and an ibac e ial ac i i ies. Compound
85a showed he bes
in i o
an i ungal ac i i y agains Gibbe ella zeae and an ioomyce e
ac i i y agains Phy opho a in es ins, wi h EC
50
= 0.47
µ
g/mL and 3.92
µ
g/mL, espec i ely.
In he
in i o
s udy agains co n scab, compound 60a showed p o ec i e and cu a i e ac i i-
ies o 90.2 and 86.3% a 200
µ
g/mL, which we e compa able o hose o ungicides boscalid
and luopy am. These 1,3,4-oxadiazole- ailo ed py azole compounds wi h hyd azide unc-
ions in he middle as a linke a e po en ial ag icul u al ungicides o con olling ungal
diseases.
The 2,5-disubs i u ed 1,3,4-oxadiazoles 77e (Figu e 25) we e e alua ed o hei
in i o
an ibac e ial ac i i y. Compound 77e.2 exhibi ed he bes b oad-spec um an ibac e ial and
an i ungal ac i i y, wi h MIC = 15.62, 7.81, 3.9, and 31.25, 62.5
µ
g/mL agains E. coli,S.
yphi,B. sub ilis,B. mega e ium, and A. nige , espec i ely [83].
De i a i es 84 (Figu e 26) we e e alua ed o hei
in i o
an imycobac e ial ac i i y
agains he M. ube culosis H37Ra-a enua ed s ain, H37R i ulen s ain, and se e al
esis an s ains. F om he 5-phenyl-subs i u ed oxadiazole subse ies, de i a i es 84a and
84b p esen ed an MIC = 4
µ
M agains py azinamide- esis an s ains. Mo eo e , hese
compounds exhibi ed selec i i y o mycobac e ia and low cy o oxici y agains human
SH-SY5Y cells (CC50 = 50 and 100 µM o 84a and 84b, espec i ely) [81].

Molecules 2025,30, 2852 49 o 71
Figu e 26. 1,3,4-oxadiazoles wi h an imycobac e ial and an ipa asi ic ac i i ies.
Also, N
3
-ace yl-1,3,4-oxadiazoline de i a i es 78c (Figu e 26) we e sc eened agains
Leishmania dono ani, and compound 78c.1 exhibi ed an an ileishmanial ac i i y wi h
IC50 = 8.98 µM on L. dono ani in amac ophage amas igo es [40].
Mo eo e , Ve ma e al. [
2
] syn hesized he hyb id compounds 77 and e alua ed
hei ac i i y agains P. alcipa um 3D7 (chlo oquine-sensi i e) and RKL 9 (chlo oquine-
esis an ) s ains. Among he e alua ed compounds 77 (Figu e 26), compound 77 .1
exhibi ed he bes ac i i y wi h an IC
50
= 0.25
µ
g/mL agains he 3D7 (chlo oquine-sensi i e)
s ain and 0.86
µ
g/mL agains he RKL 9 (chlo oquine- esis an ) s ain o P. alcipa um.
Mo eo e , he an ileishmanial ac i i y o compounds 77 agains L. dono ani p omas igo es
was also e alua ed. Compounds 77 .2,77 .3, and 77 .4 exhibi ed IC
50
= 33.3, 40.1, and
19.0
µ
g/mL, espec i ely. The same compounds (77 .2,77 .3, and 77 .4) also had e ec s
on amas igo e in ec i i y wi h IC
50
= 44.2, 66.8, and 73.1
µ
g/mL, espec i ely. Among he
es ed compounds, he mos p omising we e 77 .1 and 77 .4 o hei good an imala ial and
an ileishmanial ac i i y, espec i ely; hence, hei cy o oxici y was s udied, as well as hei
sa e y p o ile.
El-Helw e al. [
28
] epo ed compound 80l (Figu e 27) as an immunomodula o agains
he highly pa hogenic a ian in luenza i us (H5N8), wi h he high po ency o 100% p o ec-
ion, and Ramadan e al. [
103
] epo ed compound 80m (Figu e 27) as an insec icide wi h
low LC
50
= 9.67 and 1.07 mg/mL agains lab and ield s ains o he hi d la al ins a o
Culex pipiens.
Figu e 27. 1,3,4-oxadiazole-2- hiol de i a i es wi h an i i al (80l) o insec icidal ac i i y (80m).
Molecules 2025,30, 2852 50 o 71
New de i a i es o no el 2,5-disubs i u ed 1,3,4-oxadiazole (Figu e 28) we e also
syn hesized as po en ial an i-in lamma o y and an ioxidan agen s. Kashid e al. [
59
] e-
po ed compounds 77g (Figu e 28) wi h g ea an i-in lamma o y and an ioxidan ac i i ies,
o which compounds 77g.1,77g.2, and 77g.3 showed be e an i-in lamma o y ac i i ies
wi h IC
50
= 45.69, 58.54, and 56.70
µ
M, espec i ely, compa ed o he s anda d d ug di-
clo enac sodium ha p esen s an IC
50
= 90.21
µ
M. Acco ding o he DPPH assay, compound
77g.4 exhibi ed good an ioxidan ac i i y wi h IC
50
= 17.15
µ
M, which was be e han he
e e ence an ioxidan asco bic acid (IC
50
= 44.18
µ
M). Also, a molecula docking s udy
showed ha hese compounds can ecognize he ac i e si e and accomplish signi ican
bonded and non-bonded in e ac ions wi h main esidues in he an i-in lamma o y a ge
cyclooxygenase-2 (COX-2) [
59
]. Gun hanakkala e al. [
105
] epo ed compounds 77h and
77i (Figu e 28) as po en ial an ioxidan s wi h IC
50
alues be ween 32.95 and 121.12, 29.90
and 117.73, and 31.34 and 106.42
µ
g/mL, o DPPH, NO, and H
2
O
2
assays, espec i ely.
Among hem, compound 77h.2 s ood ou wi h IC
50
alues = 32.95, 31.64, and 32.42
µ
g/mL,
and compound 77i.2 wi h IC
50
alues = 32.01, 29.90, and 31.34
µ
g/mL o DPPH, NO, and
H2O2assays, espec i ely.
Figu e 28. 1,3,4-oxadiazole de i a i es as po en ial an i-in lamma o y and an ioxidan agen s.
Some oxadiazole-2- hiol de i a i es 80g (Figu e 28) also p esen ed an i-in lamma o y
ac i i y as inhibi o s o COX o lipoxygenase (LOX) enzymes [
41
,
85
]. Muni e al. [
41
]
iden i ied de i a i es 80g wi h good
in i o
cyclooxygenase inhibi ion ac i i y, wi h IC
50
alues anging om 31.5 o 39.5
µ
M o COX-2 and om 43.91 o 27.55
µ
M o COX-1. On
he o he hand, Bashi e al. [
85
] iden i ied oxadiazoles 81e.1–4, which showed good LOX
inhibi o y ac i i ies wi h IC50 alues o 21.5, 29.1, 31.3, and 24.3 µM, espec i ely.
Molecules 2025,30, 2852 51 o 71
Rana e al. [
61
] epo ed new de i a i es 81 (Figu e 28) inco po a ing he lu bip o en
moie y. Compound 81 .1 showed he highes an i-in lamma o y ac i i y o he se ies,
displaying 74.16% ac i i y a 200
µ
g/mL, which is sligh ly lowe han s anda d ibup o en
(84.31% ac i i y). The same compound also showed an ioxidan ac i i y in he DPPH assay,
wi h an IC50 = 25.35 µg/mL, while o asco bic acid, he IC50 alue was 6.13 µg/mL.
Fu he mo e, bo h de i a i es 81g and 81h (Figu e 29) showed good inhibi ion agains
α
-glucosidase. Compound 81g.1 had he inhibi ion po en ial o 72.13% a 500
µ
M, which
was highe han ha o he s anda d d ug aca bose (65.73% a 500
µ
M) [
87
]. Addi ionally,
Daud e al. [
62
] iden i ied compound 81h.1 wi h IC
50
= 56.01
µ
M as mo e ac i e han aca -
bose, he s anda d d ug, which p esen s an IC
50
= 375.82
µ
M, in he same assay. Compound
77k.1 also showed good α-glucosidase inhibi ion ac i i y wi h an IC50 = 460 µM [156].
Figu e 29. Oxadiazole de i a i es as α-glucosidase inhibi o s.
3.2.4. Thiazoles and Thiadiazoles
Syn hesis o Thiazole and Thiadiazole De i a i es
Thiazole and hiadiazole a e i e-membe ed N,S- and N,N,S-he e ocycles wi h impo -
an biological applica ions ha os e he sea ch o new de i a i es. Recen ly, Babalola
e al. [
157
] and Ahmad e al. [
158
] collec ed and discussed ecen syn he ic me hodologies
and he biological ac i i y o hiadiazoles. Babalola e al. [
157
] discussed he syn hesis
o hiadiazoles o e he las 10 yea s using he e ogeneous ca alys s, mic owa e-assis ed
syn hesis, ul asound-aided echniques, sol en - ee syn hesis, o complex ca alyzed e-
ac ions; Ahmad e al. [
158
] discussed he syn hesis o hiadiazoles, since 2008, om hy-
d azides, hiosemica bazide, acylhyd azines, hioacylhyd azone, di hioca baza es, and
iso hiocyana e. Scheme 20 p esen s he gene al app oaches o ob ain hese he e ocycles
om hyd azides 8, and Table 7desc ibes he eac ion condi ions o ob ain he di e en
de i a i es om he eac ions be ween hyd azides and ca bon disul ide, iso hiocyana e
eagen s, o Lawesson’s eagen .
Tolan e al. [
64
] epo ed he syn hesis o compounds 89 in a wo-s ep app oach
(Scheme 20). The eac ion o hyd azide 8wi h ca bon disul ide p oduced in e media y
86, which eac ed wi h an acyl b omide eagen in e hanol and was e luxed o gene a e
he hiazole ing o de i a i e 89. Abumelha e al. [
44
] syn hesized hiazole de i a i es
90 (Scheme 20). The syn he ic app oach in ol ed he con e sion o hyd azide 8in o
in e media e 87, by eac ion o 8wi h iso hiocyana e, unde hea ing. The eac ion o
in e media e 87 wi h chlo oace ic acid p omo ed he o ma ion o hiazole ing 90. Mo eo e ,
in e media y 87 was con e ed o 1,3,4- hiadiazoles 91 by ea men wi h sul u ic acid
unde e lux [94,159].
Molecules 2025,30, 2852 52 o 71
Scheme 20. Gene al app oaches o 1,3- hiazole and 1,3,4- hiadiazole syn hesis om hyd azides.
Table 7. Reac ion condi ions o he syn hesis and pu i ica ion o 1,3- hiazole and 1,3,4- hiadiazole
de i a i es om hyd azides.
Re . S a ing Ma e ial Expe imen al Condi ions Pu i ica ion P ocess P oduc s (η%)
[64]
8ac
CS2, KOH (aq.), e lux, 3 h -
86a (86%)
[64]
86a
PhCOCH
2
B , E OH, e lux, 3 h
Rec ys alliza ion om
e hanol
89a (67%)
[44]
8aaq
PhNCS, E OH, e lux, 4 h -
87a (64%)
[44]
87a
ClCH2COOH, E OH, AcONa,
e lux, 6 h -
90a (74%)
[108]
29d
Lawesson eagen (1.7 eq)
oluene, 110 ◦C, 6 h
Silica gel column
ch oma og aphy
92a (36–49%)
Molecules 2025,30, 2852 53 o 71
Table 7. Con .
Re . S a ing Ma e ial Expe imen al Condi ions Pu i ica ion P ocess P oduc s (η%)
[93]
8aa
1. Lawesson’s eagen (1 eq)
oluene, e lux, 8 h
2. RCHO (1 eq), POCl
3
(107 eq)
e lux, 4–6 h
Rec ys alliza ion om
me hanol
92b (n.s)
[94]
8aas
1. R1NCS, E OH, 2 h
2. H2SO4, e lux, 5 h
1. Rec ys alliza ion
om e hanol
2. Rec ys alliza ion
om e hanol
91a (n.s.)
n.s.—no speci ied by he au ho s.
Hyd azides 8, in he p esence o Lawesson’s eagen , gene a ed he co esponding
hio-de i a i es 88, which gene a ed 1,3,4- hiadiazole de i a i es 92 in he p esence o
phospho yl chlo ide and an aldehyde, unde hea ing (Scheme 20) [93].
Abumelha e al. [
44
] syn hesized hiazole de i a i es 93 as p ecu so s o an ioxidan
agen s. Compound 90a was con e ed o he hyb ids 93 by eac ion wi h aldehydes
unde e lux, in an acidic medium. P oduc s 93 we e ob ained in good o mode a e yields
(Scheme 21).
Scheme 21. Syn hesis o hiazole de i a i e 93: (a) A CHO, CH3COOH/AcONa, e lux, 4 h.
Compounds 94 (Scheme 22) we e yielded om hiadiazole de i a i e 91a and aldehy-
des unde e lux condi ions, in me hanol [94].
Scheme 22. Syn hesis o hiadiazole de i a i e 94: (a) R2CHO, MeOH, e lux.
Biological Ac i i y o Thiazole and Thiadiazole De i a i es
Compound 89a (Figu e 30) was e alua ed o an icance ac i i y and showed good
an ip oli e a i e ac i i ies agains MCF-7 b eas cance cells and agains hepa ocellula
HepG2 cells wi h IC
50
= 8.0 and 28.2
µ
M, espec i ely. These IC
50
alues a e be e o simila
o hose o doxo ubicin, which has IC50 = 10.3 and 28.5 µM, o he same cell lines [64].

Molecules 2025,30, 2852 54 o 71
Figu e 30. Thiazole and 1,3,4- hiadiazole de i a i es wi h an icance and an imycobac e ial ac i i y.
Compounds wi h s uc u e 92a (Figu e 30) we e sc eened agains cance cell lines
MDA-MB-231 and HeLa. Compound 92a.1 (Figu e 30) exhibi ed good an icance ac i -
i y wi h IC
50
= 15.75 and 12.82
µ
M agains cance cell lines MDA-MB-231 and HeLa,
espec i ely, al hough i had a lowe ac i i y han he posi i e con ol e oposide [
108
].
Taha e al. [
93
] epo ed he 2,5-disubs i u ed hiadiazoles 92b (Figu e 30) as po en
β
-
glucu onidase inhibi o s p esen ing IC
50
alues be ween 6.74 and 52.36
µ
M, e ealing
highe o equi alen ac i i y o he s anda d D-saccha ic acid-1,4-lac one (IC
50
= 48.4
µ
M).
Among hese, compound 92b.5 was he mos po en , wi h IC50 = 6.74 µM.
On he o he hand, hiazoles 94 (Figu e 30) we e sc eened agains Mycobac e ium
ube culosis H
37
R , and compound 94a was he mos po en wi h an inhibi o y ac i i y o
80% a 6.25 µg/mL [94].
3.2.5. T iazoles
Syn hesis o T iazole De i a i es
T iazole, also known as py odiazole, is a i e-membe ed he e ocyclic ing sys em
con aining h ee ni ogen a oms, exis ing in wo isome ic o ms, 1,2,3- 95 o 1,2,4- iazoles
96 (Figu e 31) [160]. Bo h isome s p esen a wide ange o pha macological ac i i ies.
Figu e 31. Isome ic o ms o he iazole ing.
Molecules 2025,30, 2852 55 o 71
In a ecen e iew, Hassani e al. [
161
] epo ed he ad ances in he syn hesis o iazole
de i a i es. The au ho s p esen ed mul iple me hods o ob ain 1,2,3- o 1,2,4- iazoles,
including me al- ee and me al-ca alyzed eac ions. Among hem a e he cycloaddi ion
o azides and e minal alkynes; he eac ion be ween wo ni iles and hyd oxylamine
hyd ochlo ide; he eac ion o o mamide eagen s and hyd azide; he eac ion o acylhy-
d azines wi h ca bon disul ide, ollowed by he eac ion wi h hyd azine monohyd a e; and
o he s [
161
]. Ren e al. [
162
] ecen ly epo ed a di e en app oach o he syn hesis o 1,2,3-
iazoles, in ol ing an iodine-media ed condensa ion–cycliza ion eac ion om
α
-azido
ace ophenones and p- oluenesul onyl hyd azide. Mo eo e , Cla k e al. [
163
] de eloped he
syn hesis o subs i u ed 1,2,3- iazoles om
α
-ke oace als, osyl hyd azide, and a p ima y
amine. On he o he hand, Pa e son e al. [
164
] p esen ed he syn hesis o 1,2,3- iazoles
om osylhyd azide, aldehydes, and a p ima y amine, as an al e na i e o azides.
He e, in his e iew, we p esen he syn hesis o 1,2,4- iazole (Table 8), in which hy-
d azides a e o en combined wi h hiocyana e o iso hiocyana es, ca bon disul ide, o ni ile
de i a i es (Scheme 23). Hyd azides 8, in he p esence o iso hiocyana es and unde e lux
condi ions, gene a e he in e media es 87 (in a neu al o acidic medium), which cyclize
in a basic medium unde e lux, o gi e 97 [
35
,
42
,
80
,
88
,
89
,
91
,
165
]. Se e al de i a i es o
100 we e ob ained by he condensa ion o 97 wi h elec ophiles [
42
,
88
–
91
]. The eac ion
wi h ca bon disul ide ook place in a basic medium wi h e lux, ollowed by cycliza ion
wi h hyd azine hyd a e o ob ain compounds 98 [
41
]. Re lux o high empe a u es a e also
used when ni ile de i a i es a e used as eagen s o ob ain compounds 99 [
166
,
167
]. The
p oduc s 97,98, and 99 we e ypically isola ed in good o excellen yields. The expe imen al
condi ions o he syn hesis o 1,2,4- iazole-3- hione de i a i es a e p esen ed in Table 8.
The 1,2,4- iazole-3- hione compounds we e some imes jus in e media es o ob ain he
compounds 100 o o he s wi h po en ial biological ac i i y [110].
Table 8. Reac ion condi ions o he syn hesis and pu i ica ion o 1,2,4- iazole de i a i es om
hyd azides and hei de i a i es.
Re . S a ing Ma e ial Expe imen al Condi ions Pu i ica ion P ocess In e media es o T iazoles (η%)
[35]
8ad
NH4SCN (1 eq)
HCl, E OH, e lux, 6 h
Rec ys alliza ion om
DMF/e hanol
87a (82%)
[35]
87a
KOH
E OH, e lux, 6 h
Rec ys alliza ion om
DMF/e hanol
97a (78%)
[80]
8ac
KSCN (1 eq), 10% HCl, e lux, 6–9
h
Rec ys alliza ion om
dioxane
97b (77%)
[42]
8aal
1. MeNCS (1 eq)
E OH, e lux, 1 h
2. KOH (1 eq), e lux, 1 h
3. HCl
-
97c (n.s.)
Molecules 2025,30, 2852 56 o 71
Table 8. Con .
Re . S a ing Ma e ial Expe imen al Condi ions Pu i ica ion P ocess In e media es o T iazoles (η%)
[42]
97c
(1 eq)
LiH, DMF, . , 6–17 h
o LiH, DMF, mic owa e, 33–90 s
-
100a R = A (85–90%)
[88]
8p
E NCS (1 eq)
E OH, e lux 3–4 h -
87d (98%)
[88]
87d
10% NaOH, e lux, 4 h
HCl -
97d (96%)
[88]
97d
(1 eq)
DMF, NaH, 30 min, . .
100b (62–77%)
[89]
8q
u u yl iso hiocyana e (1 eq)
MeOH, e lux, 8–10 h -
87e (97%)
[89]
87e
10% NaOH
e lux, 6–8 h
HCl
-
97e (94%)
[89]
97e
E OH, KOH(1 eq)
(1 eq), e lux, 4–5 h
-
100c R = A (89–95%)
[90]
N
NHNH2
O
H
N
O
8aao
E NCS o PhNCS (1 eq)
E OH, e lux 3–4 h -
87 (97%)
[90]
87
1. 10% NaOH, e lux
4 h
2. HCl
-
97g (98%)
[90]
97g
KOH, E OH, . ., 30 min, alkyl
halides (1 eq), e lux, 4–5 h -
100d R1= A , R2= Alk (70–99%)
Molecules 2025,30, 2852 57 o 71
Table 8. Con .
Re . S a ing Ma e ial Expe imen al Condi ions Pu i ica ion P ocess In e media es o T iazoles (η%)
[91]
N
NHNH2
O
H
N
O
8aao
PhNCS
MeOH, e lux 3–4 h -
87h (98%)
[91]
87h
1.10% NaOH, e lux, 4 h
2. HCl -
97h (95%)
[91]
97h
KOH MeOH, . ., 30 min
, e lux
, e lux 4–5 h
-
100e R1= A , R2= A (88–96%)
[165]
8abn
4-FC6H4NCS (1 eq),
CH3(CH2)3OH,
65 ◦C, 4 h
Rec ys alliza ion om
e hanol
87h (75%)
[165]
87h
4 N NaOH, hea unde Radley, 16
h, CH3COOH
Rec ys alliza ion om
e hanol
97i (60%)
[64]
8ac
CS2
KOH (aq.), e lux, 3 h -
86a (86%)
[64]
86a
H2NNH2·H2O, e lux 2 h Rec ys alliza ion om
E OH/DMF
98a (43%)
[64]
98a
PhCOCH2B (1 eq), E 3N (1 eq),
E OH, e lux, 2 h
Rec ys alliza ion om
DMF/H2O
101 (60%)
[41]
8aa
KOH
CS2
wa e /e hanol (1:1)
H2NNH2·H2O 64% (1 eq), e lux
-
98b (52–65%)
[41]
98b
RCHO (1 eq), CH3COOH (ca .),
MeOH, e lux, 12 h -
102 (72–89%)
Molecules 2025,30, 2852 64 o 71
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