Hydrazide–Hydrazones as Potential Antitubercular Agents: An Overview of the Literature (1999–2023)

This article is dedicated to my lovely parents, and my younger brother Sagar Mali, who deep-heartedly supported me to achieve my goals.

Abstract

Hydrazide–hydrazone derivatives are prevalent in numerous bioactive compounds, showcasing a diverse array of biological effects including antibacterial, antitubercular, antifungal, anticancer, anti-inflammatory, anticonvulsant, antiviral, and antiprotozoal properties. Consequently, numerous medicinal chemists have undertaken the synthesis of various hydrazide–hydrazones, subjecting them to evaluation for their biological activities. Among these, antituberculosis activity stands out as a recurring focus in the scientific literature. This paper provides a comprehensive overview of research spanning the last 24 years (1999–2023), concentrating on the antituberculosis properties of hydrazide–hydrazone derivatives. The insights presented herein could serve as a valuable roadmap for the development of novel hydrazide–hydrazones with potential antimicrobial efficacy.

Key words

hydrazide–hydrazone - antituberculosis - recent advances - tuberculosis

Biographical Sketches

Dr. Suraj Mali has a Ph.D. in pharmacy. He is an Assistant Professor in Pharmaceutical Chemistry at the School of Pharmacy, DY Patil University, Navi Mumbai, India. He has an academic background in pharmaceutical science and technology from the Institute of Chemical Technology, Mumbai, India. He serves as a respected reviewer for multiple scientific journals and was designated as a Bentham Science Brand Ambassador for 2019–2020. He has more than 124 international journal publications to his credit (Scopus H-Index: 26). He received the Institute of Chemical Technology’s (ICT) Masters Best Thesis Aditya Birla Award in 2019. His diverse expertise spans molecular modeling, synthetic chemistry, phytochemistry, pharmacology, and analytics, with a focus on drug design and synthesis. A recent publication in Nature Scientific Reports highlights his work in identifying antimycobacterial agents using computational tools. Dr. Mali was listed among the world’s top 2% of scientists by Stanford University, USA, in 2023.

Dr. Anima Pandey is an Assistant Professor at the Department of Pharmaceutical Sciences & Technology, B.I.T. Mesra, Ranchi, India. She has guided many M. Pharm and Ph.D. candidates in her tenure. Currently, she is senior most faculty of Pharmacognosy and Phytochemistry division at Birla Institute of Technology, Ranchi.

Dr Umang Shah is an Associate Professor at the Department of Pharmaceutical Chemistry and Analysis at Charotar University of Science & Technology, India. He has a demonstrated history of working in the education management industry and is skilled in good laboratory practice (GLP), liquid chromatography-mass spectrometry (LC-MS), pharmaceutical research, patent law, and nanoparticles. He obtained his Doctor of Philosophy (Ph.D.) focused in medicinal and pharmaceutical chemistry from Ramanbhai Patel College of Pharmacy, Charusat. His area of interest covers drug design and synthesis, cytotoxicity assays, and computational studies.

Prof. Rahul Jawarkar specializes in QSAR, molecular docking, MD simulations, MMGBSA studies, and QSAR based virtual screening. Currently, he has 845 citations with a h-index of 18. He is currently an Associate Professor at the Department of Medicinal Chemistry and Drug Discovery at the Dr. Rajendra Gode Institute of Pharmacy, India.

Dr. Rakesh Somani is currently a Professor of Pharmaceutical Chemistry & Acting Principal at the School of Pharmacy, Dr. D. Y. Patil University, India. He has guided many M. Pharm and Ph.D. candidates in his tenure. He is a President of the Association of Pharmaceutical Teachers of India (APTI), Maharashtra, India. Currently, he has a H-index of 15 with 821 citations in his GoogleScholar profile. His area of specialization includes various disciplines such as green chemistry and environmentally friendly chemical reactions; microwave synthesis; heterocyclic chemistry in anti-TB, anti-HIV and anti-cancer areas.

1

Background

In 2023, tuberculosis (TB) continued to pose a significant global health challenge as reported by the World Health Organization (WHO).[1] TB, an infectious disease, is responsible for the deaths of 1.5 million people every year throughout the world.[1] [2] TB is caused by the pathogenic bacteria Mycobacterium tuberculosis. Despite being a preventable infectious disease, millions of people die every year.[1b] TB has emerged as a major cause of mortality from infectious diseases worldwide, surpassing HIV/AIDS (the human immunodeficiency virus).[1] [2] The disease is prevalent in low- and middle-income countries, where more than 95% of TB deaths occur per year.[3] Additionally, TB is a significant contributor to antimicrobial resistance, with roughly 465,000 individuals worldwide developing drug-resistant TB in 2022.[1] [4] [5] TB is the main cause of HIV deaths and has contributed to anti-TB drug resistance. The WHO estimates that one-quarter of the world’s population is infected with TB. As TB bacteria exist in replicating and dormant forms, it is challenging to develop novel anti-TB drugs. Anti-TB agents should act on both forms of the bacterium. Previously, we focused on the development of anti-TB drugs acting on the replicating forms; however, it is also important to develop drugs that act on and inhibit the dormant forms of Mtb. With the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains, these infections have been amplified further and have become difficult to cure with conventional anti-TB therapy. Figure [1] illustrates the first-line anti-TB agents known to date.

Figure 1 First-line anti-TB drugs, streptomycin, and others used in clinical therapy

Hydrazones [the active functional group (-C(=O)-NH-NH₂)] play a crucial role as intermediates in synthesizing diverse heterocyclic compounds, often exhibiting broad biological activities.[1b] These derivatives find extensive utility, serving as chemical preservatives for plants, pharmaceutical agents, key components in polymer manufacturing, adhesives in various industries, and more.[1b] Acid hydrazides and their derivatives are particularly valuable synthons for generating heterocyclic rings with five, six, or seven members, containing one or more heteroatoms. These compounds have demonstrated notable effectiveness in various applications, including as antibacterial agents, pharmaceuticals, herbicides, antimalarials, antimycobacterial, anticonvulsants, anti-inflammatories, antidepressants, anticancer agents, antimicrobials,[1b] and dyes. Figure [2] lists drug moieties containing a hydrazide-hydrazone core.

2

Methodology and Search Strategy

This review focuses on a specific activity; namely, reported anti-TB agents containing hydrazides. For this, we carried out a literature survey from 1999 to 2024, using keywords such as ‘hydrazides’, ‘hydrazones’, ‘antitubercular’, ‘anti-TB’. These keywords were queried using a range of databases such as, ‘Scopus’, ‘PubMed’, ‘Web of Science’, ‘ScienceDirect’, and ‘GoogleScholar’. In total, 63 papers were selected and reviewed for the writing of this review article.

Figure 2 Marketed drug candidatures based on the hydrazide scaffold

One recent review article covering recent advancements for hydrazones as anti-TB agents was published in the Pharmaceuticals.[1b]

Literature Survey

Küçükgüzel et al. (1999), studied hydrazones derived from 4-aminobenzoic acid hydrazones (the diazonium salts) and subsequently tested them for their anti-TB activity against Mycobacterium fortuitum ATCC 6841 and H37Rv strains.[1] [2] Some of compounds (1–3) were found to be active against M. fortuitum ATCC 6841 at an MIC value ≈ 32 μg/mL (Figure [3]). Subsequently, Cocco et al. (1999), presented the anti-TB activities of some new isonicotinoylhydrazones (4).[2] Their group also reported their pyridylmethyleneamino analogues and tested them against a clinically isolated M. tuberculosis INH resistant strain. Their results pointed out that there would be an increase in the activity if an amino group was positioned near the C=N bond. Further, Savini et al. (2002) demonstrated antimycobacterial activities of novel 4-quinolylhydrazones.[3] They identified two analogues, 5 and 6, as the most active and evaluated them against both M. avium and M. tuberculosis strains.[3] Sriram et al. (2005) reported the synthesis of newer isonicotinoyl hydrazones and tested them for their antimycobacterial potential.[4] This synthesis was conducted using reactants such as ortho-hydroxy acetophenone and INH (isoniazid). The microplate alamar blue assay (MABA) protocol was used to assess the anti-TB activity against M. tuberculosis H37Rv. It was also noted that their compounds demonstrated strong antimycobacterial activity of 0.56–4.61 μM. Among their synthesized compounds, compound 7 (with an MIC of 0.56 μM; INH: 2.04 μM) was found to be the most potent analogue.[4]

Figure 3

Sriram et al. (2006) designed and synthesized some new thiourea analogues having anti-TB activity (Figure [4]).[5] Their anti-TB (M. tuberculosis H37Rv and INH resistant- M. tuberculosis) evaluation was based on the BACTEC 460 radiometric system. Among all synthesized hydrazones, compound 8 was found to be the most active analogue, with an MIC value of 0.49 μM against both aforesaid strains of mycobacteria. In search of potent anti-TB agents, 16 pyrrole enabled hydrazones were synthesized by Bijev (2006).[6] Among their synthesized pyrrole enabled hydrazones, nine compounds (9–16) exhibited activity against M. tuberculosis H37Rv at 6.25 μg/mL. It was also noted that increasing the lipophilicities of the compounds would not always result in increased activity.[6]

Figure 4

Imramovský et al. (2007) proposed a new way to design and synthesize newer anti-TB analogues (17) by connecting standard drugs such as ETH (ethambutol) and (CPX) ciprofloxacin (Figure [5]).[7] An interesting review on the biological activities of hydrazones up to 2007 was published by Rollas and Kucukguzel.[8] Joshi et al. (2008) screened a series of hydrazides originating from heterocyclic ring systems such as oxadiazoles and triazoles. The antimycobacterial activity was conducted using the standard broth dilution assay against M. tuberculosis H37Rv. Compounds 18–21 displayed good antimycobacterial activities with MIC values of 31.25 μg/mL.[9]

Figure 5

Raparti et al. (2009) exploited the synthesis of some newer benzohydrazides analogues wherein they further evaluated all compounds for their anti-TB activity using the luciferase reporter phages (LRP) (Figure [6]).[10] Moreover, they also studied quantitative structure–activity relationship (2D-QSAR) analysis to see how physicochemical properties corresponded with the observed biological activity. Two compounds, 22 and 23, were found to be most potent against M. tuberculosis H37Rv.

Figure 6

In another attempt, Kaymakcioglu et al. (2009) screened a set of hydrazones synthesized from 4-fluorobenzoic acid hydrazide against M. tuberculosis H37Rv (Figure [7]).[11] As per their results, compound 24 demonstrated the highest inhibitory activity. The most potent analogue had 85% inhibition and contained a 2,6-dichlorophenyl group. Candéa et al. (2009) reported 21 analogues obtained from 7-chloro-4-quinolinylhydrazones.[12] It was found that three compounds from this series (25–27) had lower cytotoxic profiles with good MIC values at 2.5 μg/mL compared to standard anti-TB drugs such as rifampicin (2.0 μg/mL) and ETH (3.12 μg/mL).[12] A series of compounds bearing a 4-quinolylhydrazone moiety was reported by Gemma et al. (2009), and these were tested for antitubercular activity at 6.25 μg/mL concentration.[13] It was noted that many of their compounds, such as 28, showed 100% inhibitory activity at 6.25 μg/mL concentration against M. tuberculosis. Some indole-based hydrazones (29) were synthesized and investigated by Sonar and Crooks (2009).[14] They examined a range of hydrazone and 3-nitrovinyl analogues derived from indole-3-carboxaldehydes and related compounds for their ability to inhibit Mycobacterium tuberculosis H37RV. Screening was conducted using the microplate alamar blue assay (MABA) in BACTEC 12B medium. Several compounds exhibited significant inhibitory activity against M. tuberculosis in initial screening assays, demonstrating potency at a concentration of 6.25 μg/mL.

Figure 7

Raja et al. (2010) intended to exploit antimycobacterial activities of diphenyl hydrazones and semicarbazones (Figure [8]). The agar double dilution (ADD) method was employed to assess the anti-TB activities of said compounds. Compound 30 depicted 80% inhibition (MIC >6.25 mg/mL) against M. tuberculosis H37Rv strain.[15]

Figure 8

Sankar and Pandiarajan (2010) attempted the synthesis of new isonicotinoylhydrazones.[16] Some of their compounds having a -OCH₃ group in meta-position of the aromatic ring demonstrated good antimycobacterial activity compared with standard drug INH as tested by the luciferase reporter phage (LRP) assay (Figure [9]). Among the synthesized compounds, four compounds (31; R¹ = H, R² = 4-Cl, 4-F, 3-Cl, 4-OCH₃) exhibited inhibition of all microbial strains of bacteria and fungi. Pavan et al. (2010) successfully synthesized hydrazones based on a carbazone moiety such as thiosemicarbazone.[17] In-vitro cytotoxicities on J774 cells were also reported in the study. Hydrazide/hydrazones 32–35 were identified as best in-vitro candidates against M. tuberculosis and showed results comparable to those of the standard ‘1st line’ or/and ‘2nd line’ anti-TB drugs, when the authors carried anti-TB activity tests using the resazurin microtiter assay (REMA).[17] Their results suggested that compounds with higher lipophilicity had maximum activity. Furthermore, it was also identified that replacing the sulfur in the thiosemicarbazone with an oxygen atom, resulted in decreased anti-TB activity.[17]

Figure 9

Eswaran and colleagues conducted a study in which they synthesized quinoline-clubbed analogs (compound 36) and assessed their in vitro antituberculosis activity against three distinct strains of Mycobacterium (Figure [10]).[18] They used the standard MDA method (broth microdilution) to test against Mycobacterium. Their analysis revealed that the introduction of a -CF₃ at position 8 substantially increased the biological activity, wherein analogues with a -F substituent resulted in reduced activity. Furthermore, in the same year, the authors also evaluated a newer set of quinoline-based hydrazones (37) by adapting a multistep synthesis protocol.[19] Within the series, it was observed that at the R1 position, the incorporation of an imidazole or 4-methyl imidazole moiety resulted in enhanced anti-TB activity. Bijev and Georgieva (2010) analyzed antimycobacterial potentials of some pyrrole-based hydrazones and subsequently evaluated their various physicochemical parameters such as Log P, MW, and molar refractivity.[20] It was also found that compounds with moderate molecular surface would likely result in enhanced anti-TB activity. Their findings suggested that the compounds with moderate molecular surfaces exhibited the highest level of activity. This conclusion was supported by the analysis of different physicochemical molecular descriptors. Another study by Sriram et al. (2010) described anti-TB activities of some furoic acid hydrazones tested using the ICL assay (M. tuberculosis isocitrate lyase). The active compound 38 exhibited potent activity for ICL inhibition at 10 μM.[21]

Figure 10

Vavříková et al. (2011) synthesized fluorine-substituted hydrazones that were active against multi-drug-resistant tuberculosis strains (Figure [11]).[22] From their study, a total of nine compounds demonstrated good results against MDR-TB (MIC: 0.5 μg/mL). Two compounds, 39, exhibited strong activity against M. kansasii (MIC: 1–4 μmol/L) with non-cytotoxic profiles. Subsequently, Pinheiro et al. (2011) reported a new set of l-serinyl hydrazones 40 and evaluated them for antitubercular potentials.[23] Some INH-hydrazones 41 were also studied by Vavríková et al. (2011).[24]

Figure 11

Thomas et al. (2011) tested a series of quinoline-3-carbohydrazides against M. tuberculosis H37Rv (Figure [12]).[25] Amongst the evaluated analogues, six compounds 42–47 demonstrated promising activity. The authors also conducted molecular docking analysis and their results suggested that their compounds interacted with enoyl-ACP reductase.[25]

Figure 12

Utku et al. (2011) and Almasirad et al. (2011), reported compounds 48 and 49, respectively (Figure [13]).[26] [27] All compounds were tested against Mtb H37Rv using the agar proportion method and MABA assay, respectively. In the first case, it was found that electron-withdrawing groups on the aryl (-Ar) moiety had substantial effects on the biological activity in the second case, the importance of the -NO₂ group attached to the heteroaryl moieties was highlighted. Some other interesting reviews on hydrazones published in that year covered a variety of hydrazones acting as antimycobacterial agents.[28] [29] [30]

Figure 13

In another attempt to design and synthesize newer carbohydrazides, Telvekar et al. (2012) carried out the synthesis of benzofuran-based carbohydrazides and tested them for their anti-TB activities using the REMA assay (Figure [14]).[31] Among the tested compounds, two benzofuran-based compounds, 50 and 51 were found to be most promising and were active against both Candida albicans and Mtb.

Figure 14

In another study reported by Coelho et al. (2012), 23 hydrazones derived from isonicotinic hydrazide were tested against three INH-resistant Mtb strains (Figure [15]).[32] One of the compounds, 52, presented the best activity (MIC: 0.98 μg/mL) against Mtb. Cihan-Üstündağ and Çapan (2012), screened a set of indole hydrazides 53–57;[33] however, their compounds exhibited lower anti-Mtb activity than the control standard (MIC: 0.125 μg/mL).

Figure 15

In their study, Naveen Kumar and colleagues (2014) designed and evaluated InhA inhibitors based on isonicotinic acid hydrazide and evaluated them against Mtb H37Rv and two human clinical isolates (Figure [15]).[34] Compound 58 showed excellent anti-TB activity, with a MIC of 0.096 μM against the Mtb H37Rv strain and 0.049 μM against both human clinical isolates (Mtb-1 and Mtb-2).[34] The compound had a high lipophilicity, as indicated by its Log P value of 8.02, and the estimated LD₅₀ was >5000 mg/kg BW. Compound 58 was found to be six times more potent than isoniazid.[34]

In an investigation conducted by More et al. (2014),[35] 52 novel pyrrole hydrazine analogues were synthesized to specifically target the critical InhA (enoyl-ACP reductase) enzyme (Figure [15]). The authors[35] proposed, based on the binding model analysis, that the pyrrole hydrazones had H-bonding interactions with the InhA enzyme. The lead compound identified was compound 59,[35] which exhibited a MIC of 0.2 μg/mL (4.86 μM) and was found to have the same binding site as PT70 and TCL.

Pahlavani et al. (2015) identified and reported hydrazones derived from isonicotinyl hydrazide (Figure [16]).[36] Analogue 60 showed trong activity against Mtb H37Rv with an MIC value of 4 μg/mL. However, the activity of 60 was far less than standard INH (MIC: 0.025 μg/mL).

Figure 16

Figure 17

A previous literature analysis suggested that many hydrazones reported in 2016 had quite interesting anti-Mtb activity, especially covered by Unissa et al. (2016)[37] and John et al. (2016).[38] Cihan-Üstündă et al. (2016) exploited the synthesis of newer indole-based hydrazones and tested them for their anticancer and anti-Mtb activities (Figure [16]).[39] Compound 61 exhibited anti-Mtb activity with MIC greater than 25 μg/mL (0.067 μM). Velezheva et al. (2016) investigated a series of hydrazides-hydrazones derived from indole-pyridine (Figure [17]).[40] They reported antimycobacterial activities on two strains of Mtb (H37Rv and CN-40).[40]Among examined analogues, compound 65 presented the best activity (MIC: 0.05 μg/mL).[40]

Angelova et al. (2017) reported hydrazide-hydrazones of heterocyclic moieties such as 2H-chromene, coumarin, and pyrazol-4(1H)-one cores (Figure [18]).[41] Overall, 22 compounds were synthesized and tested against Mtb H37Rv strain. Compound 66 [41] was observed to have a lower MIC of 0.13 μM, which was surprisingly 11× more potent than standard INH (MIC: 1.45 μM).[41] Additionally, they reported pyrazol-based hydrazones, wherein compound 67 was the most active (MIC: 0.32 μM).[42] Some newer tosyl hydrazones were also investigated by Concha et al. (2017).[43] These compounds were submitted for anti-Mtb analysis with Mtb mc26230 strain. It was found that these tosyl hydrazones 68 (MIC: 183 μM) were less active than the standard drug INH. Isoniazid derivatives with phenolic or heteroaromatic frames were synthesized via mechanochemical methods by Oliveira et al.[44] Activity against M. tuberculosis was also assessed, highlighting compounds such as phenolic hydrazine 69a and heteroaromatics 69b–d as more potent molecules than isoniazid.[44] Selected derivatives, including 69a and 69d, exhibited high activity against M. tuberculosis MDR clinical isolates, with compound 69d showing a selectivity index of >1400 on MRC5 human fibroblast cells.[44]

Figure 18

In 2018, Bonnett et al.[45] examined a class of hydrazone compounds active against non-replicating Mtb. Among the studied compounds, compound 70 exhibited a MIC of 14 ± 7 μM against Mtb (Figure [19]). The authors also analyzed the same compounds using the low-oxygen-recovery assay (LORA). Compound 70 had IC₉₀ values of 22 ± 12 μM and 6.4 ± 2.4 μM, respectively for anaerobic and aerobic conditions. Nogueira et al. (2018), studied varieties of hydrazone analogues bearing a vitamin B6 moiety.[46] Compound 71 presented activity at 10.90 μM concentration, wherein compound 72 was found to have a minimum inhibitory concentration value at 72.72 μM.

In another study, Angelova and Simeonova (2019)[47] carried out an extended study on female mice for compound 73 (MIC: 0.3969 μM) to establish its effects on various functions of the liver and kidneys (Figure [19]). Three doses (100, 200, and 400 mg/kg bw) were administered to mice for a period of two weeks, wherein INH was used as a control. It was noticed that compound 73 did not have any impact when checked against various biochemical parameters. Sampiron et al. (2019) evaluated various hydrazones against Mtb. Interestingly, analogue 74 had a MIC of 4.98 μM.[48]

Figure 19

Ghiano et al. (2020) synthesized 30 tosyl N′-acryl-hydrazones, which were subsequently tested against Mtb H37Rv strain (Figure [20]).[49] Notably, among the tested compounds, E-isomers 75–77 presented the most promising anti-Mtb activity (MIC ≤10 μM). The authors also carried out molecular docking simulations to establish binding mechanisms underlying the activity. Amino acid residues, Tyr158 and Ile194 were found to be crucial for the biological activity.

Figure 20

Compound 78 reported by Hassan et al. (2020), was found to have the lowest MIC value at 0.78 μg/mL (Figure [21]).[50] Similarly, compounds (79–81) displayed 4 μg/mL MIC (control, RIF: MIC: 3.038 μM) values when tested using the broth microdilution (BMD) method as reported in a study by Sruthi et al. (2020).[51]

Figure 21

In 2020, Desale et al. attempted to synthesize halogen-containing 2-aryloxyacetohydrazones and tested them for their antimycobacterial activities (3.125–100 μg/mL).[52]All the synthesized compounds were found to have a strong affinity towards enoyl reductase. Compound 82 was obtained as a best-docked candidate with –8.058 kcal/mol docking score (Figure [21]). Subsequently, Thorat et al. (2020) designed and prepared a newer set of hydrazones 83–86 with moderate anti-Mtb activity with MIC value of 12.5 μg/mL.[53] Padmini et al. (2021) analyzed antitubercular activities of new hydrazones bearing pyrazole acetamide cores (Figure [22]). Their results suggested that compound 87 had a promising anti-Mtb MIC value of 3.12 μg/mL.[54] Molecular docking analysis with these compounds highlighted the importance of H-bonding with key amino acid residues for a target InhA. Further, Faria et al. (2021) conducted the synthesis and examined the anti-Mtb activities of alkyl hydrazides and hydrazones.[55] Molecules 88 and 89 both had MIC values of 0.3 μM. They were also found to have moderate anti-Mtb activity for the H37RvINH strain with values >128 μM and 128 μM, respectively. A novel isatin hydrazone, 90, was reported by Karunanidhi et al. (2021).[56] Some isonicotinoylhydrazine moieties 91 were reported by Pflégr et al. (2021).[57] Thorat et al. (2021) carried out the synthesis of 10 new hydrazones from benzohydrazides. All compounds 92 showed MIC values in the range 3.125–50 μg/mL against the Mtb H37Rv strain.[58]

Figure 22

Figure 23

Gobis et al. (2022) examined antimicrobial activities of hydrazones of methyl 4-phenylpicolinimidate (Figure [23]).[59] The lead analogue 93 had an MIC value of 0.009 μM against two Mtb strains (sensitive and resistant). A whole-cell-based screening was performed by Briffotaux et al. (2022),[60] to assess the anti-Mtb potentials of hydrazine-hydrazones bearing an adamantine moiety 94. Compounds 95 and 96 were found to have promising anti-Mtb activities as reported by Akki et al. (2022) and Abdelhamid et al. (2022), respectively.[61] [62] Lone et al. (2023) examined hydrazones of butanoic acid 97 for their anti-Mtb activity and found that compound 97 was active against H37Ra and H37Rv strains with MIC values of 0.0042 μM each.[63]

Summary

In summary, this article provides an overview of the antitubercular properties of hydrazide-hydrazones reported since 1999. The study highlights the versatility of the hydrazide-hydrazone structure, which can be incorporated into diverse bioactive compounds. Therefore, this review underscores the significance of advancing hydrazide-hydrazones for their potential as antitubercular/antimycobacterial agents. Other potential reviews (from different time periods)[64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] [75] [76] were also found in the literature for various bioactivities of hydrazide-hydrazone; however, they lack full coverage of articles having anti-TB activity.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

S.M. is thankful to the School of Pharmacy, D.Y. Patil, University, Navi Mumbai, India for providing the facilities for preparing this article.

• References

• 1a Küçükgüzela SG, Rollas S, Küçükgüzel I, Kiraz M. Eur. J. Med. Chem. 1999; 34: 1093
• 1b Teneva Y., Simeonova R., Valcheva V., Angelova V. T. Pharmaceuticals 2023, 16, 484.
• 2 Cocco MT, Congiu C, Onnis V, Pusceddu MC, Schivo ML, Logu AD. Eur. J. Med. Chem. 1999; 34: 1071
• 3 Savini L, Chiasserini L, Gaeta A, Pellerano C. Bioorg. Med. Chem. Lett. 2002; 10: 2193
• 4 Sriram D, Yogeeswari P, Madhu K. Bioorg. Med. Chem. Lett. 2005; 15: 4502
• 5 Sriram D, Yogeeswari P, Madhu K. Bioorg. Med. Chem. Lett. 2006; 16: 876
• 6 Bijev A. Lett. Drug Des. Discovery 2006; 3: 506
• 7 Imramovsky A, Polanc S, Vinsova J, Kocevar M, Jampılek J, Reckova Z, Kaustova J. Bioorg. Med. Chem. 2007; 17: 2551
• 8 Rollas S, Kucukguzel SG. Molecules 2007; 12: 1910
• 9 Joshi SD, Vagdevi HM, Vaidya VP, Gadaginamath GS. Eur. J. Med. Chem. 2008; 43: 1989
• 10 Raparti V, Chitre T, Bothara K, Kumar V, Dangre S, Khachane C, Gore S, Deshmane B. Eur. J. Med. Chem. 2009; 45: 3954
• 11 Koçyiğit-Kaymakçıoğlu B, Oruç-Emre EE, Unsalan S, Rollas S. Med. Chem. Res. 2009; 18: 277
• 12 Candéa AL. P, Ferreira MD. L, Pais KC, Cardoso LN. D, Kaiser CR, Henriques MG. M. O, Lourenco MC. S, Bezerra FA. F. M, de Souza MV. N. Bioorg. Med. Chem. Lett. 2009; 19: 6272
• 13 Gemma S, Savini L, Altarelli M, Tripaldi P, Chiasserini L, Coccone SS. Kumar V, Camodeca C, Campiani G, Novellino E, Clarizio S, Delogu G, Butini S. Bioorg. Med. Chem. 2009; 17: 6063
• 14 Sonar VN, Crooks PA. J. Enzyme Inhib. Med. Chem. 2009; 24: 117
• 15 Raja AS, Agarwal AK, Mahajan N, Pandey SN, Ananthan S. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2010; 49: 1384
• 16 Sankar C, Pandiarajan K. Eur. J. Med. Chem. 2010; 45: 5480
• 17 Pavan FR, Maia PI. D, Leite SR. A, Deflon VM, Batista AA, Franzblau SG, Leite CQ. F. Eur. J. Med. Chem. 2010; 45: 1898
• 18 Eswaran S, Adhikari AV, Pal NK, Chowdhury IH. Bioorg. Med. Chem. Lett. 2010; 20: 1040
• 19 Eswaran S, Adhikari AV, Pal NK, Chowdhury IH, Pal NK, Thomas KD. Eur. J. Med. Chem. 2010; 42: 3374
• 20 Bijev A, Georgieva M. Lett. Drug Des. Discovery 2010; 7: 430
• 21 Sriram D, Yogeeswari P, Vyas DR. K, Senthilkumar P, Bhat P, Srividya M. Bioorg. Med. Chem. Lett. 2010; 20: 4313
• 22 Vavríková E, Polanc S, Kocevar M, Horváti K, Bosze S, Stolaríková J, Vavrova K, Vinsova J. Eur. J. Med. Chem. 2011; 46: 4937
• 23 Pinheiro AC, Kaiser CR, Nogueira TC. M, Carvalhoa SA, da Silva EF, Feitosa LD. O, Maria GM. O. H, Andre LP. C, Maria CS. L, Marcus VN. S. Med. Chem. 2011; 7: 611
• 24 Vavríková E, Polanc S, Kocevar M, Kosmrlj J, Horváti K, Bosze S. Eur. J. Med. Chem. 2011; 46: 5902
• 25 Thomas KD, Adhikari AV, Telkar S, Chowdhury IH, Mahmood R, Pal NK, Row G, Sumesh E. Eur. J. Med. Chem. 2011; 46: 5283
• 26 Utku S, Gokce M, Aslan G, Bayram G, Ulger M, Emekdas G, Şahin MF. Turk. J. Chem. 2011; 35: 331
• 27 Almasirad A, Sadar SS, Shafiee A. Iran. J. Pharm. Res. 2011; 10: 727
• 28 Singh M, Raghvan V. Int. J. Pharm. Pharm. Sci. 2011; 3: 26
• 29 Verma G, Marella A, Shaquiquzzaman M, Akhtar M, Ali MR, Alam MM. J. Pharm. BioAllied Sci. 2011; 6: 69
• 30 Sharma S, Sharma PK, Kumar N, Dudhe H. Biomed. Pharmacother. 2011; 65: 244
• 31 Telvekar VN, Belubbi A, Bairwa VK, Satardekar K. Bioorg. Med. Chem. Lett. 2012; 22: 2343
• 32 Coelho TS, Cantos JB, Bispo ML. F, Gonçalves RS. B, Lima CH. S, da Silva PE. A, Souza M. Infect. Dis. Rep. 2012; 4: e13
• 33 Cihan-Üstündağ G, Çapan G. Mol. Diversity 2012; 16: 525
• 34 Naveen Kumar HS, Parumasivam T, Ibrahim P, Asmawi MZ, Sadikun A. Med. Chem. Res. 2014; 23: 1267
• 35 More UA, Joshi SD, Aminabhavi TM, Gadad AK, Nadagouda MN, Kulkarni VH. Eur. J. Med. Chem. 2014; 71: 199
• 36 Pahlavani E, Kargar H, Rad NS. Zahedan J. Res. Med. Sci. 2015; 17: e1010
• 37 Unissa AN, Hanna LE, Swaminatha S. Chem. Biol. Drug Des. 2016; 87: 537
• 38 John SF, Aniemeke E, Ha NP, Chong CR, Gu P, Zhou J, Zhang Y, Graviss EA, Liu JO, Olaleye OA. Tuberculosis 2016; 101: S73
• 39 Cihan-Üstündağ G, Şatana D, Özhan G, Çapan G. J. Enzyme Inhib. Med. Chem. 2016; 31: 369
• 40 Velezheva V, Brennan P, Ivanov P, Koronienko A, Lyubimov S, Kazarian K, Nikonenko B, Majorov K, Apt A. Bioorg. Med. Chem. Lett. 2016; 26: 978
• 41 Angelova VT, Valcheva V, Vassilev NG, Buyukliev R, Momekov G, Dimitrov I, Saso L, Djukic M, Shivachev B. Bioorg. Med. Chem. Lett. 2017; 27: 223
• 42 Angelova VT, Valcheva V, Pencheva T, Voynikov Y, Vassilev N, Mihaylova R, Momekov G, Shivachev B. Bioorg. Med. Chem. Lett. 2017; 27: 2996
• 43 Concha C, Quintana C, Klahn AH, Artigas V, Fuentealba M, Biot C, Halloum I, Kremer L, López R, Romanos J, Huentupil Y, Arancibia R. Polyhedron 2017; 131: 40
• 44 Oliveira PF. M, Guidetti B, Chamayou A, André-Barrès C, Madacki J, Korduláková J, Mori G, Orena BS, Chiarelli LR, Pasca MR, Lherbet C, Carayon C, Massou S, Baron M, Baltas M. Molecules 2017; 22: 1457
• 45 Bonnett SA, Dennison D, Files M, Bajpai A, Parish T. PLoS ONE 2018; 13: e0198059
• 46 Nogueira T, Cruz L, Lourenço M, Souza M. Lett. Drug Des. Discovery 2018; 15: 792
• 47 Angelova VT, Pencheva T, Vassilev N, Simeonova R, Momekov G, Valcheva V. Med. Chem. Res. 2019; 28: 485
• 48 Sampiron EG, Costacurta GF, Baldin VP, Almeida AL, Ieque AL, Santos NC, Alves-Olher VG, Vandresen F, Gimenes AC, Siqueira VL, Caleffi-Ferracioli KR, Cardoso RF, Scodro RB. L. Future Microbiol. 2019; 14: 981
• 49 Ghiano DG, Recio-Balsells A, Bortolotti A, Defelipe LA, Turjanski A, Morbidoni HR, Labadie GR. Eur. J. Med. Chem. 2020; 208: 112699
• 50 Hassan NW, Saudi MN, Abdel-Ghany YS, Ismail A, Elzahhar PA, Sriram D, Nassra R, Abdel-Aziz MM, El-Hawash SA. Bioorg. Chem. 2020; 96: 103610
• 51 Shruthi TG, Subramanian S, Eswaran S. Heterocycl. Commun. 2020; 26: 137
• 52 Desale VJ, Mali SN, Chaudhari HK, Mali MC, Thorat BR, Yamgar RS. Curr. Comput.-Aided Drug Des. 2020; 16: 618
• 53 Thorat BR, Rani D, Yamgar RS, Mali SN. Comb. Chem. High Throughput Screening 2020; 23: 392
• 54 Padmini T, Bhikshapathi D, Suresh K, Kulkarni R, Kamal BR. Med. Chem. 2021; 17: 344
• 55 deFaria CF, Moreira T, Lopes P, Costa H, Krewall JR, Barton CM, Santos S, Goodwin D, Machado D, Viveiros M. Biomed. Pharmacother. 2021; 144: 112362
• 56 Karunanidhi S, Chandrasekaran B, Karpoormath R, Patel HM, Kayamba F, Merugu SR, Kumar V, Dhawan S, Kushwaha B, Mahlalela MC. Bioorg. Chem. 2021; 115: 105133
• 57 Pflégr V, Horváth L, Stolăríková J, Pál A, Korduláková J, Bösze S, Vinšová J, Krátký M. Eur. J. Med. Chem. 2021; 223: 113668
• 58 Thorat BR, Mali SN, Rani D, Yamgar RS. Curr. Comput.-Aided Drug Des. 2021; 17: 294
• 59 Gobis K, Szczesio M, Olczak A, Korona-Głowniak I, Augustynowicz-Kopéc E, Mazernt-Politowicz I, Ziembicka D, Główka ML. Materials 2022; 15: 3085
• 60 Briffotaux J, Xu Y, Huang W, Hui Z, Wang X, Gicquel B, Liu SA. Molecules 2022; 27: 7130
• 61 Akki M, Reddy DS, Katagi KS, Kumar A, Devarajegowda HC, Kumari MS, Babagond V, Joshi SD. ChemistrySelect 2022; 7: e202203260
• 62 Abdelhamid E, Mahfouz N, Omar F, Ibrahimc Y, Abouwarda A. SSRN Electron. J. 2022; in press; doi:
• 63 Lone M, Mubarak M, Nabi S, Amin S, Nabi S, Kantroo H, Samim M, Shafi S, Ahmad S, Ahmad Z, Rizvi SO, Javed K. Med. Chem. Res. 2023; 32: 808
• 64 Mali SN, Pandey A, Thorat BR, Lai CH. Struct. Chem. 2022; 33: 679
• 65 Mali SN, Thorat BR, Gupta DR, Pandey A. Eng. Proceed. 2021; 11: 21
• 66 Popiołek Ł. Med. Chem. Res. 2017; 26: 287
• 67 Murugappan S, Dastari S, Jungare K, Barve NM, Shankaraiah N. J. Mol. Struct. 2024; 138012
• 68 Narang R, Narasimhan B, Sharma S. Curr. Med. Chem. 2012; 19: 569
• 69 Verma G, Marella A, Shaquiquzzaman M, Akhtar M, Ali MR, Alam MM. J. Pharm. Bioallied Sci. 2014; 6: 69
• 70 Rollas S, Küçükgüzel ŞG. Molecules 2007; 12: 1910
• 71 Raj V. EC Pharm. Sci. 2016; 2: 278
• 72 Angelova V, Karabeliov V, Andreeva-Gateva PA, Tchekalarova J. Drug Dev. Res. 2016; 77: 379
• 73 de Oliveira Carneiro Brum J, França TC. C, LaPlante SR, Villar JD. F. Mini-Rev. Med. Chem. 2020; 20: 342
• 74 Shakdofa MM, Shtaiwi MH, Morsy N, Abdel-rassel T. Main Group Chem. 2014; 13: 187
• 75 Mandewale MC, Patil UC, Shedge SV, Dappadwad UR, Yamgar RS. Beni-Suef Uni. J. Basic Appl. Sci. 2017; 6: 354
• 76 Popiołek Ł. Int. J. Mol. Sci. 2021; 22: 9389

Publication History

Received: 10 June 2024

Accepted after revision: 03 July 2024

Accepted Manuscript online:
16 July 2024

Article published online:
19 August 2024