Design and Synthesis of Novel Derivatives of 4-(6-(4-Substituted Phenyl)-7H-[1,2,4] Triazolo[3,4-b][1,3,4]Thiadiazin-3- yl) Phenol as a Potent Inhibitor of Tubulin with Antitumor Activity

Kubba, Ammar A. Razzak Mahmood; Shihab, Wurood Ahmed; Al-Shawi, Nada N.; Jabir, Majid S.

doi:10.14499/indonesianjpharm31iss2pp92

Cited by 3 publications

(1 citation statement)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Such compounds bear the potential to wield substantial pharmaceutical activity and manifest in diverse medical applications, thus underscoring their significance and multifaceted nature [11]. Extensive studies have elucidated the therapeutic effects of compounds harboring the 1,3,4-thiadiazole ring [12][13], shedding light on their prowess in combating a myriad of pathological states encompassing antibacterial, antimycotic, antitubercular, anti-Parkinson, cancer-fighting, anti-inflammatory, and anticonvulsant activities. [14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Characterization of some new heterocyclic derivatives from aromatic carbonyl ‎compounds and carboxylic acids with Evaluation some of them for biological activity

Al-Khazraji,

Ahamed,

Ali

2024

Iraqi Journal of Science

View full text Add to dashboard Cite

In this research investigation, a total of eighteen diverse tetra- and penta-lateral cyclic compounds were synthesized. These included 1,3,4-thiadiazole, thiazolidin-4-one (via an alternative method), 1,2,4-triazole, carbothioamide, thiazole-4-one, azetidin-2-one, and oxazole. The synthesis procedure entailed a sequence of reactions. The thiazolidine-4-one 1 was obtained by reaction p-aminobenzoic acid with thiosemicarbazide, followed by treatment with p-tolualdehyde to produce Schiff base 2. Reaction Schiff base 2 with mercaptoacetic acid in dry benzene was carried out to produce thiazolidine-4-one 3. In another synthesis pathway, the esterification of p-nitro benzoic acid with ethanol in the presence of sulfuric acid was obtained to formation of compound 4. Compound 4 was subsequently reacted with thiosemicarbazide, yielding compound 5. Cyclization of compound 5 was then achieved using 4% sodium hydroxide solution. This formed the 1,2,4-triazole heterocycle, designated compound 6. Thiosemicarbazone 7-9 were prepared by reaction of thiosemicarbazide with different aldehydes. Additionally, 2-substituted-1,3-thiazolidine-4-one derivatives 10-12 were synthesized through the reaction of thiosemicarbazone with chloroacetic acid in the presence of anhydrous sodium acetate. The Oxazole derivative 15 was obtained through a series of reactions starting with the reaction of p-amino benzoic acid with ethyl chloroacetate, resulting in compound 13. Compound 13 was then treated with urea to obtain compound 14, followed by a reaction with 4-phenyl phenacyl bromide to yield the final product, the Oxazole derivative 15. The 2-aminooxadiazole derivative 16 was synthesized by reaction urea with 4-bromoacetophenone which was reacted with 4-bromobenzaldehyde to produce Schiff base derivative 17. Finally, β-lactam 18 is obtained through reaction Schiff base with chloroacetyl chloride in the presence of triethyl amine. FT-IR, 1H-NMR, and 13C-NMR spectroscopy were used to confirm their proposed structures. Moreover, the antibacterial and antifungal activities of certain synthesized compounds, specifically 2,3,6,11,13,15,17, and 18, were assessed against Staphylococcus aureus, Escherichia coli, and Candida albicans, demonstrating encouraging outcomes.Keywords: Antibacterial, antifungal activity, oxadaizole, heterocyclic derivatives, Oxazole.

show abstract

Section: Introductionmentioning

confidence: 99%

Synthesis and Characterization of some new heterocyclic derivatives from aromatic carbonyl ‎compounds and carboxylic acids with Evaluation some of them for biological activity

Al-Khazraji,

Ahamed,

Ali

2024

Iraqi Journal of Science

View full text Add to dashboard Cite

show abstract

Discovery of 2‐Amino‐4H‐1, 3, 4‐thiadiazine‐5(6H)‐one Derivatives and Their In Vitro Antitumor Investigation

et al. 2022

View full text Add to dashboard Cite

Novel 2‐Amino‐4H‐1,3,4‐thiadiazine‐5‐(6H)‐one derivatives 3–6 were designed, synthesized, and assessed for their anticancer effects on MCF‐7 and A549 cell lines. The cytotoxicity screening found several active compounds. Meanwhile, compound 5 b exhibited the strongest cytotoxic activity compared to Doxorubicin (DOX). Furthermore, DNA flow cytometry investigation over MCF‐7 cells indicated that compound 5 b demonstrated arrest at G1/S stages of the cell cycle and induction of apoptosis by rising pre‐G1 stage. In addition, the underlying mechanistic studies of compound 5b′s proapoptotic activities revealed that they induced the elevation of P53 and the BAX/BCL‐2 ratio expression that led to a rise in active Caspase 3/7 levels and triggered apoptosis. Finally, Compound 5 b displayed a significant dual topoisomerase IIβ enzyme and β‐tubulin polymerization inhibition.

show abstract

Design, Synthesis, in silico and in vitro Evaluation of New Combretastatin A-4 Analogs as Antimitotic Antitumor Agents

Hussein

Kubba

Balakit

et al. 2023

View full text Add to dashboard Cite

Background: Combretastatin A-4 (CA-4) binds β-tubulin at the colchicine-binding site preventing tubulin from polymerizing into microtubules. CA-4 and cis combretastatin analogs isomerize to the trans form resulting in decreased cytotoxicity and anti-tubulin activity. However, the excellent anti-cancer potential and relatively simple molecular structure of CA-4 provide an encouraging starting point for the development of new, more stable and more potent anti-tubulin compounds. Objective: This study aimed to synthesize a new series derived from 4-(3,4,5-trimethoxyphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione derivatives (compounds 10-12) with substituted phenyl group at C5 of the triazole ring (B-ring) as analogs of CA-4, with different alkyl and aryl side chain substituents at the triazole moiety, resulting in the permanent cis configuration of the two phenyl rings. Moreover, the anti-cancer activities of the new compounds were assessed. Methods: Chemical synthesis was carried out by conventional organic methods. The newly synthesized CA-4 analogs were characterized by FT-IR, 1HNMR, 13CNMR, and HR-MS(ESI) techniques. Molecular docking studies, including docking score (G) ADMET, DFT, and molecular similarities, were performed. The anti-proliferative activity of the new compounds against three human cancer cell lines (A549, Hep G2, and HCT-116) and the normal cell line WI-38 was evaluated using the MTT assay, and their ability to inhibit tubulin polymerization, and consequently, their effects on cell cycle progression and induction of apoptosis were assessed. Results: Molecular docking studies showed that compounds 11b and 11d exhibited the highest docking scores (-13.30 and -14.01 Kcal/mol, respectively) into the colchicine-binding site, scores very close to the reference drug colchicine (-13.50 Kcal/mol), and that hydrogen bonding and hydrophobic interaction are essential for binding. The most active cytotoxic compound, 11b, had potent IC50 values against the three human cancer cell lines (3.83, 10.20, and 10.67 µM against Hep G2, HCT-116, and A549, respectively) while exhibiting low cytotoxicity against non-cancer-human WI-38, suggesting that compound 11b targets rapidly growing cancer cells. Moreover, compound 11b exhibited potent anti-tubulin activity which was comparable to CA-4. Targeting microtubules caused cell cycle arrest at the G2/M phase resulting in the induction of apoptosis. Conclusion: These findings indicate that compound 11b is a promising β-tubulin-binding compound with antimitotic action that has the potential to treat cancer.

show abstract

Design and Synthesis of Novel Derivatives of 4-(6-(4-Substituted Phenyl)-7H-[1,2,4] Triazolo[3,4-b][1,3,4]Thiadiazin-3- yl) Phenol as a Potent Inhibitor of Tubulin with Antitumor Activity

Cited by 3 publications

References 1 publication

Synthesis and Characterization of some new heterocyclic derivatives from aromatic carbonyl ‎compounds and carboxylic acids with Evaluation some of them for biological activity

Synthesis and Characterization of some new heterocyclic derivatives from aromatic carbonyl ‎compounds and carboxylic acids with Evaluation some of them for biological activity

Discovery of 2‐Amino‐4H‐1, 3, 4‐thiadiazine‐5(6H)‐one Derivatives and Their In Vitro Antitumor Investigation

Design, Synthesis, in silico and in vitro Evaluation of New Combretastatin A-4 Analogs as Antimitotic Antitumor Agents

Contact Info

Product

Resources

About