Biologically Active Pyridazines and Pyridazinone Derivatives: A Scaffold for the Highly Functionalized Compounds

Imran, Mohd; Asif, Mohammad

doi:10.1134/s1068162020050155

Cited by 21 publications

(13 citation statements)

References 82 publications

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“…Therefore, designing a non-toxic lipophilic IBP with a high binding affinity (DS) for the DprE1 is challenging but feasible. This task can be achieved by modifying the pyridazinone ring and its substituents [10][11][12] . TB treatment is lengthy, leading to side effects, drug interaction, and drugresistance issues with the existing anti-TB drugs 1,25.…”

Section: Resultsmentioning

confidence: 99%

“…It is proposed that the metabolic protection of the hydrazine unit of INH with a lipophilic moiety can improve its clinical benefits 9 . Pyridazinone is a six-membered diazine of pharmaceutical importance, and many pyridazinone-based drugs are in clinical use to treat various diseases [10][11][12] . Recent studies have also demonstrated pyridazinone ring-based compounds as promising anti-TB agents 8,9,11,[14][15][16][17] .…”

Section: Introductionmentioning

confidence: 99%

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Discovery of New Isoniazid Derivatives As Anti-tubercular Agents: In silico Studies, Synthesis, and In vitro Activity Evaluation

Mohd,

Imran,

Alnaser

et al. 2023

Orient. J. Chem

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This research aimed to discover novel isoniazid (INH) derivatives as anti-tubercular (anti-TB) agents. The chemical structures of isoniazid-based pyridazinone (IBP) derivatives were designed, and their toxicity and pharmacokinetic properties were predicted using the ProTox II and Swiss-ADME databases. The molecular docking of non-toxic IBPs was also performed concerning INH, pyrazinamide (PYZ), ethionamide (ETH), macozinone (MCZ), and BTZ043 utilizing DprE1 enzyme’s proteins (PDB IDs: 4F4Q, 4NCR and 6HEZ). Based on the in silico study results, IBP19, IBP21, IBP22, and IBP29 were selected for their synthesis, and the spectral analysis confirmed their chemical structures. In vitro, anti-TB activity against Mtb H37Rv strain and MTT assay (against HepG2 and Vero cell lines) of IBP19, IBP21, IBP22, and IBP29 were also carried out. A total of eleven non-toxic IBPs were identified with promising pharmacokinetic parameters. The docking score (DS in kcal/mol against 6HEZ protein) of IBP19 (-9.52), IBP21 (-8.78), IBP22 (-9.07), and IBP29 (-9.99) was better than MCZ (-8.76) and BTZ043 (-8.56) revealing their DprE1 enzyme inhibitory action. The in vitro anti-TB activity evaluation (MIC values) confirmed that IBP19 (1.562 µg/ml), IBP21 (1.562 µg/ml), IBP22 (1.562 µg/ml), and IBP29 (1.562 µg/ml) had almost double potency than INH (3.125 µg/ml), and PYZ (3.125 µg/ml). IBP19, IBP21, IBP22, and IBP29 also displayed a CC50 value of > 300 µg/ml against HCL and VCL cell lines. This effect was better than INH (> 200 µg/ml), ETH (> 150 µg/ml), and PYZ (> 200 µg/ml). Accordingly, IBP19, IBP21, IBP22, and IBP29 provide a new template for developing safe and effective novel DprE1 inhibitors.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Discovery of New Isoniazid Derivatives As Anti-tubercular Agents: In silico Studies, Synthesis, and In vitro Activity Evaluation

Mohd,

Imran,

Alnaser

et al. 2023

Orient. J. Chem

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“…Among the biologically important diazoles and diazines, one of the most privileged heterocycles are pyrazoles [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ] and pyridazines [ 10 , 11 , 12 , 13 , 14 ], which are rarely found in nature but have been discovered as versatile pharmacophores. These heterocycles offer the ability to engage in diverse types of molecular interactions and demonstrate favorable physicochemical properties such as lipophilicity and water solubility [ 15 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

“…At the same time, pyridazine derivatives have attracted extensive attention due to their broad spectrum of biological activity, which has found use in therapeutic agents for the treatment of vasoconstriction (levosimendan [ 26 ]), allergies (azelastine [ 27 ]), cancer (olaparib [ 28 ]), and depression (minaprine [ 29 ]). In particular, pyridazinone scaffold is considered crucial for the discovery of drugs [ 11 , 14 , 30 , 31 , 32 , 33 , 34 , 35 ].…”

Section: Introductionmentioning

confidence: 99%

Exploring Three Avenues: Chemo- and Regioselective Transformations of 1,2,4-Triketone Analogs into Pyrazoles and Pyridazinones

Edilova,

Osipova,

Slepukhin

et al. 2023

IJMS

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A convenient approach to substituted pyrazoles and pyridazinones based on 1,2,4-triketones is presented. Chemo- and regiocontrol in condensations of t-Bu, Ph-, 2-thienyl-, and CO2Et-substituted 1,2,4-triketone analogs with hydrazines are described. The direction of preferential nucleophilic attack was shown to be switched depending on the substituent nature in triketone as well as the reaction conditions. The acid and temperature effects on the selectivity of condensations were revealed. Regiochemistry of heterocyclic core formation was confirmed by NMR and XRD studies. The facile construction of heterocyclic motifs bearing acetyl and (or) carbethoxy groups suggests them as promising mono- or bifunctional building blocks for subsequent transformations.

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“…Meanwhile, morpholine is used as an important pharmacophore group in medicinal chemistry. Morpholine nucleus is incorporated in a variety of therapeutically important drugs like reboxetine [17], emorfazone [18], fenpropimorph [19], linezolid [20], timolol [21], finafloxacin [22], gefitinib [21] and aprepitant [23]. These exhibits antidepressant, antiinflammatory, antifungal, antibiotic, antihypertension, antimicrobial, anticancer, antiemetic activities (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Synthesis, characterization and antibacterial evaluation of N‐(2‐Morpholinoethyl)‐3‐phenylquinoxalin‐2‐amine derivatives

Shruthi

Kiran

Divyashree

et al. 2022

Journal of Heterocyclic Chem

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A series of substituted N‐(2‐Morpholinoethyl)‐3‐phenylquinoxalin‐2‐amines (5a–j) (5ab, 5ac) were synthesized in good yield and characterized for their structural confirmation. The pure quinoxaline products were screened for their in‐vitro antibacterial activity against Salmonella paratyphi, a well‐known food borne pathogen. The preliminary results revealed that among the series, compounds 5a, 5c, 5d, 5e, 5f, 5h, 5ab and 5ac bearing bromo, fluoro, methoxy, methyl groups at para position on phenyl ring which inturn substituted at third position of quinoxaline and methyl, benzoyl groups at sixth position on the quinoxaline were emerged as potential candidates by displaying antisalmonella activity. Among the potential candidates, compounds 5c, 5e, 5f and 5ac were effective against Salmonella whereas compounds 5a, 5f and 5ac effectively inhibited the biofilm formation of Salmonella.

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Biologically Active Pyridazines and Pyridazinone Derivatives: A Scaffold for the Highly Functionalized Compounds

Cited by 21 publications

References 82 publications

Discovery of New Isoniazid Derivatives As Anti-tubercular Agents: In silico Studies, Synthesis, and In vitro Activity Evaluation

Discovery of New Isoniazid Derivatives As Anti-tubercular Agents: In silico Studies, Synthesis, and In vitro Activity Evaluation

Exploring Three Avenues: Chemo- and Regioselective Transformations of 1,2,4-Triketone Analogs into Pyrazoles and Pyridazinones

Synthesis, characterization and antibacterial evaluation of N‐(2‐Morpholinoethyl)‐3‐phenylquinoxalin‐2‐amine derivatives

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