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

Academic Editors: Michail Christodoulou and Constantinos Athanassopoulos Received: 11 May 2025 Revised: 20 June 2025 Accepted: 30 June 2025 Published: 3 July 2025 Citation: Teixeira, S.; Castanheira, E.M.S.; Carvalho, M.A. Hydrazides as Powerful Tools in Medicinal Chemistry: Synthesis, Reactivity, and Biological Applications. Molecules 2025,30, 2852. https://doi.org/ 10.3390/molecules30132852 Copyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/ licenses/by/4.0/). Review Hydrazides as Powerful Tools in Medicinal Chemistry: Synthesis, Reactivity, and Biological Applications Sofia Teixeira 1,2 , Elisabete M. S. Castanheira 2and M. Alice Carvalho 1,* 1Centre of Chemistry of University of Minho (CQ-UM), Campus de Gualtar, 4710-057 Braga, Portugal; [email protected] 2Centre of Physics of Minho and Porto Universities (CF-UM-UP), University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; [email protected] *Correspondence: [email protected] Abstract The increase in drug resistance and the high toxicity of current drugs have inspired the scientific community to develop new drugs for various diseases. Hydrazides have become an attractive functional group to easily obtain a plethora of novel compounds with a broad range of biological activities. This review, which contains studies in the literature from the previous five years, focuses on the synthesis methods and biological applications of hydrazides and their derivatives. Here, the details of the experimental reaction conditions used for the synthesis of hydrazides and their derivatives (hydrazide–hydrazones and heterocycle derivatives) are presented, as well as the purification methods and the biological activity of the synthesized compounds. Keywords: hydrazides; hydrazide derivatives; synthesis; bioactive hydrazide derivatives 1. Introduction According to the World Health Organization [ 1 ], diabetes, cardiovascular (ischemic heart disease and stroke), respiratory (chronic obstructive pulmonary disease and respiratory infections), cancers, and Alzheimer’s and dementia diseases are some of the leading causes of death worldwide. Besides these diseases, malaria, tuberculosis, HIV/AIDS, and cirrhosis of the liver are among the leading causes of death in low-income countries. The main obstacles to treating/eradicating these diseases include the increase in drug resistance to current drugs [2–9] and the high toxicity of the drugs used in the treatments [2,10–12]. Nowadays, many efforts have been made to develop novel and safer therapeutic alternatives. The scientific community has been searching for new compounds with reduced toxicity and improved biological efficacy, or even potential probes for bioimaging in disease diagnosis [13]. Hydrazides are a class of organic compounds with the functional group R-CON-R 1 NR 2 R 3 [ 14 ]. It is an extremely important group in organic chemistry, being an effective substrate in both domains of chemical reactions and medicinal chemistry [15,16]. Since the 20th century, several hydrazides such as isoniazid 1(isonicotinic acid hydrazide) [ 9 , 17 , 18 ], p-aminosalicylic acid hydrazide 2[ 19 ], fonturacetam hydrazide 3[ 20 , 21 ], isocarboxazide 4[ 22 ], iproniazid 6[ 23 ], nialamide 7[ 11 ] and benserazide 5[ 24 ] have been introduced for therapeutic purposes, as antituberculosis, antiviral, anticonvulsant, neurostimulator, antidepressive (monoamine oxidase inhibitor), and anti-Parkinson agents (Figure 1). Molecules 2025,30, 2852 https://doi.org/10.3390/molecules30132852 Molecules 2025,30, 2852 2 of 71 Figure 1. Examples of hydrazides and their therapeutic applications. Over time, hydrazides 8were found to be great precursors of other bioactive compounds such as hydrazine–hydrazones 9[ 25 , 26 ]. Hydrazides 8were also employed as building block synthons of different classes of heterocycles, like pyrrolones 10 [ 27 , 28 ], pyrazoles 11 [ 29 , 30 ], oxadiazoles 12 [ 31 ], thiadiazoles 13 [ 30 , 32 ], triazoles 14 [ 30 ], by cyclization or cycloaddition reactions with other reagents [ 28 , 33 ] (Figure 2). These hydrazide derivatives similarly revealed a wide range of biological activities, including antitumor [ 34 – 37 ], antimicrobial [ 38 ], antifungal [ 39 ], antimalarial [ 2 ], antileishmanial [ 40 ], anti-inflammatory [ 41 ], antidiabetic [ 42 , 43 ] and antioxidant [ 44 ] properties. They also showed herbicide activity or were used as dyes [45,46]. Figure 2. Linear and heterocyclic compounds synthesized from hydrazides. Molecules 2025,30, 2852 3 of 71 A review describing the synthesis of hydrazides and heterocyclic rings from hydrazides was published in 2014 by Majumdar et al. [ 47 ]. In 2018, Hosseini et al. [ 32 ] reported a compilation of the synthesis of heterocycles from cyanoacetohydrazides. Also, in 2021, Mali et al. [ 48 ] briefly reported the importance of the hydrazides and their derivatives (specifically hydrazide–hydrazones) as bioactive compounds over the years. This review presents a comprehensive compilation and description of the methods used to synthesize hydrazides in the last 5 years, their use as precursors or synthons to generate new derivatives, and their main biological applications. Moreover, throughout the review, tables will be provided summarizing the experimental conditions for the synthesis and purification of hydrazides and their derivatives. 2. Hydrazides 2.1. Synthesis of Hydrazides The first existing hydrazides, specifically formic and acetic acid hydrazides, were produced by Kurzius in 1895 [ 49 ]. Currently, many hydrazides with alkyl, aryl, and heteroaryl substituents are being synthesized to overcome drug resistance and toxicity. Hydrazides 8(Scheme 1) are conventionally synthesized from compounds 16, such as esters [2,13,26,34–41,43,44,50–95], anhydrides [96], and acyl chlorides [2,97,98], or others [ 99 – 103 ] that possess a good leaving group, and hydrazine. When it is not possible to have compounds 16 available, the leaving group is produced from the acid derivative 15 [ 82 , 85 , 88 , 96 ]. According to the reaction conditions outlined in Table 1, the experimental reaction conditions to generate hydrazide 8from precursor 16 do not differ much, and usually, the reaction takes place in an alcohol solvent, at room temperature, or under reflux. The reactions did not last more than 24 h, and generally, product 8was purified by recrystallization or by column chromatography. Hydrazides 8a to 8abb were obtained in low to excellent yields (26–98%) from esters (17a–17aaw), anhydrides (18), acyl chlorides (19a–c), or others (20–23). Scheme 1. Representative scheme of hydrazide synthesis. Besides the regular functional groups, Zhao et al. [ 99 ] obtained the hydrazide 8aay from activated intermediary 20 by reaction with hydrazine hydrate (Scheme 2). The acid derivative 8abc was obtained from 8aay by reaction with sodium hydroxide in aqueous methanol. Scheme 2. Synthesis of hydrazide 8abc. (a) H 2 NNH 2· H 2 O, Et 3 N, Na 2 SO 4 , CHCl 3 , 35 ◦ C; (b) NaOH, MeOH/H2O, r.t. Molecules 2025,30, 2852 4 of 71 Singh et al. [ 104 ] obtained hydrazides via the transamidation of N-Boc, N-nitroso, and N-tosyl amides with hydrazine hydrate, at room temperature, in 76–94% yields (Scheme 3). Scheme 3. Synthesis of hydrazides 8 by transamidation; (a) 2 HNNH 2 (2-3 eq), DCM, r.t., 30 min–2 h; when R 2 = Boc and R 3 = Me, or R 1 = Alk, DBU (1 eq) is also used; (b) 25 (3 eq), DCM, r.t., 1 h; (c) 2HNNH2(3 eq), DCM, r.t., 1 h. Table 1. Reaction conditions for the synthesis and purification of hydrazides from esters, anhydrides, acyl chlorides, and others. Ref. Starting Material Experimental Conditions Purification Process Hydrazide Compounds (η%) [50] 17a Hydrazine hydrate (1.2 eq) EtOH 75–80 ◦C 2 h Silica gel column chromatography 8a X=N,O;R=Alk (70–95%) [51] 17b Hydrazine hydrate (10 eq) MeOH Reflux 3 h - 8b [26] 17c Hydrazine hydrate (n.s.) EtOH or MeOH 85 ◦C 6 h Recrystallization from aqueous ethanol or methanol 8c (88%) [26] 17d Hydrazine hydrate (n.s.) EtOH or MeOH 85 ◦C 6 h Recrystallization from aqueous ethanol or methanol 8d (54%) Molecules 2025,30, 2852 5 of 71 Table 1. Cont. Ref. Starting Material Experimental Conditions Purification Process Hydrazide Compounds (η%) [26] 17e Hydrazine hydrate (n.s.) EtOH or MeOH 85 ◦C 6 h Recrystallization from aqueous ethanol or methanol 8e (75%) [26] 17f Hydrazine hydrate (n.s.) EtOH or MeOH 85 ◦C 6 h Recrystallization from aqueous ethanol or methanol 8f (83%) [55] 17g Hydrazine hydrate (10 eq added dropwise) MeOH Reflux 2 h - 8g (80%) [56] 17g Hydrazine hydrate (9 eq added dropwise) MeOH Reflux 2 h Silica gel column chromatography 8g (55%) [57] 17h Hydrazine hydrate (80%) (20.6 eq) Neat Reflux n.s. - 8h (96%) [43] 17i Hydrazine 80% (n.s.) EtOH Reflux 6h n.s. 8i (50%) [43] 17j Hydrazine 80% (n.s.) EtOH Reflux 6 h n.s. 8j (57%) [43] 17k Hydrazine 80% (n.s.) EtOH Reflux 6 h n.s. 8k (47%) [13] 17l Hydrazine hydrate (1.7 eq) MeOH Reflux 4.5 h Recrystallization from methanol 8l (63%) [34] 17m Hydrazine hydrate (n.s.) EtOH Reflux 8–10 h n.s. 8m R = H, Br (n.s.) Molecules 2025,30, 2852 6 of 71 Table 1. Cont. Ref. Starting Material Experimental Conditions Purification Process Hydrazide Compounds (η%) [38] 17n Hydrazine hydrate (1.1 eq) EtOH Reflux 3 h Recrystallization from ethanol 8n (75%) [40] 17o R2= H, R3= H 17p R2= Cl, R3= H 17q R2= H, R3= Cl Hydrazine hydrate 80% (n.s.) EtOH Reflux 3 h n.s. 8o R2= H, R3= H 8p R2= Cl, R3= H 8q R2= H, R3= Cl (n.s.) [53] 17r Hydrazine hydrate (1 eq) Anhydrous EtOH ~0 ◦C 30 min Recrystallization from ethanol 8r (73%) [54] 17s Hydrazine hydrate (n.s.) MeOH Reflux 6 h Recrystallization from ethanol 8s (n.s.) [39] 17t Hydrazine monohydrate (8 eq) EtOH Ice bath 30 min - 8t (n.s.) [59] 17u Hydrazine hydrate (2 eq) EtOH Reflux 8 h - 8u (91%) [105] 17v 17w Hydrazine hydrate (1.1 eq) MeOH Pyridine (cat.) Reflux 6–7 h Recrystallization from methanol 8v 8w (n.s) [61] 17x Hydrazine hydrate (2 eq) EtOH Reflux 4 h - 8x (n.s.) [62] 17y Hydrazine hydrate 80% (~8 eq, dropwise) EtOH 95–100 ◦C 12 h Recrystallization from ethanol 8y (89%) Molecules 2025,30, 2852 7 of 71 Table 1. Cont. Ref. Starting Material Experimental Conditions Purification Process Hydrazide Compounds (η%) [36] 17z Hydrazine hydrate (n.s.) EtOH 80–90 ◦C 8 h - 8z (n.s.) [41] 17aa Hydrazine hydrate 85% (~6.5 eq) MeOH Reflux 8 h - 8aa R = Me, OMe (82–92%) [63] 17ab Hydrazine hydrate (~10 eq) MeOH Reflux 5 h Recrystallization from methanol 8ab (37%) [64] 17ac Hydrazine hydrate (n.s.) EtOH Reflux 6 h - 8ac (78%) [35] 17ad Hydrazine (4 eq) EtOH Reflux 5 h Recrystallization from ethanol 8ad (73%) [65] 17ae Hydrazine hydrate (6 eq.) EtOH 30 ◦C 1 h Recrystallization from ethanol 8ae (26%) [66] 17af Hydrazine hydrate 80% (31 eq) EtOH Reflux 8 h Recrystallization from ethanol 8af (n.s.) [67] 17ag Hydrazide hydrate (4.6 eq) EtOH Reflux 3 h Recrystallization from ethanol 8ag (78%) [68] 17ah Hydrazine hydrate 80% (31 eq) EtOH Reflux 4 h Recrystallization from ethanol 8ah (70%) [43] 17ai Hydrazine hydrate 80% (15 eq) EtOH Reflux 8 h Recrystallization from ethanol 8ai (63%) Molecules 2025,30, 2852 8 of 71 Table 1. Cont. Ref. Starting Material Experimental Conditions Purification Process Hydrazide Compounds (η%) [43] 17aj Hydrazine 80% (n.s.) EtOH Reflux 6 h n.s. 8aj R′= Alk, Halide (39–54%) [43] 17ak Hydrazine 80% (n.s.) EtOH Reflux 6 h n.s. 8ak (46%) [43] 17al Hydrazine 80% (n.s.) EtOH Reflux 6 h n.s. 8al (57%) [43] 17am Hydrazine 80% (n.s.) EtOH Reflux 6 h n.s. 8am (56%) [72] 17ao Hydrazine hydrate (~3 eq) EtOH Reflux 12 h - 8ao (n.s.) [73] 17ap Hydrazine hydrate (2 eq) EtOH Reflux 8 h - 8ap (80%) [75] 17aq Hydrazine hydrate 85% (3 eq) EtOH r.t. 4 h Recrystallization from isopropyl alcohol 8aq (67%) [76] 17ar Hydrazine hydrate 99% (1 eq) EtOH Reflux 6 h Recrystallization from ethanol 8ar R1= H, Cl, CH3 (67–73%) [77] 17as Hydrazine hydrate (1.5 eq) EtOH Reflux 4 h Recrystallization from ethanol 8as (90%) [78] 17at Hydrazine hydrate (1.02 eq) EtOH Reflux 3 h Recrystallization from ethanol or methanol 8at (89–97%) Molecules 2025,30, 2852 9 of 71 Table 1. Cont. Ref. Starting Material Experimental Conditions Purification Process Hydrazide Compounds (η%) [79] 17au Hydrazine hydrate (20 eq) EtOH Reflux 4 h Recrystallization from ethanol 8au (61%) [37] 17av Hydrazine hydrate 80% (3 eq) EtOH Reflux 3 h Recrystallization from ethanol/DMF 8v (90%) [80] 17ac Hydrazine monohydrate (1 eq) EtOH Reflux 4 h Recrystallization from dioxane 8ac(90%) [81] 17w Hydrazine hydrate (4 eq) EtOH Reflux 6 h - 8aw X = N, CH (48–55%) [82] 17x Hydrazine (1 eq) EtOH Reflux 3 h - 8ax(94%) [83] 17ay R = 4-F-C6H4, 17az R = 4-CH3–C6H4 17aaa R = 2-Cl,4-Cl-C6H3 Hydrazine hydrate (n.s.) EtOH Reflux n.s. n.s. 8ay R = 4-F-C6H4, 8az R = 4-CH3–C6H4 8aaaR = 2-Cl,4-Cl-C6H3 (n.s.) [84] 17aab Hydrazine hydrate (10 eq) EtOH Reflux 7 h - 8aab (80%) [2]17aac R = 2-furyl 17aad R = 3,4,5-(MeO)3C6H2 17aai R = 3,4-(MeO)2C6H3 Hydrazine hydrate (n.s.) - Reflux n.s. - 8aac R = 2-furyl 8aad R = 3,4,5-(MeO)3C6H2 8aai R = 3,4-(MeO)2C6H3 (n.s.) [85] 17al Hydrazine hydrate (~11 eq) EtOH r.t. 3–4 h - 8al (98%) Molecules 2025,30, 2852 16 of 71 Scheme 9. Synthesis of hydrazides 47 and moclobemide: (a) toluene, 456 nm, rt, 16 h; (b) DCM, r.t., 20 h; (c) i. MsCl, DCM, Et3N, DMAP, r.t., 24 h; ii. morpholine, 100 ◦C, 6 h. Scheme 10. Synthesis of compounds 50; (a) Et 3 N (0.5–3.5 eq), CH 3 CN, r.t., 30 min–15 h; (b) Et 3 N (3.5 eq), H2O, CH3CN, r.t., 24 h. 2.2. Biological Activity of Hydrazides The compounds presented in Figure 3showed anticancer activity against various cancer cell lines. Hydrazide 8ac showed good anticancer activity against MCF-7 breast cancer and HepG2 hepatocellular carcinoma cell lines with IC 50 = 8.1 µ M and IC50 = 28.6 µM, respectively [ 64 ]. Hydrazides 8aap.1 and 29c.1 also displayed anticancer activity towards the MCF-7 cancer cell line with IC 50 values of 2.37 and 1.83 µ M, respectively [ 92 ]. Besides that, Sabry et al. [ 92 ] reported that these hydrazides showed a strong dual inhibition activity of EGFR/HER2 kinase with IC 50 values of 0.153 µ M (EGFR) and 0.108 µ M (HER2) for 29c.1 and 0.122 µ M (EGFR) and 0.108 µ M (HER2) for 8aap.1. In in vivo studies in Swiss albino mice mammary glands, compounds 8aap.1 and 29c.1 showed tumor volume reductions by 65.3 and 76.5%, respectively, at 10 mg/kg. Derivatives 29a.1 and 29a.2, reported by Ramírez et al. [ 106 ], were also tested against the MCF-7 cancer cell line. Compounds 29a.1 and 29a.2 presented IC 50 values of 15.41 and 12.99 µ M, respectively. In addition, derivatives 29a.3 and 29a.2 were active against the A549 cell line (lung cancer) with IC50 values of 37.17 and 31.02 µM, respectively [106]. Hydrazides 8ad and 29b.1, reported by Abdelrehim et al. [ 35 ] and Han et al. [ 107 ], presented activity against the HCT-116 colorectal cancer cell line with IC 50 values of 8.44 µg/mL and 2.02 µ M (Figure 3). Compound 29b.1 also showed activity against PC-3 (prostatic adenocarcinoma), A549 (lung cancer), and MDA-MB-231 (triple-negative breast cancer) cancer cell lines, with IC 50 values of 1.95, 1.62, and 1.55 µ M. It also showed potent inhibitory activities against phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic sub- Molecules 2025,30, 2852 17 of 71 unit alpha isoform (PI3K α ) with an IC 50 = 0.46 nM and mammalian targeting of rapamycin (mTOR) with an IC50 = 12 nM [107]. Figure 3. Hydrazides with anticancer activity. Hydrazide 8b (Figure 4) was evaluated for its antibacterial and antifungal activities. It showed a strong antibacterial and antifungal activity, with inhibition zones of 29, 30, 28 and 16 mm against Bacillus subtilis,Escherichia coli,Candida albicans and Aspergillus niger, respectively [ 51 ]. Compounds 8c–8f also exhibited activity against E. coli,B. subtils, and Asp. niger strains, presenting inhibition zones varying between 2 and 5 mm [26]. Compounds 28 (Figure 4) were evaluated as fungicides [ 109 ]. Compounds 28a.1– 28a.5 exhibited growth inhibition activity against Botryosphaeria dothidea,Rhizoctonia solani, and Gibberella zeae with EC 50 values within the 10.0–0.306 µ g/mL range, which were higher activity than those of the commercial agrochemicals azoxystrobin, boscalid, and fluxapyroxad [109]. Disubstituted hydrazides 29 were tested as antimalarial agents. Compounds 29a.4 and 29a.5 (Figure 5) showed antimalarial activity with IC 50 values of 0.65 and 0.64 µ M, respectively [106]. Hydrazides present in Figure 6were evaluated as antivirals. Compound 8abc showed antiviral activity against influenza A as a Neuraminidase inhibitor against H5N1 and H1N1 subtypes with IC 50 values of 26.8 nM and 11.9 nM, respectively [ 99 ]. Moreover, hydrazide 8aax.1 was presented as a great immunomodulator, presenting 80% protection against the highly pathogenic avian influenza virus (H5N8) [28]. Myeloperoxidase plays a key role in the human antimicrobial system by oxidizing vital molecules of microorganisms in phagolysosomes through the production of hypochlorous acid. It has been associated with inflammatory diseases such as renal injury, multiple sclerosis, and cardiovascular and neurodegenerative diseases. Saylam et al. [ 65 ] reported compound 8ae (Figure 7) as an excellent myeloperoxidase inhibitor with an IC50 = 0.393 µM, which is comparable to the standard drug 4-aminobenzoic acid hydrazide. Molecules 2025,30, 2852 18 of 71 Figure 4. Hydrazides with antibacterial and antifungal activity. Figure 5. Hydrazides with antiparasitic activity. Figure 6. Hydrazides with antiviral activity. Figure 7. Myeloperoxidase inhibitor. Molecules 2025,30, 2852 19 of 71 3. Hydrazide Derivatives 3.1. Hydrazide–Hydrazones 3.1.1. Synthesis of Hydrazide–Hydrazones Hydrazide–hydrazone derivatives are among the most frequently synthesized and reported hydrazide derivatives in the literature. These compounds stand out in organic and medicinal chemistry since they have exhibited a wide range of biological activities and have been used as important intermediates in the synthesis of heterocycle rings from hydrazides. The hydrazide–hydrazone moiety contains the functional group -CO-NHN=CR 1 R 2 , which is a combination of the hydrazide and imine groups. The imine group confers E/Z isomerism and photochromism in both solution and the solid state [ 55 , 97 ]. Moreover, the -NHand C=O groups allow the compounds to have the capability of binding to anions/cations and biomolecules; the coexistence of imine and carbonyl groups allows them to establish metallo-assemblies [55]. In the past few years, hydrazides have been extensively used to synthesize several hydrazide–hydrazone derivatives, as potential aggregation-induced emission luminogens (AIEgens), probes, or anticancer, antimicrobial, antifungal, antituberculosis, antimalarial, antiviral, and antioxidant agents. Some derivatives exert their activity through the inhibition of specific enzymes such as acetylcholinesterase, butyrylcholinesterase, α -glucosidase, and others. Hydrazide–hydrazones 52 are synthesized from the reaction between a hydrazide and an aldehyde/ketone [ 13 , 34 , 37 , 38 , 43 , 53 , 54 , 56 , 57 , 66 – 68 , 71 – 73 , 75 – 79 , 95 – 98 , 101 , 117 – 127 ] (Scheme 11). According to the studies in this review, these reactions, in general, occur in alcohols (ethanol or methanol) and at high temperatures (Table 3). The reactions occurred without or with acid catalysis, such as acetic acid [34,43,54,66,71,73,76,77,79,95,96,117,119,121,123,127] or p-TsOH [ 55 , 56 ], and in these cases, the reactions may occur at room [ 55 , 56 , 79 , 117 ] or high temperatures [ 34 , 38 , 43 , 54 , 66 , 68 , 71 – 73 , 76 , 77 , 95 , 96 , 119 , 121 , 123 , 127 ]. Hydrazide–hydrazone derivatives were obtained in low to excellent yields. As mentioned earlier, some hydrazides are commercially available. However, others are synthesized by the scientific community to originate the required compounds. Here, hydrazide–hydrazones synthesized from alkyl, aryl, or heteroaryl hydrazides as starting materials, produced or not by the authors, will be presented. The biological activity of the generated compounds will also be reviewed. Scheme 11. Representative scheme of hydrazide–hydrazones synthesis. Table 3. Reaction conditions for the synthesis and purification of hydrazide–hydrazones. Ref. Starting Material Experimental Conditions Purification Process Hydrazone Compounds (η%) [124] 8abd (1 eq) EtOH, reflux, 2 h Recrystallization from ethanol 52a (71%) Molecules 2025,30, 2852 20 of 71 Table 3. Cont. Ref. Starting Material Experimental Conditions Purification Process Hydrazone Compounds (η%) [97] 8aaw RCHO (1.25 eq) MeCN:CHCl 3 (1:1), HOAc (0.9 eq), 65 ◦C, 24 h R = Ar Silica gel column chromatography 52b R = Ar (72–94%) [68] 8ah RCHO (1.1 eq) EtOH, glacial CH3COOH (drops), reflux, 8 h R = Ar Recrystallization from ethanol 52c R = Ar (56–95%) [96] MeO MeO NHNH2 O OMe OMe R1 8aau (1 eq) MeOH, CH3COOH (cat.), reflux, 1h Flash column chromatography 52d (63–85%) [72] 8as RCHO (1 eq), EtOH, piperidine (0.3 eq), reflux, 2 h R = Ar - 52e R = Ar (n.s.) [77] 8ao RCHO (1 eq), EtOH, CH3COOH (drops), reflux, 6–8 h R = Ar Recrystallization from ethanol 52f R = Ar (85–92%) [57] 8h RCHO (1 eq) EtOH, reflux R = Ar - 52g R = Ar (26–55%) [57] 8h MeCOR (1 eq) EtOH, reflux R = Ar - 52h R = Ar (15–61%) [75] 8aq MeCOR1(n.s.) EtOH, reflux, 1 h Recrystallization from EtOH, n-BuOH, or i-PrOH 52j (61–89%) [73] 8ap MeCOR (1 eq), CH3COOH (17 eq), EtOH, reflux, 6–8 h R = Ar Recrystallization from acetic acid 52k R = Ar (85–95%) Molecules 2025,30, 2852 21 of 71 Table 3. Cont. Ref. Starting Material Experimental Conditions Purification Process Hydrazone Compounds (η%) [101] 8aba.1 (1 eq) dioxane, reflux, 30 min Recrystallization from ethanol/dioxane mixture (1:1) or dioxane 52l (77%) [76] 8ar R2CHO (1 eq) EtOH, CH 3 COOH (cat.), reflux, 6 h R2= Ar Recrystallization from ethanol 52m R2= Ar (41–60%) [76] 8ar MeCOR (1 eq) EtOH, CH 3 COOH (cat.), reflux, 6 h R = Ar Recrystallization from ethanol 52n R = Ar (46–62%) [117] 8abe R1= H 8abf R1= CH3 (1 eq) EtOH, CH3COOH (0.9 eq), r.t. Recrystallization from dichloromethane/ethanol (1:2) 52o (40–84%) [43] 8ai–8am (antranorin) EtOH, CH3COOH, 50 ◦C, 2h Silica gel column chromatography 52p (73–89%) [55] 8g RCHO (1 eq) MeOH, p-TsOH (cat.), r.t., 2 h R = Ar Silica gel column chromatography 52q R = Ar (90–95%) Molecules 2025,30, 2852 22 of 71 Table 3. Cont. Ref. Starting Material Experimental Conditions Purification Process Hydrazone Compounds (η%) [56] 8g RCHO (n.s.) MeOH, p-TsOH (cat.), r.t., overnight R = Ar Silica gel column chromatography 52q R = Ar (60–79%) [95] 8aat RCHO (1.1 eq) EtOH, CH3COOH (few drops), reflux, 12 h R = Ar Recrystallization from ethanol 52s R = Ar (68–90%) [66] 8af RCHO (1.1 eq) EtOH, CH3COOH (few drops), reflux, 8 h R = Ar Recrystallization from ethanol 52t R = Ar (55–80%) [67] 8ag RCHO (1.1 eq) EtOH, reflux, 3 h R = Ar Recrystallization from ethanol N H O N R I Br 52u R = Ar (24–90%) [118] 8abj R = 2-HO 8af R = 4-HO R2CHO (0.99 eq) EtOH or i-PrOH, 60 ◦C, 0.5–6 h R2= Ar Recrystallization from i-PrOH 52v R = 2-HO, 4-HO; R2= Ar (66–92%) [38] O NHNH2 I OH 8n RCHO (1.1 eq) EtOH, reflux, 3–35 min R = HetAr Recrystallization from ethanol 52w R = HetAr (18–97%) [43] 8j,8k (n.s.) EtOH, CH3COOH, 50 ◦C, 2h Silica gel column chromatography 52p (73–89%) [13] 8l 2,4-(HO)2C6H3CHO (1 eq) MeOH, reflux, 6 h - 52y (84%) [34] 8m 1. (1 eq) CH3COOH (28 eq), 90 ◦C, 6 h 2. NaHCO3 Recrystallization from ethanol 52z R, R1, R2= alkyl or halide (86–90%) Molecules 2025,30, 2852 23 of 71 Table 3. Cont. Ref. Starting Material Experimental Conditions Purification Process Hydrazone Compounds (η%) [98] 8aax RCHO (1 eq), EtOH, 78 ◦C, 4 h R = Ar Recrystallization from acetonitrile or 70% ethanol 52aa R = Ar (50–86%) [37] 8av RCHO (2.1 eq) EtOH/DMF, reflux, 5 h R = Ar Recrystallization from DMF/ethanol 52ab R = Ar (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) EtOH or CH3COOH, reflux n.s. 52ac (46–65%) [119] (n.s) EtOH or CH3COOH, reflux R1, R2= alkyl n.s. 52ad R1, R2= alkyl (72–95%) [53] 8r RCHO (1.1 eq), EtOH, reflux, 2 h R = Ar Recrystallization from ethanol 52ae R = Ar (10–93%) [120] 1X=N,Y=CH 8abg.1 X=CH,Y=N (1 eq) EtOH, reflux, 5 h Silica gel column chromatography 52af R=R=H,OCH3, F, Cl (89–94%) [43] 8al EtOH, CH3COOH, 50 ◦C, 2 h Silica gel column chromatography 52p.12 [54] 8s R1COR2(1 eq) EtOH, acetic acid (~0.2 eq), reflux, 8 h - 52ag R1= Ar, R2= H or alkyl (62–92%) Molecules 2025,30, 2852 24 of 71 Table 3. Cont. Ref. Starting Material Experimental Conditions Purification Process Hydrazone Compounds (η%) [121] 1X=N,Y=CH 8abh X, Y = C-Br, C-Cl, CH, N, C-Me, C-NO2(1 eq) EtOH, CH 3 COOH (cat.), reflux, 3 h Recrystallization from ethanol 52ah (60–80%) [122] 8abi (1 eq) MeOH, reflux Recrystallization from methanol 52ai (78–95%) [123] 1(1 eq) MeOH, CH 3 COOH (drops), reflux, 2 h Recrystallization from ethanol 52aj R1= Ar (75–87%) [78] 8at (n.s.), 25 min - 52ak R = Ar (93%) [79] 8au 4-HOC6H4CHO (1 eq) EtOH, CH3COOH (drops), r.t., 30 min Recrystallization from ethanol 52al (23%) [125] 8abh RCHO (1 eq), EtOH, reflux, 1–2h R = HetAr Recrystallization from ethanol/water or ethanol 52an R = HetAr (82–95%) [126] 1(1 eq), MeOH, Ar (g), reflux, 3–60 h; Y1: CHO, Z: H, Ph, cyclopentyl Recrystallization from a mixture of chloroform/ether or silica gel column chromatography 52ao (40–86%) Y2: CONH=CHPy; Z: H, Ph, cyclopentyl [126] 1(1 eq), MeOH, Ar (g), r.t., 18–48 h Y1: CHO, Z: H, Ph, cyclopentyl Recrystallization from a mixture of chloroform/ether or silica gel column chromatography 52ap (78–81%) Y2: CONH=CHPy; Z: H, Ph, cyclopentyl [127] 8abh (1 eq), EtOH, CH3COOH (0.8 eq), reflux, 4–7 h R1= Me or Ph; R2= Me or H; R3= Me or OC2H5 Recrystallization from ethanol 52aq (73%) n.s.—not specified by the authors. Molecules 2025,30, 2852 25 of 71 3.1.2. Biological Activity of Hydrazide–Hydrazones The new hydrazide–hydrazone derivatives represented in Figure 8were evaluated as anticancer agents. Compounds 52a,52c.1,52d.1, and 52e.1 showed good activity against human breast cancer cell lines, specifically against the MCF7 line, with IC 50 values of 7.38, 59.81, 3.49, and 14.6 µ M, respectively [ 68 , 72 , 96 , 124 ]. Moreover, compound 52c.1 also showed promising anticancer activity, with IC 50 = 22.42 µ M, against the human breast cancer cell line MDA-MB-231. Compound 52c.1 was tested in vivo and decreased the tumor volume in both low (60 mg/kg) and high (120 mg/kg) doses in mice [ 68 ]. Besides the activity against breast cancer, compound 52a showed activity against the HepG2 cancer cell line with IC 50 = 8.79 µ M [ 124 ]. In addition, derivatives 52d were also tested against HCT-116 and SK-MEL-28 (melanoma) cancer cell lines. Compound 52d.1 displayed the highest activity with IC 50 values of 6.82 and 10.39 µ M, respectively, with no relevant toxicity on non-malignant HaCaT (human keratinocyte) cells [96]. According to Halil et al. [ 97 ], natural compounds with bioactive properties, when combined with hydrazides, can lead to new active compounds with increased activity. Hence, Halil et al. [ 97 ] synthesized molecules with structure 52b (Figure 8) starting from the natural product oleanolic acid. The in vitro anticancer activity was studied on the A549 (adenocarcinomic human alveolar basal epithelial) cell line. Of the thirteen compounds synthesized, compound 52b.1 showed the best activity with IC 50 = 0.08 µ M and low cytotoxicity on the BEAS-2B cells (human non-tumorigenic lung epithelial cells). The anticancer activity of combretastatin–oxindole 52d, pyrimidine derivatives 52e, and triazoles 52f (Figure 8) was also evaluated against the A549 cell line. Compounds 52d.1 and 52e.1 were promising anticancer agents with IC 50 values of 1.26 and 11.3 µ M, respectively [ 72 , 77 , 96 ]. Furthermore, Abba et al. [ 72 ] identified the derivative 52e.1 as a potent compound against DU145 (prostate cancer) using HeLa (cervical cancer) cell lines with IC50 values of 13.4 and 9.1 µM, respectively [72]. According to Almehmadi et al. [ 77 ], molecules 52f revealed an anticancer capacity, presenting a growth inhibition ranging from 55 to 90% at 400 µ g/mL against the A549 cell line. Han et al. [ 95 ] described derivatives 52s.1 and 52s.2 with high anticancer activity against the human colorectal adenocarcinoma (Colo-205) cell line ( IC50 = 50.0 and 20.5 µM, respectively ). On the other hand, compounds 52s.3, 52s.4, 52s.5, 52t.1, and 52t.2 displayed the great anticancer activity against the liver hepatocellular carcinoma HepG2 cell line with IC 50 = 30.5, 35.9, 20.8, 42.4, and 37.4 µ M, respectively [ 66 ]. Derivatives 52t.1 and 52t.2, reported by Han et al. [ 66 ] (Figure 8) exhibited lower activity than derivatives 52s. Among the thirteen different hydrazones 52u, described by Popiołek et al. [ 67 ], compound 52u.1 exhibited the best cytotoxicity with IC 50 = 33.45 and 11.94 µ M against hepatocellular carcinoma (HepG2) and renal adenocarcinoma (769-P) cell lines, respectively, and additionally showed high selectivity, with low cytotoxicity against the normal Vero cell line, with IC50 = 320.54 µM. Among indole derivatives 52z [ 34 ], compound 52z.1 was the most active against the A549 lung adenocarcinoma cell line with IC 50 = 0.793 µ M. This compound also showed great activity against cervical HeLa and breast MCF-7 cancer cells with IC 50 = 1.69 and 1.19 µ M. The authors studied the mechanisms of action of compound 52z.1 regarding different signaling pathways triggered in HeLa and MCF-7 cells, and it was verified that this compound induced cell apoptosis through the generation of reactive oxygen species and activation of many signal transduction pathways [34]. Molecules 2025,30, 2852 32 of 71 when placed in the presence of human serum albumin (HSA), they disassemble and display an evident fluorescence signal. Figure 15. Hydrazide–hydrazone as potential probes. Compounds 52aj,52ak, and 52al (Figure 16) were tested as potential antioxidants [ 78 , 79 , 123 ]. Among the twelve derivatives 52aj tested in vitro , compound 52aj.1 showed the best activity according to the DPPH method (SC 50 = 0.03 mg/mL) [ 123 ]. However, compound 52ak showed antioxidant activity in vivo in rats according to Abdelhamid et al. [ 78 ]. Amongst the quinoline hydrazide–hydrazone derivatives synthesized by Cahyana et al. [ 79 ], compound 52al showed the best antioxidant activity by DPPH assay with IC50 = 843.52 ppm, yet this was weak compared to ascorbic acid with IC50 = 11 ppm. Figure 16. Hydrazide–hydrazone with antioxidant activity. Apart from their biological importance, hydrazide–hydrazone compounds are occasionally mentioned in the following points as useful intermediate synthons for the synthesis of some heterocyclic rings [40,47]. 3.2. Heterocycles from Hydrazides Hydrazides are widely used as synthons in the synthesis of a variety of heterocycles via electrophilic reactions. After the cyclization process, the different heterocycles can also be further modified or not to obtain compounds with biological activity. Within the heterocycles generated from hydrazides, it has become possible to identify the synthesis of pyrrolones, pyrazoles, oxadiazoles, thiadiazoles, triazoles, and triazepinones in the recent literature, which will be discussed in the following sections. The biological activity of the synthesized compounds will also be presented. 3.2.1. Pyrrolones Synthesis of Pyrrolones Pyrrolones are five-membered heterocyclic lactams recognized as important scaffolds whose origin may be natural or synthetic, with a wide variety of pharmacological activities [ 133 , 134 ]. These compounds can present anticancer [ 27 , 135 – 137 ], antimalarial [ 138 ], anti-inflammatory [ 139 ], antiviral [ 28 ], and antioxidant activities [ 140 ]. In 2015, Pelkey et al. [ 141 ] reported different methods, including one-component intramolecular or two-component intermolecular cyclization approaches for pyrrolone synthesis that were reported through the end of 2014. Molecules 2025,30, 2852 33 of 71 According to the literature mentioned in Table 4, from 2019 to 2024, [27,28,101,137,140], pyrrolones 53 and 54 can be formed from the reaction of hydrazides (compounds 8aax or 8aba) and electrophiles (e.g., acyl chlorides or aldehydes) (Scheme 12) [ 27 , 28 , 101 , 137 , 140 ]. The reactions with acyl chlorides occurred under reflux [ 27 , 28 , 140 ] or at room temperature [ 28 , 137 ], and in some cases, a base [ 28 ] was used. When the reaction occurred with aldehydes [ 28 , 101 , 140 ], the reactions were performed via the catalysis of acetic acid, in ethanol, under reflux conditions. The products were generally obtained in good yields. Table 4. Reaction conditions for the synthesis and purification of pyrrolones from hydrazides. Ref. Hydrazide Experimental Conditions Purification Process Final Compounds (η%) [27] 8aba.2 (n.s) Benzene, reflux n.s. 53a (78%) [137] 8aba.2 (1 eq, dropwise) DMF, r.t., 4 h Recrystallization from ethanol 53b (78%) [28] 8aax.1 (1 eq) Et3N, dioxane, r.t., 1 h Recrystallization from ethanol 53c (86%) [28] 8aax.1 PhCOCl (1 eq) Benzene, reflux, 1 h Recrystallization from ethanol 53d (68%) [140] 8aax.2 CH3COOCOCH3(10.5 eq), r.t., 1 h Recrystallization from benzene 53e (65%) [140] 8aax.2 CH3COOCOCH3(10.5 eq), reflux, 4 h Recrystallization from petroleum ether (60–80) 53f (60%) [140] 8aax.2 PhCOCl, benzene, reflux, 3 h Recrystallization from benzene 53g (60%) Molecules 2025,30, 2852 34 of 71 Table 4. Cont. Ref. Hydrazide Experimental Conditions Purification Process Final Compounds (η%) [140] 8aax.2 RCHO (1 eq), EtOH, CH3COOH, reflux, 3 h Recrystallization from dioxane 54c (80%) [28] 8aax.1 (1 eq), CH 3 COOH, ethanol, reflux, 1 h Recrystallization from ethanol/dioxane mixture (1:1) 54a (87%) [101] 8aba.2 RCHO (1 eq) EtOH, CH 3 COOH (cat.), reflux, 1 h Recrystallization from ethanol/dioxane mixture 54b (80–84%) n.s.—not specified by the authors. Scheme 12. Representative scheme of pyrrolone synthesis from hydrazides. Biological Activity of Pyrrolone Derivatives The pyrrolone derivative 53a exhibited great in vitro anticancer activity against HCT116 and MCF-7 cell lines, with IC 50 = 7.49 and 8.51 µ M [ 27 ], respectively (Figure 17). Also, compound 53b showed IC50 = 46.3 µg/mL against HePG2 cell lines [137]. Molecules 2025,30, 2852 35 of 71 Figure 17. Pyrrolones with anticancer activity. Compounds 53c and 53d, reported by El-Helw et al. [ 28 ], showed a high percentage of protection against the pathogenic avian influenza virus (H5N8) [ 28 ], higher than 80% of immunomodulators. Morsy et al. [ 101 ] reported on compounds 54b.2 and 54b.3, which exhibited antiviral activity with 100% protection against Newcastle disease virus (Figure 18). Figure 18. Pyrrolones with antiviral activity. Moreover, Youssef et al. [ 140 ] used the phosphomolybdenum method to determine the antioxidant capacity of compounds 53e–gand 54c (Figure 19). The compounds showed good to moderate antioxidant capacity, presenting 163.0 to 262.27 mg of acid ascorbic equivalents per gram (AEE/g) of dry compound. Figure 19. Pyrrolones with antioxidant activity. Molecules 2025,30, 2852 36 of 71 3.2.2. Pyrazoles Synthesis of Pyrazoles Pyrazole derivatives are five-membered N-heterocycle compounds with two adjacent nitrogen atoms (1,2-positions) [ 29 ]. Unsubstituted pyrazole is a planar structure with three possible tautomeric forms (55-A,55-B, and 55-C), as represented in Figure 20.However, it can also exist as a dimer (55-D), in concentrated solution, via hydrogen bonding [142]. Figure 20. Tautomeric structures and dimer of pyrazole. In the azole family, pyrazole derivatives are one of the most studied compounds, with a wide range of chemical and biological properties [ 29 , 143 , 144 ]. In clinical use, rimonabant, sildenafil, fomepizole, celecoxib, and ruxolitinib are some of the pyrazole-based drugs [ 142 ]. In the literature, pyrazoles have been described as antimicrobial [ 128 , 145 , 146 ], anti-inflammatory [147,148], and anticancer agents [149–151]. Hassani et al. [ 29 ] and Ríos et al. [ 143 ] compiled the works reporting the synthesis of pyrazole derivatives between 2013 and 2023 and between 2017 and 2022, respectively. Pyrazoles were obtained from the reaction between hydrazine and a carbon unit, such as 1,3-dicarbonyl, α , β -unsaturated carbonyl compounds, acetylenic ketones, or β -enaminones or similar compounds. Although pyrazoles are usually obtained from hydrazine, in this review, we present hydrazides as precursors of pyrazoles, dihydropyrazoles, or pyrazolidine-diones ( Table 5 ). The synthesis of these compounds occurred between hydrazides 8and several carbonyl/nitrile compounds as represented in Scheme 13. Pyrazoles 63 to 66 were obtained in ethanol, under reflux, in the presence or not of an organic base [ 80 , 146 ]. Dihydropyrazoles 67–70 [ 80 , 128 , 146 ] or pyrazolidine-diones 71 [ 80 ] were generated from hydrazides and carbonyl/nitrile compounds in the presence of a strong inorganic base, in ethanol or DMF, at room temperature or under reflux. The products were usually obtained with good yields [80]. Table 5. Reaction conditions for the synthesis and purification of pyrazoles, dihydropyrazoles, and pyrazolidine-dione from hydrazides. Ref. Starting Material Experimental Conditions Purification Process Pyrazole Compounds (η%) [80] 8ac CH2(COOC2H5)2 C2H5ONa/EtOH Reflux, 14–17 h Recrystallization from dioxane 71a (90%) [80] 8ac CH3COCH2COOC2H5 DMF K2CO3 Reflux, 12–15 h Recrystallization from methanol 69a (85%) Molecules 2025,30, 2852 37 of 71 Table 5. Cont. Ref. Starting Material Experimental Conditions Purification Process Pyrazole Compounds (η%) [80] 8ac CNCH2COOEt DMF K2CO3 Reflux, 14–17 h Recrystallization from methanol 68a (77%) [80] 8ac CNCH2COPh EtOH Reflux, 6–9 h Recrystallization from dioxane 65a (72%) [80] 8ac CH3COCH2COCH3 EtOH Piperidine (cat.) Reflux, 10–15 h Recrystallization from methanol 64a (95%) [80] 8ac CNCH2CN EtOH Piperidine (cat.) Reflux, 20–25 h Recrystallization from DMF 66a (70%) [128] 1 NaOH/EtOH r.t. 8–9 min Recrystallization from methanol 67a (82–88%) [128] 8abg.1 NaOH/EtOH r.t. 8–9 min Recrystallization from methanol 67b (82–87%) [146] 8abk CH3COCH2COOC2H5 DMF/EtOH CH3COOH Reflux, 5 h Column chromatography 70a (62–67%) [146] 8abk CH3COCH2COCH3 DMF/EtOH CH3COOH Reflux 8 h Column chromatography 64b (61–72%) Molecules 2025,30, 2852 38 of 71 Scheme 13. Representative scheme of pyrazoles, dihydropyrazoles, and pyrazolidine-dione synthesis from hydrazides. Also, recently, Ardakani et al. [ 145 ] reported the synthesis of dihydropyrazole 72 by the reaction of substituted hydrazide 28c with alkyl isocyanides and dialkyl acetylenedicarboxylates at room temperature, in 72–84% yields (Scheme 14). Scheme 14. Synthesis of dihydropyrazole derivatives 48: (a) acetone, –5 ◦C, 10 min, r.t., 24 h. Biological Activity of Dihydropyrazole and Pyrazole Derivatives Compounds 67a,b(Figure 21) were screened for their in vitro antibacterial and antifungal activities. Compound 67a.2, with an MIC = 100 µ g/mL against Gram-positive B. subtilis and a stronger MIC = 50 µ g/mL against C. tetani, was equipotent or more potent than the reference drugs ampicillin (MIC 250 µ g/mL) and ciprofloxacin (MIC 100 µg/mL ). Molecules 2025,30, 2852 39 of 71 Compound 67a.4 was more potent than ampicillin against S. aureus (MIC 62.5 µ g/mL). In general, compounds 67a, with isoniazid moieties, were more effective against all microorganisms than those with nicotinic hydrazide derivatives 67b (Figure 21) [128]. Figure 21. Pyrazole derivatives with antibacterial, antifungal, or anticancer activities. Compounds 70a and 64b (Figure 21) demonstrated effective antibacterial activity against Staphylococcus aureus,Bacillus subtilis,E. coli, and Pseudomonas aeruginosa, with MIC values ranging from 8 to 16 µ g/mL, and good cytotoxicity in vitro against two human cancer cells, HCT-116 (colon) and HL-60 (leukemia), though it was less than the standard 5-fluorouracil [146]. 3.2.3. Oxadiazoles Synthesis of Oxadiazole Derivatives Oxadiazoles are one of the most valuable five-membered heterocycles, holding one oxygen and two nitrogen atoms, with an extensive spectrum of applications [ 31 ]. From the oxadiazole isomers of 1,2,3-oxadiazole 73, 1,2,4-oxadiazole 74, 1,2,5-oxadiazole 75, and 1,3,4-oxadiazole 76, presented in Figure 22, 1,3,4-oxadiazole 76 stands among the most studied and used, due to its broad activity spectrum [ 152 , 153 ]. This isomer appears in some available drugs, such as Zibotentan, Furamizole, Raltegravir, and Nesapidil [ 83 ], but recently, new derivatives have been shown to have biological activities, including anticancer [ 82 ], antibacterial, antifungal [ 154 ], antimalarial [ 2 ], antileishmanial [ 40 ], antitubercular [ 81 ], antiviral [ 28 ], anti-inflammatory [ 41 , 85 ], antioxidant [ 105 ], and insecticidal activities [103]. Figure 22. Structures of oxadiazole isomers. Sharma et al. [ 31 ] collected and discussed the synthesis of 1,3,4-oxadiazoles in the past 15 years. The authors discussed dehydrogenative cyclization of 1,2-diacylhydrazines with phosphorus oxychloride (POCl 3 ), phosphoric acid (H 3 PO 4 ), and thionyl chloride (SOCl 2 ); oxidative cyclization of hydrazide–hydrazones; and decarboxylative cyclization. Molecules 2025,30, 2852 40 of 71 Here, we report the use of hydrazides in the synthesis of 1,3,4-oxadiazoles. According to Table 6, 1,3,4-oxadiazoles can be synthesized from the reaction between a hydrazide and carbon electrophilic reagents such as aldehydes, oxalyl chlorides, carboxylic acids, or carbon disulfide, as represented in Scheme 15. Some 2,3-dihydro-1,3,4-oxadiazol-2-yl derivatives 78 have been synthesized from hydrazides 8, with hydrazide–hydrazones 52 as intermediates [ 40 , 82 , 154 ]. This method starts with the reaction of hydrazide and an aldehyde, and then the reaction follows in the presence of acetic anhydride under reflux. The oxadiazoles 78 obtained by this method were generally obtained in low to excellent yields. On the other hand, Paidi et al. [ 153 ] reported the synthesis of 2,5-disubstituted 1,3,4-oxadiazoles 77 via one-pot NaOCl-mediated oxidative cyclization from hydrazide– hydrazones 52, generated in situ from hydrazides 8and aldehydes (Scheme 15). The best conditions reported by Paidi et al. [ 153 ] included hydrazide 8in the presence of aldehydes and t-BuOH, under reflux, followed by a reaction with 10–12% aqueous NaOCl at room temperature. These reaction conditions were applied to hydrazides and aldehydes with both electron-donating and electron-withdrawing groups, and the desired products 77 were obtained in moderate to excellent yields. Compounds 77 were also generated directly from 8by reaction with acetic anhydride [80]. Table 6. Reaction conditions for the synthesis and purification of 1,3,4-oxadiazoles and their derivatives. Ref. Starting Material Experimental Conditions Purification Process Oxadiazole Compounds (n%) [154] 8abl 1. RCHO EtOH, reflux, 3 h 2. Ac2O (32 eq), reflux, 3 h Recrystallization from ethanol/acetone (3:1 v/v) mixture 78a R = Ar (22–76%) [82] 8ax 1. RCOR1 70 ◦C, 2 h 2. Ac2O (10.5 eq), reflux, 8 h Recrystallization from ethanol 78b R = Ar, R1= H, CH3(n.s.) [40] 8o R2= H, R3=H 8p R2= Cl, R3= H 8q R2= H, R3= Cl 1. EtOH, CH3COOH (cat.) 80 ◦C, 3 h 2. Ac2O (10.5 eq), 155 ◦C, 90 min Flash chromatography 78c R 1 = CH 3 , H, F; Y = CH, N; R2and R3= H, Cl (40–71%) [153] 8R1= Alk, Ar 1. R2CHO, t-BuOH, reflux, 2–3 h 2. NaOCl, r.t., 1–2 h Column chromatography 77 R1= Alk, Ar; R2= Alk, Ar (50–93%) [80] 8ac Ac2O, 10–15 min, EtONa, 6–8 h; Recrystallization from ethanol 77a (88%) [80] 8ac Ac2O, reflux, 25–30 h Recrystallization from methanol 77b Molecules 2025,30, 2852 41 of 71 Table 6. Cont. Ref. Starting Material Experimental Conditions Purification Process Oxadiazole Compounds (n%) [84] 8aab R-X-CO2H (1 eq) POCl3(5 eq), 50 ◦C, 4 h X-R = CH2O-Ar, CH2-Ar or Ar Recrystallization from ethanol 77c X-R = CH2O-Ar, CH2-Ar or Ar (46–66%) [152] 1Y=Nor8o Y = CH (1 eq) POCl3(48 eq), reflux, 9 h Recrystallization from an appropriate solvent 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.), reflux 6–7 h Recrystallization from isopropanol 77e R = Ar (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 Recrystallization from methanol 77f R = Aryl, HetAr; R1= H, CH3, F (80–89%) [59] 8u R1CO2H (1 eq), POCl3(6.7 eq), reflux, 6–8 h Recrystallization from methanol 77g R1= Ar (78–90%) [105] 8v (0.5 eq) POCl3ultrasonication (35 kHz) 35–60 min Recrystallization from 2-propanol 77h (80–92%) [105] 8w (0.5 eq) POCl3(53 eq) ultrasonication (35 kHz) 35–50 min Recrystallization from 2-propanol 77i (87–91%) [81] 1X=Nor8o X = CH 1. CH2Cl2, 0◦C ClCOCOOEt (1.1 eq) Et3N r.t., 8 h 2. p-TosCl (1 eq) r.t., 4 h Recrystallization from ethanol 79a X = N or CH (87, 83%) Molecules 2025,30, 2852 48 of 71 Figure 24. 1,3,4-oxadiazole-2-thiol derivatives with anticancer and/or antibacterial activities. Compound 78a.1 (Figure 25) showed promising activity against Staphylococcus epidermidis with an MIC = 0.48 µ g/mL, as well as low cytotoxicity against the L929 normal cell line [154]. Figure 25. 1,3,4-oxadiazoles as antibacterial and antifungal agents. Long et al. [ 39 ] designed, synthesized, and evaluated oxadiazole derivatives 85 ( Figure 25 ) for their antifungal, antioomycete, and antibacterial activities. Compound 85a showed the best in vitro antifungal activity against Gibberella zeae and antioomycete activity against Phytophora infestins, with EC 50 = 0.47 µ g/mL and 3.92 µ g/mL, respectively. In the in vivo study against corn scab, compound 60a showed protective and curative activities of 90.2 and 86.3% at 200 µ g/mL, which were comparable to those of fungicides boscalid and fluopyram. These 1,3,4-oxadiazole-tailored pyrazole compounds with hydrazide functions in the middle as a linker are potential agricultural fungicides for controlling fungal diseases. The 2,5-disubstituted 1,3,4-oxadiazoles 77e (Figure 25) were evaluated for their in vitro antibacterial activity. Compound 77e.2 exhibited the best broad-spectrum antibacterial and antifungal activity, with MIC = 15.62, 7.81, 3.9, and 31.25, 62.5 µ g/mL against E. coli,S. typhi,B. subtilis,B. megaterium, and A. niger, respectively [83]. Derivatives 84 (Figure 26) were evaluated for their in vitro antimycobacterial activity against the M. tuberculosis H37Ra-attenuated strain, H37Rv virulent strain, and several resistant strains. From the 5-phenyl-substituted oxadiazole subseries, derivatives 84a and 84b presented an MIC = 4 µ M against pyrazinamide-resistant strains. Moreover, these compounds exhibited selectivity for mycobacteria and low cytotoxicity against human SH-SY5Y cells (CC50 = 50 and 100 µM for 84a and 84b, respectively) [81]. Molecules 2025,30, 2852 49 of 71 Figure 26. 1,3,4-oxadiazoles with antimycobacterial and antiparasitic activities. Also, N 3 -acetyl-1,3,4-oxadiazoline derivatives 78c (Figure 26) were screened against Leishmania donovani, and compound 78c.1 exhibited an antileishmanial activity with IC50 = 8.98 µM on L. donovani intramacrophage amastigotes [40]. Moreover, Verma et al. [ 2 ] synthesized the hybrid compounds 77f and evaluated their activity against P. falciparum 3D7 (chloroquine-sensitive) and RKL 9 (chloroquineresistant) strains. Among the evaluated compounds 77f (Figure 26), compound 77f.1 exhibited the best activity with an IC 50 = 0.25 µ g/mL against the 3D7 (chloroquine-sensitive) strain and 0.86 µ g/mL against the RKL 9 (chloroquine-resistant) strain of P. falciparum. Moreover, the antileishmanial activity of compounds 77f against L. donovani promastigotes was also evaluated. Compounds 77f.2,77f.3, and 77f.4 exhibited IC 50 = 33.3, 40.1, and 19.0 µ g/mL, respectively. The same compounds (77f.2,77f.3, and 77f.4) also had effects on amastigote infectivity with IC 50 = 44.2, 66.8, and 73.1 µ g/mL, respectively. Among the tested compounds, the most promising were 77f.1 and 77f.4 for their good antimalarial and antileishmanial activity, respectively; hence, their cytotoxicity was studied, as well as their safety profile. El-Helw et al. [ 28 ] reported compound 80l (Figure 27) as an immunomodulator against the highly pathogenic avian influenza virus (H5N8), with the high potency of 100% protection, and Ramadan et al. [ 103 ] reported compound 80m (Figure 27) as an insecticide with low LC 50 = 9.67 and 1.07 mg/mL against lab and field strains of the third larval instar of Culex pipiens. Figure 27. 1,3,4-oxadiazole-2-thiol derivatives with antiviral (80l) or insecticidal activity (80m). Molecules 2025,30, 2852 50 of 71 New derivatives of novel 2,5-disubstituted 1,3,4-oxadiazole (Figure 28) were also synthesized as potential anti-inflammatory and antioxidant agents. Kashid et al. [ 59 ] reported compounds 77g (Figure 28) with great anti-inflammatory and antioxidant activities, of which compounds 77g.1,77g.2, and 77g.3 showed better anti-inflammatory activities with IC 50 = 45.69, 58.54, and 56.70 µ M, respectively, compared to the standard drug diclofenac sodium that presents an IC 50 = 90.21 µ M. According to the DPPH assay, compound 77g.4 exhibited good antioxidant activity with IC 50 = 17.15 µ M, which was better than the reference antioxidant ascorbic acid (IC 50 = 44.18 µ M). Also, a molecular docking study showed that these compounds can recognize the active site and accomplish significant bonded and non-bonded interactions with main residues in the anti-inflammatory target cyclooxygenase-2 (COX-2) [ 59 ]. Gunthanakkala et al. [ 105 ] reported compounds 77h and 77i (Figure 28) as potential antioxidants with IC 50 values between 32.95 and 121.12, 29.90 and 117.73, and 31.34 and 106.42 µ g/mL, for DPPH, NO, and H 2 O 2 assays, respectively. Among them, compound 77h.2 stood out with IC 50 values = 32.95, 31.64, and 32.42 µ g/mL, and compound 77i.2 with IC 50 values = 32.01, 29.90, and 31.34 µ g/mL for DPPH, NO, and H2O2assays, respectively. Figure 28. 1,3,4-oxadiazole derivatives as potential anti-inflammatory and antioxidant agents. Some oxadiazole-2-thiol derivatives 80g (Figure 28) also presented anti-inflammatory activity as inhibitors of COX or lipoxygenase (LOX) enzymes [ 41 , 85 ]. Munir et al. [ 41 ] identified derivatives 80g with good in vitro cyclooxygenase inhibition activity, with IC 50 values ranging from 31.5 to 39.5 µ M for COX-2 and from 43.91 to 27.55 µ M for COX-1. On the other hand, Bashir et al. [ 85 ] identified oxadiazoles 81e.1–4, which showed good LOX inhibitory activities with IC50 values of 21.5, 29.1, 31.3, and 24.3 µM, respectively. Molecules 2025,30, 2852 51 of 71 Rana et al. [ 61 ] reported new derivatives 81f (Figure 28) incorporating the flurbiprofen moiety. Compound 81f.1 showed the highest anti-inflammatory activity of the series, displaying 74.16% activity at 200 µ g/mL, which is slightly lower than standard ibuprofen (84.31% activity). The same compound also showed antioxidant activity in the DPPH assay, with an IC50 = 25.35 µg/mL, while for ascorbic acid, the IC50 value was 6.13 µg/mL. Furthermore, both derivatives 81g and 81h (Figure 29) showed good inhibition against α -glucosidase. Compound 81g.1 had the inhibition potential of 72.13% at 500 µ M, which was higher than that of the standard drug acarbose (65.73% at 500 µ M) [ 87 ]. Additionally, Daud et al. [ 62 ] identified compound 81h.1 with IC 50 = 56.01 µ M as more active than acarbose, the standard drug, which presents an IC 50 = 375.82 µ M, in the same assay. Compound 77k.1 also showed good α-glucosidase inhibition activity with an IC50 = 460 µM [156]. Figure 29. Oxadiazole derivatives as α-glucosidase inhibitors. 3.2.4. Thiazoles and Thiadiazoles Synthesis of Thiazole and Thiadiazole Derivatives Thiazole and thiadiazole are five-membered N,Sand N,N,S-heterocycles with important biological applications that foster the search for new derivatives. Recently, Babalola et al. [ 157 ] and Ahmad et al. [ 158 ] collected and discussed recent synthetic methodologies and the biological activity of thiadiazoles. Babalola et al. [ 157 ] discussed the synthesis of thiadiazoles over the last 10 years using heterogeneous catalysts, microwave-assisted synthesis, ultrasound-aided techniques, solvent-free synthesis, or complex catalyzed reactions; Ahmad et al. [ 158 ] discussed the synthesis of thiadiazoles, since 2008, from hydrazides, thiosemicarbazide, acylhydrazines, thioacylhydrazone, dithiocarbazates, and isothiocyanate. Scheme 20 presents the general approaches to obtain these heterocycles from hydrazides 8, and Table 7describes the reaction conditions to obtain the different derivatives from the reactions between hydrazides and carbon disulfide, isothiocyanate reagents, or Lawesson’s reagent. Tolan et al. [ 64 ] reported the synthesis of compounds 89 in a two-step approach (Scheme 20). The reaction of hydrazide 8with carbon disulfide produced intermediary 86, which reacted with an acyl bromide reagent in ethanol and was refluxed to generate the thiazole ring of derivative 89. Abumelha et al. [ 44 ] synthesized thiazole derivatives 90 (Scheme 20). The synthetic approach involved the conversion of hydrazide 8into intermediate 87, by reaction of 8with isothiocyanate, under heating. The reaction of intermediate 87 with chloroacetic acid promoted the formation of thiazole ring 90. Moreover, intermediary 87 was converted to 1,3,4-thiadiazoles 91 by treatment with sulfuric acid under reflux [94,159]. Molecules 2025,30, 2852 52 of 71 Scheme 20. General approaches to 1,3-thiazole and 1,3,4-thiadiazole synthesis from hydrazides. Table 7. Reaction conditions for the synthesis and purification of 1,3-thiazole and 1,3,4-thiadiazole derivatives from hydrazides. Ref. Starting Material Experimental Conditions Purification Process Products (η%) [64] 8ac CS2, KOH (aq.), reflux, 3 h - 86a (86%) [64] 86a PhCOCH 2 Br, EtOH, reflux, 3 h Recrystallization from ethanol 89a (67%) [44] 8aaq PhNCS, EtOH, reflux, 4 h - 87a (64%) [44] 87a ClCH2COOH, EtOH, AcONa, reflux, 6 h - 90a (74%) [108] 29d Lawesson reagent (1.7 eq) toluene, 110 ◦C, 6 h Silica gel column chromatography 92a (36–49%) Molecules 2025,30, 2852 53 of 71 Table 7. Cont. Ref. Starting Material Experimental Conditions Purification Process Products (η%) [93] 8aar 1. Lawesson’s reagent (1 eq) toluene, reflux, 8 h 2. RCHO (1 eq), POCl 3 (107 eq) reflux, 4–6 h Recrystallization from methanol 92b (n.s) [94] 8aas 1. R1NCS, EtOH, 2 h 2. H2SO4, reflux, 5 h 1. Recrystallization from ethanol 2. Recrystallization from ethanol 91a (n.s.) n.s.—not specified by the authors. Hydrazides 8, in the presence of Lawesson’s reagent, generated the corresponding thio-derivatives 88, which generated 1,3,4-thiadiazole derivatives 92 in the presence of phosphoryl chloride and an aldehyde, under heating (Scheme 20) [93]. Abumelha et al. [ 44 ] synthesized thiazole derivatives 93 as precursors of antioxidant agents. Compound 90a was converted to the hybrids 93 by reaction with aldehydes under reflux, in an acidic medium. Products 93 were obtained in good to moderate yields (Scheme 21). Scheme 21. Synthesis of thiazole derivative 93: (a) ArCHO, CH3COOH/AcONa, reflux, 4 h. Compounds 94 (Scheme 22) were yielded from thiadiazole derivative 91a and aldehydes under reflux conditions, in methanol [94]. Scheme 22. Synthesis of thiadiazole derivative 94: (a) R2CHO, MeOH, reflux. Biological Activity of Thiazole and Thiadiazole Derivatives Compound 89a (Figure 30) was evaluated for anticancer activity and showed good antiproliferative activities against MCF-7 breast cancer cells and against hepatocellular HepG2 cells with IC 50 = 8.0 and 28.2 µ M, respectively. These IC 50 values are better or similar to those of doxorubicin, which has IC50 = 10.3 and 28.5 µM, for the same cell lines [64]. Molecules 2025,30, 2852 54 of 71 Figure 30. Thiazole and 1,3,4-thiadiazole derivatives with anticancer and antimycobacterial activity. Compounds with structure 92a (Figure 30) were screened against cancer cell lines MDA-MB-231 and HeLa. Compound 92a.1 (Figure 30) exhibited good anticancer activity with IC 50 = 15.75 and 12.82 µ M against cancer cell lines MDA-MB-231 and HeLa, respectively, although it had a lower activity than the positive control etoposide [ 108 ]. Taha et al. [ 93 ] reported the 2,5-disubstituted thiadiazoles 92b (Figure 30) as potent β - glucuronidase inhibitors presenting IC 50 values between 6.74 and 52.36 µ M, revealing higher or equivalent activity to the standard D-saccharic acid-1,4-lactone (IC 50 = 48.4 µ M). Among these, compound 92b.5 was the most potent, with IC50 = 6.74 µM. On the other hand, thiazoles 94 (Figure 30) were screened against Mycobacterium tuberculosis H 37 Rv, and compound 94a was the most potent with an inhibitory activity of 80% at 6.25 µg/mL [94]. 3.2.5. Triazoles Synthesis of Triazole Derivatives Triazole, also known as pyrrodiazole, is a five-membered heterocyclic ring system containing three nitrogen atoms, existing in two isomeric forms, 1,2,395 or 1,2,4-triazoles 96 (Figure 31) [160]. Both isomers present a wide range of pharmacological activities. Figure 31. Isomeric forms of the triazole ring. Molecules 2025,30, 2852 55 of 71 In a recent review, Hassani et al. [ 161 ] reported the advances in the synthesis of triazole derivatives. The authors presented multiple methods to obtain 1,2,3or 1,2,4-triazoles, including metal-free and metal-catalyzed reactions. Among them are the cycloaddition of azides and terminal alkynes; the reaction between two nitriles and hydroxylamine hydrochloride; the reaction of formamide reagents and hydrazide; the reaction of acylhydrazines with carbon disulfide, followed by the reaction with hydrazine monohydrate; and others [ 161 ]. Ren et al. [ 162 ] recently reported a different approach for the synthesis of 1,2,3triazoles, involving an iodine-mediated condensation–cyclization reaction from α -azido acetophenones and p-toluenesulfonyl hydrazide. Moreover, Clark et al. [ 163 ] developed the synthesis of substituted 1,2,3-triazoles from α -ketoacetals, tosyl hydrazide, and a primary amine. On the other hand, Patterson et al. [ 164 ] presented the synthesis of 1,2,3-triazoles from tosylhydrazide, aldehydes, and a primary amine, as an alternative to azides. Here, in this review, we present the synthesis of 1,2,4-triazole (Table 8), in which hydrazides are often combined with thiocyanate or isothiocyanates, carbon disulfide, or nitrile derivatives (Scheme 23). Hydrazides 8, in the presence of isothiocyanates and under reflux conditions, generate the intermediates 87 (in a neutral or acidic medium), which cyclize in a basic medium under reflux, to give 97 [ 35 , 42 , 80 , 88 , 89 , 91 , 165 ]. Several derivatives of 100 were obtained by the condensation of 97 with electrophiles [ 42 , 88 – 91 ]. The reaction with carbon disulfide took place in a basic medium with reflux, followed by cyclization with hydrazine hydrate to obtain compounds 98 [ 41 ]. Reflux or high temperatures are also used when nitrile derivatives are used as reagents to obtain compounds 99 [ 166 , 167 ]. The products 97,98, and 99 were typically isolated in good to excellent yields. The experimental conditions for the synthesis of 1,2,4-triazole-3-thione derivatives are presented in Table 8. The 1,2,4-triazole-3-thione compounds were sometimes just intermediates to obtain the compounds 100 or others with potential biological activity [110]. Table 8. Reaction conditions for the synthesis and purification of 1,2,4-triazole derivatives from hydrazides and their derivatives. Ref. Starting Material Experimental Conditions Purification Process Intermediates or Triazoles (η%) [35] 8ad NH4SCN (1 eq) HCl, EtOH, reflux, 6 h Recrystallization from DMF/ethanol 87a (82%) [35] 87a KOH EtOH, reflux, 6 h Recrystallization from DMF/ethanol 97a (78%) [80] 8ac KSCN (1 eq), 10% HCl, reflux, 6–9 h Recrystallization from dioxane 97b (77%) [42] 8aal 1. MeNCS (1 eq) EtOH, reflux, 1 h 2. KOH (1 eq), reflux, 1 h 3. HCl - 97c (n.s.) Molecules 2025,30, 2852 56 of 71 Table 8. Cont. Ref. Starting Material Experimental Conditions Purification Process Intermediates or Triazoles (η%) [42] 97c (1 eq) LiH, DMF, r.t, 6–17 h or LiH, DMF, microwave, 33–90 s - 100a R = Ar (85–90%) [88] 8p EtNCS (1 eq) EtOH, reflux 3–4 h - 87d (98%) [88] 87d 10% NaOH, reflux, 4 h HCl - 97d (96%) [88] 97d (1 eq) DMF, NaH, 30 min, r.t. 100b (62–77%) [89] 8q furfuryl isothiocyanate (1 eq) MeOH, reflux, 8–10 h - 87e (97%) [89] 87e 10% NaOH reflux, 6–8 h HCl - 97e (94%) [89] 97e EtOH, KOH(1 eq) (1 eq), reflux, 4–5 h - 100c R = Ar (89–95%) [90] N NHNH2 O H N O 8aao EtNCS or PhNCS (1 eq) EtOH, reflux 3–4 h - 87f (97%) [90] 87f 1. 10% NaOH, reflux 4 h 2. HCl - 97g (98%) [90] 97g KOH, EtOH, r.t., 30 min, alkyl halides (1 eq), reflux, 4–5 h - 100d R1= Ar, R2= Alk (70–99%) Molecules 2025,30, 2852 57 of 71 Table 8. Cont. Ref. Starting Material Experimental Conditions Purification Process Intermediates or Triazoles (η%) [91] N NHNH2 O H N O 8aao PhNCS MeOH, reflux 3–4 h - 87h (98%) [91] 87h 1.10% NaOH, reflux, 4 h 2. HCl - 97h (95%) [91] 97h KOH MeOH, r.t., 30 min , reflux , reflux 4–5 h - 100e R1= Ar, R2= Ar (88–96%) [165] 8abn 4-FC6H4NCS (1 eq), CH3(CH2)3OH, 65 ◦C, 4 h Recrystallization from ethanol 87h (75%) [165] 87h 4 N NaOH, heat under Radley, 16 h, CH3COOH Recrystallization from ethanol 97i (60%) [64] 8ac CS2 KOH (aq.), reflux, 3 h - 86a (86%) [64] 86a H2NNH2·H2O, reflux 2 h Recrystallization from EtOH/DMF 98a (43%) [64] 98a PhCOCH2Br (1 eq), Et3N (1 eq), EtOH, reflux, 2 h Recrystallization from DMF/H2O 101 (60%) [41] 8aa KOH CS2 water/ethanol (1:1) H2NNH2·H2O 64% (1 eq), reflux - 98b (52–65%) [41] 98b RCHO (1 eq), CH3COOH (cat.), MeOH, reflux, 12 h - 102 (72–89%) Molecules 2025,30, 2852 64 of 71 4. Verma, S.; Lal, S.; Narang, R.; Sudhakar, K. 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