INTERNATIONAL JOURNAL OF LATEST TECHNOLOGY IN ENGINEERING,  
MANAGEMENT & APPLIED SCIENCE (IJLTEMAS)  
ISSN 2278-2540 | DOI: 10.51583/IJLTEMAS | Volume XIV, Issue XI, November 2025  
Synthesis and Molecular Docking Studies of Pyrazolylpyrazoline-  
Clubbed Triazole and Tetrazoles.  
Dr. Kokane Balaji Digambar  
Department of Chemistry Shri Kumarswami Mahavidyalaya, Ausa Dist. Latur (MS) 413520.  
DOI: https://doi.org/10.51583/IJLTEMAS.2025.1411000025  
Received: 21 November 2025; Accepted: 28 November 2025; Published: 03 December 2025  
ABSTRACT:  
To increase the antitubercular potency, we synthesized a series of novel pyrazolylpyrazoline derivatives (9a−n)  
using the one-pot multi component reaction of the substituted hetero aryl aldehyde (3a,b), 2-acetyl  
pyrrole/thiazole (4a,b),and substituted hydrazine hydrates(5−8) in the presence of base KOH as a catalyst in  
ethanol as the solvent at room temperature. Substituted hetero aryl aldehyde (3a,b) was synthesized from 5-  
chloro-3-methyl-1-phenyl-1H-pyrazole-4 methyl-carbaldehyde by treatment with 4-amino triazole/5-amino  
tetrazole. 5-Chloro-4-(1,3-dioxolan-2-yl)-3-methyl-1-phenyl-1H-pyrazole (1) was reacted with 4H-1,2,4-  
triazol-4-amine (a) and 1H-tetrazol-5-amine (b) in the presence of K2CO3 in 1,4-dioxane at 80 °C for 13 h.  
Similarly, 5-((4H-1,2,4-triazol-4-yl)amino)-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (3a) and 5-((1H-  
tetrazol-5-yl)amino)-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (3b) were achieved further reacted with 2-  
acetyle thiophene (4a) and 2-acetyle furan (4b) and substituted hydrazide derivatives (5–8) in the presence of  
50% ethanolic KOH solution at room temperature All of the compounds were tested against  
Mycobacteriumtuberculosis H37Rv, Theoretical results were in good accord with the observed experimental  
values. The docking score of the most active compound 9n was found good Glide energy .  
Key Words: K2CO3 in 1,4-dioxane, Pyrazolylpyrazoline  
INTRODUCTION:  
According to the World Health Organization, 10 million new cases of tuberculosis were reported worldwide  
with 5.6 million men, 3.3 million women, and 1.1 million children.1 Tuberculosis is the 13th leading cause of  
death and the second leading infectious killer. Tuberculosis predominantly triggered by Mycobacterium  
tuberculosis is one of the leading causes of human morbidity and mortality universally. Rifampicin, isoniazid,  
and ethambutol are the most effective drugs against tuberculosis that are available in the market, but bacteria  
have started developing resistance to these drugs, and it is a major public health concern in many countries for  
a couple of years. Nearly 6% of patients with tuberculosis have multidrug-resistant tuberculosis in the world,  
but in some areas, like Ukraine, Moldova, Kazakhstan, and Kyrgyzstan, this ratio increases up to 25%. Treatment  
for patients with multidrug-resistant tuberculosis is long, and patients with multidrug-resistant tuberculosis have  
less favorable outcomes than those treated for drug-susceptible tuberculosis. (2) The increasing occurrence of  
extensively drug-resistant (XDR)-TB coinfection with HIV and multidrug-resistant (MDR)-TB has driven the  
new tubercular drug discovery. Therefore it is an urgent need to develop antitubercular agents with a novel  
mechanism of action and potent biological activity against the drug-resistant tuberculosis strain.  
In recent years, there has been endless interest in the exploration of novel pyrazole-clubbed pyrazoline moieties.  
A variety of modifications have been made to the pyrazole and pyrazoline moiety to boost its pharmacological  
effect because pyrazole–pyrazoline derivatives are widely studied for broad-spectrum biological  
activities. (3−12) The pyrazoline derivatives are widely used as anticancer, (13) antibacterial,  
antifungal, (14) antitubercular, (15) antimalarial, (16) anti-inflammatory, (17) etc. The chemistry of triazole-  
and tetrazole-fused heterocyclic derivatives has gathered a lot of attention in recent years due to their synthetic  
and biological importance. 1,2,4-Triazoles and their fused heterocyclic derivatives have been reported to possess  
a
wide  
range  
of  
bioactivities  
such  
as  
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neuroprotectant, (18) antioxidant, (19) antimalarial, (20) antileishmanial, (21) antiurease, (22) anticonvulsant, (  
23) and antiviral. (24) Tetrazole is a carboxylic acid bio isostere that can be used to substitute the carboxyl group  
in therapeutic molecules to improve lipophilicity, bioavailability, and side effects. Tetrazole can interact  
noncovalently with  
a
variety of enzymes and receptors in organisms, resulting in  
anticancer, (25) antifungal, (26) antitubercular, and antimalarial (27) effects. Figure 1 illustrates commercially  
available pharmaceuticals active ingratiates with pyrazole and pyrazoline analogues. To improve antitubercular  
activity, our research work focused on the synthesis of certain novel structural hybrids of pyrazole–pyrazoline  
clubbed with triazole and tetrazole pharmacophores in a single molecular framework. We synthesized scaffolds  
(9a–n) by incorporating the pharmacophores feature of isoniazid (antitubercular), fezolamine (antidepressant),  
and dipyrone (anti-inflammatory) in quest of novel heterocycles with good potency against drug-resistant  
tuberculosis. The structure–activity relationship (SAR) of the various pharmacophores was taken into account  
when designing the targeted compounds (9a–p; Figure 1). By altering the nitrogen atom and cyclization reaction  
of the side chain of the isoniazid drug, modification of the side chain of the dipyrone drug by adding the five-  
member heterocycles, and introducing the 1,3,4 substituents into the fezolamine drug, novel scaffolds (9a–n)  
were created and investigated for the in vitro antitubercular activity.  
RESULT & DISCUSSSION:  
The traditional synthesis pathways for novel pyrazolylpyrazoline-clubbed triazole and tetrazole derivatives (9a–  
n) are shown in scheme 1.  
The starting compound 5-Chloro-4-(1,3-dioxolan-2-yl)-3-methyl-1-phenyl-1H-pyrazole (1) was reacted with  
4H-1,2,4-triazol-4-amine (a) and 1H-tetrazol-5-amine (b) in the presence of K2CO3 in 1,4-dioxane at 80 °C for  
13 h. Similarly, 5-((4H-1,2,4-triazol-4-yl)amino)-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (3a) and 5-  
((1H-tetrazol-5-yl)amino)-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (3b) were achieved further reacted  
with 2-acetyle thiophene (4a) and 2-acetyle furan (4b) and substituted hydrazide derivatives (5–8) in the  
presence of 50% ethanolic KOH solution at room temperature. The obtained solid precipitate was filtered,  
washed with ethanol, and dried in an oven. The products (9a–n) were received quantitatively in 80–90% yields  
with excellent purity (see Table 1).  
N N  
N N  
N
N
a
NH2  
CHO  
CH3  
HN  
N
KOH, 1,4-dioxane  
800 C Reflux, 1 hr  
N
CHO  
CH3  
3a  
Cl  
N
A
N N  
N
N
N N  
NH2  
N
HN  
N
H
b
CHO  
CH3  
HN  
KOH, 1,4-dioxane  
800 C Reflux,1 hr  
N
N
3b  
Scheme 1. Synthesis of Triazole/Tetrazole Hybrid Pyrazole Derivatives (3a,b)  
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R
CHO  
HN  
CH3  
N
N
3a-b  
N
N
N
N
N
HN  
N
H
N
R=  
O
50% EtOH  
NHNH2  
(4 a-b)  
X= S,O  
O
KOH rt, 2 hr  
N
X
5
O
H
N
NH2  
NH2  
N
N
N
H
NHNH2  
N
R
H
N
6
7
8
H
N
N
N
H
H
N
R
N
N
N
R
N
N
N
S
H
N
N
X
N
N
N
N
O
N
R
N
N
N
O
X
X
N
N
9 a-d  
N
9 a-d  
X
N
9 i-l  
N
9 m-p  
Scheme 2. Synthesis of Novel Pyrazolylpyrazoline-Clubbed Triazole and Tetrazole Derivatives (9a–n).  
Sr  
1
R
Hydrazine derivatives  
Compound  
9a  
Yield  
75  
N
N
H
N
N
NHNH2  
N
2
3
4
5
9b  
9c  
9d  
9e  
77  
72  
78  
77  
N
N
H
N
N
N
N
N
NHNH2  
N
N
N
S
NHNH2  
N
N
N
S
NHNH2  
N
N
N
O
NH2  
N
H
N
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6
7
8
9f  
80  
85  
83  
N
N
O
O
O
N
N
N
NH2  
NH2  
NH2  
N
H
N
N
9g  
9h  
N
N
N
H
N
N
N
N
H
9
9i  
9j  
9k  
79  
80  
82  
N
N
N
H
N
HN  
N
N
N
N
NHNH2  
NHNH2  
N
10  
11  
N
S
N
HN  
O
N
HN  
NH2  
N
H
N
12  
13  
14  
9l  
86  
87  
90  
N
N
N
O
O
O
N
HN  
N
N
N
NH2  
NH2  
NH2  
N
H
N
N
9m  
9n  
N
HN  
N
H
N
HN  
N
N
H
Experimental Section:  
Materials and Methods: All reactions were performed with analytical grade reagents (Sigma-Aldrich), which  
were used without further purification. The progress of reactions was monitored by thin-layer chromatography  
(TLC) on aluminum plates coated with silica gel 60F 254 (layer thickness 0.25mm; Merck); components were  
detected by exposure to UV light or iodine vapor. The melting points were determined in open capillary tubes  
on an electro thermal melting point apparatus. The IR spectra were recorded in KBr on a Perkin Elmer FT-IR  
spectrophotometer (490−8500cm−1).The 1H NMR and 13CNMR spectra were recorded in DMSO-d6 on a  
Bruker Advance 400 spectrometer at 400 and 100MHz, respectively, using DMSO-d6 as a solvent and TMS as  
an internal standard. Chemical shifts are reported in parts per million (ppm). Elemental analysis (% C,H,N) was  
performed using a Perkin Elmer 2400 Series II elemental analyzer. A mass spectrum was scanned on a Shimadzu  
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LC−MS 2010 spectrophotometer. Preparation of 5-Chloro-4-(1,3-dioxolan-2-yl)-3-methyl-1 phenyl-1H-  
pyrazole(1). A mixture of the starting material 5 chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (A, 30  
mmol), 1,4-dioxane (20 mL), in to a 100mL RBF. Preparation of N-(4-(1,3-Dioxolan-2-yl)-3-methyl-1-phe nyl-  
1H-pyrazol-5-yl)-4H-1,2,4-triazol-4-amine (2a) and N (4-(1,3-Dioxolan-2-yl)-3-methyl-1-phenyl-1H-pyrazol-  
5-yl) 1H-tetrazol-5-amine (2b). In a three-neck RBF, 0.1 mol of compound1 was added to dry acetone (60mL),  
followed by addition of 0.15mol of anhydrous K2CO3. After that, 0.11mol of 4H-1,2,4-triazol-4-amine(a) or 1H-  
tetrazol-5-amine(b) was added to the above reaction mass. The mixture was stirred at 90°C for 2−3h.The progress  
of the reaction was monitored by TLC. The product mass was added to cold water, followed by extraction with  
ethyl acetate.The organic layer was dried over sodium sulfate and evaporate under reduced pressure to achieve  
compounds 2a,b in good yields (84−87%). Preparationof5-((4H-1,2,4-Triazol-4-yl)amino)-3-methyl 1-phenyl-  
1H-pyrazole-4-carbaldehyde (3a) and 5-((1H Tetrazol-5-yl)amino)-3-methyl-1-phenyl-1H-pyrazole-4-car  
baldehyde (3b).  
General Procedure for the Synthesis of Pyrazolylpyrazo line-Clubbed Triazole andTetrazole  
Derivatives(9a−n): In a 200mL RBF, derivatives 3a,b(2.5mmol) and derivatives 4a,b were added to a solution  
of substituted hydrazide derivatives (5−8,2.5mmol) in a 50% ethanolic KOH solution (25mL) and the reaction  
mass was stirred for 2−3h at Room T. Obtained sproduct were filtered, washed with ethanol, and dried.The final  
products (9a−p) werer eceived quantitatively in 70−90% yields with excellent purity. All synthesized compounds  
were well characterized through different spectroscopic techniques.  
Molecular Docking Study: The in silico approach of molecular docking is one of the most frequently used  
strategies because of its ability to predict the conformation of small molecules with in the appropriate target  
binding site. Therefore, to rationalize the promising level of antitubercular activity demonstrated by  
pyrazolylpyrazoline derivatives (9d,9i,9k,9l, 9o,and 9n) and gain an insight in to their plausible mechanism of  
action, amolecular docking study was performed against mycobacterial enoyl reductase (InhA) (pdb code:  
̈
4TZK) using the GLIDE (Grid-Based Ligand Docking with Energetics) module of Schrodinger molecular  
̈
modeling software (Schrodinger, LLC, NewYork, NY). InhA,30 the enoyl acyl carrier protein reductase (ENR)  
from M. tuberculosis, is one of the key enzymes contributing to mycolic acid biosynthesis,which is a major  
component of the bacterial cell wall. Inhibition of InhA disrupts the integrity of the mycobacterial cellwall and  
thus qualifies it as the promising target of novel antimycobacterial drugs.31 All of the six compounds (9d, 9i,  
9k, 9l, 9o, and 9n) were docked in the binding site of InhA and displayed a good binding affinity with docking  
scores in the range from−8.884to−7.113(Table 3).  
Table3.Molecular Docking of Novel Compounds in the Active Site of MTB Enoyl Reductase (InhA)  
Comp.  
9c  
Glide code  
-6.812  
Glide energy (kcal/mol) H-bonding (A0)  
Pi-Pi staking A’  
Tyr158(2.31)  
Tyr158(2,12)  
Tyr158(1.92)  
Tyr158(1.91)  
Tyr158(1.82)  
-45.64  
-46.23  
-48.54  
-51.74  
-56.23  
Tyr158(2.501)  
Lys165(1.98)  
Lys165(2.23)  
Lys165(2.34)  
Lys165(2.12)  
9k  
-7.124  
9l  
-7.843  
9m  
9n  
-7.526  
-8.451  
Characterization of 2-(1H-Benzo[d]imidazol-2-yl)-5′ methyl-1′-phenyl-5-(thiophen-2-yl)-N-(4H-1,2,4-triazol-4  
yl)-3,4-dihydro-1′H,2H-[3,4′-bipyrazol]-3′-amine (9a). Yield 79%, mp 225−226°C; IR (KBr) λmax:3350 (N−H  
stretching), 3320(N−Hstretching), 3062(Ar−CHstretching), 2925(C− Haliphatic stretching), 1610(C-  
Cstretching), 1599(C- N),760(−S-linkage);  
1HNMR(DMSO-d6,400MHz):1.81  
(dd,  
1H,CH2),  
1.86(dd,  
1H,CH2),  
1.89(dd,  
1H,CH),2.30(s,3H,−CH3),5.16(s,1H,−NH),6.04 (s,1H,NH),7.07−7.96(m,14H,Ar−H);  
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13CNMR(DMSO d6, 100MHz): 21.3, 43.4, 56.0, 115.2, 115.4, 115.8, 120.2, 120.8, 121.6, 121.7, 122.2, 124.2,  
125.9, 127.0, 127.2, 128.2, 128.3, 128.5, 130.4, 130.8, 131.9, 133.3, 135.0, 148.8, 150.0, 152.2;  
LCMS:m/z=507.10(M+);anal.calcdforC26H22N10S: C, 61.64;H, 4.38;N, 27.65%; found:C, 61.96;H, 4.52;N,  
27.68%.  
Characterization of 2-(1H-Benzo[d]imidazol-2-yl)-5 (furan-2-yl)-5′-methyl-1′-phenyl-N-(4H-1,2,4-triazol-4-yl)  
3,4-dihydro-1′H,2H-[3,4′-bipyrazol]-3′-amine  
(9b).  
Yield  
84%,  
mp225−227°C;  
IR(KBr)  
λmax:3350(N−Hstretching), 3321(N−Hstretching), 3058(Ar−CHstretching),2950(C− stretching), 1605(C-  
Cstretching), 1599(C-N),759(−S-linkage); 1HNMR(DMSO-d6,400MHz):1.81 (dd, 1H,CH2), 1.86(dd, 1H,CH2),  
1.88(dd, 1H,CH),2.30(s,3H,−CH3),5.14(s,1H,−NH),6.05 (s,1H,NH),7.07−8.10(m,14H,Ar−H);  
13CNMR(DMSO d6, 100MHz): 21.4, 43.4, 56.0, 115.4, 115.6, 115.9, 120.2, 120.8, 121.6, 121.7, 122.2, 124.2,  
125.9, 127.0, 128.0, 128.2, 128.3, 128.5, 130.4, 130.9, 131.9, 133.3, 135.0, 148.8, 150.0, 152.4;  
LCMS:m/z=491.2(M+);anal.calcdforC26H22N10O: C, 63.66;H, 4.52;N, 28.55%; found:C, 63.26;H, 4.60;N,  
28.52%.  
Characterization of 2-(1H-Benzo[d]imidazol-2-yl)-5′ methyl-1′-phenyl-N-(1H-tetrazol-5-yl)-5-(thiophen-2-yl)-  
3,4 dihydro-1′H,2H-[3,4′-bipyrazol]-3′-amine (9c). Yield 79%, mp 226−230 °C; IR(KBr) λmax: 3345  
(N−Hstretching),  
3340(N−Hstretching),  
3321(N−Hstretching),  
3058(Ar−  
CHstretching),2950(C−Haliphaticstretching),1605(C- C stretching), 1599 (C-N), 759 (−S-linkage);  
1HNMR (DMSO-d6,400MHz):1.83(dd,1H,CH2group),1.84(dd, 1H, CH2), 1.85 (dd, 1H, CH), 2.30 (s, 3H,  
−CH3),5.16(s,1H,−NH),5.18(s,1H,−NH),6.06(s,1H, NH),7.10−8.10(m,12H,Ar−H); 13CNMR(DMSO-d6,100  
MHz): 20.3, 44.4, 56.0, 113.2, 115.4, 115.8, 120.2, 120.8, 121.6, 121.7, 122.2, 124.2, 125.9, 127.0, 127.2, 128.2,  
128.3, 128.5,130.4,131.8,131.9,133.3,135.2,148.8,163.4;  
CONCLUSIONS  
Optimization of the titled compounds will be important in the development of new antitubercular drugs in the  
upcoming years. Conventional synthesis and the hybrid molecule idea were used to develop the active analogues.  
The salient features of this green protocol are the one-pot reaction, short reaction time, and straightforward  
workup procedure. The majority of the derivatives were produced in good yields with high purity. The inclusion  
of electron-withdrawing and-donating groups in compounds 9l, 9k, resulted in excellent antitubercular activity.  
The pyrazolylpyrazoline derivatives may fit well into the active site of InhA, forming significant bonded and  
nonbonded interactions, according to molecular docking studies. These in silico findings, which are validated  
by in vitro antitubercular outcomes, provide a foundation for continuing the structure-based drug design  
approach to uncover potent leads with better selectivity. The fact that compound 9n with isoniazid, thiol link,  
and 2-acetylfuran. The compound fused with the pyrazole andpyrazoline ring has outstanding antitubercular  
activity and a high docking score motivated us to develop new hybrids based on the core structure and explore  
their antitubercular activity.  
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