Novel Indole‐Quinazolinone Based Amides as Cytotoxic Agents

Gokhale, Nikhila; Panathur, Naveen; Dalimba, Udayakumar; Nayak, Pawan G.; Pai, K. Sreedhara Ranganath

doi:10.1002/jhet.2403

Cited by 8 publications

(9 citation statements)

References 40 publications

(63 reference statements)

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“…The reaction between intermediates 2 and 6 in the presence of glacial acetic acid (HOAc) at 105°C yielded ethyl 1‐(2‐methyl‐8‐(trifluoromethyl)quinolin‐4‐yl)‐1 H ‐pyrazole‐3‐carboxylate ( 7 ) in good yield . The carboxylic acid derivative 8 , which is the key intermediate for the synthesis of the target compounds, was synthesized by the lithium hydroxide (LiOH) mediated ester hydrolysis of intermediate 7 . The target derivatives ( 9a , 9b , 9c , 9d , 9e , 9f , 9g , 9h , 9i , 9j , 9k , 9l , 9m , 9n , 9o , 9p , 9q , 9r , 9s , 9t ) were synthesized by coupling the acid derivative ( 8 ) with different primary and secondary amines using N ‐[(dimethylamino)‐1 H ‐1,2,3‐triazolo‐[4,5‐ b ]pyridin‐1‐yl‐methylene]‐ N ‐methylmethanaminium hexafluorophosphate N ‐oxide (HATU) as the coupling agent and diisopropyl ethylamine (DIPEA) as the base in dimethyl formamide (DMF) medium .…”

Section: Resultsmentioning

confidence: 99%

“…The carboxylic acid derivative 8 , which is the key intermediate for the synthesis of the target compounds, was synthesized by the lithium hydroxide (LiOH) mediated ester hydrolysis of intermediate 7 . The target derivatives ( 9a , 9b , 9c , 9d , 9e , 9f , 9g , 9h , 9i , 9j , 9k , 9l , 9m , 9n , 9o , 9p , 9q , 9r , 9s , 9t ) were synthesized by coupling the acid derivative ( 8 ) with different primary and secondary amines using N ‐[(dimethylamino)‐1 H ‐1,2,3‐triazolo‐[4,5‐ b ]pyridin‐1‐yl‐methylene]‐ N ‐methylmethanaminium hexafluorophosphate N ‐oxide (HATU) as the coupling agent and diisopropyl ethylamine (DIPEA) as the base in dimethyl formamide (DMF) medium . The structure of the synthesized intermediates and target compounds was confirmed by 1 H NMR, 13 C NMR, and mass spectral techniques as well as by the elemental analysis.…”

Section: Resultsmentioning

confidence: 99%

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Design, Synthesis, and Biological Evaluation of New 8‐Trifluoromethylquinoline Containing Pyrazole‐3‐carboxamide Derivatives

Nayak

Ramprasad

Dalimba

2015

Journal of Heterocyclic Chem

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The article describes the design, synthesis, and characterization of a new series of 8‐trifluoromethylquinoline substituted pyrazole‐3‐carboxamides (9a, 9b, 9c, 9d, 9e, 9f, 9g, 9h, 9i, 9j, 9k, 9l, 9m, 9n, 9o, 9p, 9q, 9r, 9s, 9t) derived from different primary and secondary amines. The intermediate and target compounds were characterized using spectroscopic methods. The structures of intermediate 7 and target molecule 9d were evidenced by the single crystal X‐ray study. All the synthesized target compounds (9a, 9b, 9c, 9d, 9e, 9f, 9g, 9h, 9i, 9j, 9k, 9l, 9m, 9n, 9o, 9p, 9q, 9r, 9s, 9t) and three intermediates (6, 7, 8) were screened for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv strain. Two compounds, 9k and 9t, showed significant inhibition activity with MIC of 3.13 µg/mL, which is comparable with the activity of standard drug, ethambutol. The carboxamides derived from benzylamine derivatives were more active than their aniline analogs. In general, the hybrid amides with a N‐methylene linkage (‐CONHCH2‐) exhibited enhanced antitubercular activity. In the antibacterial screening, intermediate 3‐hydrazinyl‐2‐methyl‐8‐(trifluoromethyl)quinoline (6) displayed remarkable activity against the tested bacterial strains. Further, the active anti‐TB derivatives were non‐toxic to benign NIH 3T3 cells, which demonstrate the lack of general cellular toxicity and hence signifies their suitability for further lead development.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of New 8‐Trifluoromethylquinoline Containing Pyrazole‐3‐carboxamide Derivatives

Nayak

Ramprasad

Dalimba

2015

Journal of Heterocyclic Chem

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“…The crude residue was suspended in petroleum ether, the mixture stirred for 15 min and then filtered to afford the corresponding N -methyl, N -ethyl or N -benzyl 2-alkoxycabonyl-3-formyl indole derivatives 8a–d , 8e–h and 8i–l , respectively, which was used for the next reaction without further purification. Compounds 8a , 8 b and 8i are known (see references 32 , 34 , 35 ).…”

Section: Methodsmentioning

confidence: 99%

Design, synthesis, in vitro antiproliferative activity and apoptosis-inducing studies of 1-(3′,4′,5′-trimethoxyphenyl)-3-(2′-alkoxycarbonylindolyl)-2-propen-1-one derivatives obtained by a molecular hybridisation approach

Preti

Romagnoli

Rondanin

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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Inhibition of microtubule function using tubulin targeting agents has received growing attention in the last several decades. The indole scaffold has been recognized as an important scaffold in the design of novel compounds acting as antimitotic agents. Indole-based chalcones, in which one of the aryl rings was replaced by an indole, have been explored in the last few years for their anticancer potential in different cancer cell lines. Eighteen novel (3′,4′,5′-trimethoxyphenyl)-indolyl-propenone derivatives with general structure 9 were synthesized and evaluated for their antiproliferative activity against a panel of four different human cancer cell lines. The highest IC50 values were obtained against the human promyelocytic leukemia HL-60 cell line. This series of chalcone derivatives was characterized by the presence of a 2-alkoxycarbonyl indole ring as the second aryl system attached at the carbonyl of the 3-position of the 1-(3′,4′,5′-trimethoxyphenyl)-2-propen-1-one framework. The structure–activity relationship (SAR) of the indole-based chalcone derivatives was investigated by varying the position of the methoxy group, by the introduction of different substituents (hydrogen, methyl, ethyl or benzyl) at the N-1 position and by the activity differences between methoxycarbonyl and ethoxycarbonyl moieties at the 2-position of the indole nucleus. The antiproliferative activity data of the novel synthesized compounds revealed that generally N-substituted indole analogues exhibited considerably reduced potency as compared with their parent N-unsubstituted counterparts, demonstrating that the presence of a hydrogen on the indole nitrogen plays a decisive role in increasing antiproliferative activity. The results also revealed that the position of the methoxy group on the indole ring is a critical determinant of biological activity. Among the synthesized derivatives, compound 9e, containing the 2-methoxycarbonyl-6-methoxy-N-1H-indole moiety exhibited the highest antiproliferative activity, with IC50 values of 0.37, 0.16 and 0.17 μM against HeLa, HT29 and MCF-7 cancer cell lines, respectively, and with considerably lower activity against HL-60 cells (IC50: 18 μM). This derivative also displayed cytotoxic properties (IC50 values ∼1 μM) in the human myeloid leukemia U-937 cell line overexpressing human Bcl-2 (U-937/Bcl-2) via cell cycle progression arrest at the G2-M phase and induction of apoptosis. The results obtained also demonstrated that the antiproliferative activity of this molecule is related to inhibition of tubulin polymerisation. The presence of a methoxy group at the C5- or C6-position of the indole nucleus, as well as the absence of substituents at the N-1-indole position, contributed to the optimal activity of the indole-propenone-3′,4′,5′-trimethoxyphenyl scaffold.

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“…Based on these findings, quinazolinonebased indolyl amides were created and manufactured, and then their anti-cancer activity was tested. 34 .…”

Section: Anti-cancer Activity Of Quinazolinonementioning

confidence: 99%

Nanocatalyzed Synthetic Approach for the Quinazolinone and Quinazoline Derivatives: A Review (2015 – Present)

Vishwakarma

Kashaw

2023

J. Drug Delivery Ther.

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Due to their diverse chemical reactivities and essential range of biological action, quinazolines and their derivatives rank among the most significant heterocyclic compounds. Quinazoline and quinazolinone scaffolds pharmacological properties have sparked medicinal chemists' interest in creating original medications or drug candidates. The growth of quinazoline hybrid lead compounds and the related heterocycles is summarised in the current review of medicinal chemistry. Additionally, by shedding light on the potential significance of these hybridised pharmacophoric characteristics in the demonstrating a range of pharmacological activities, the review contributes to the acceleration of the drug development process. Keywords: Fused Heterocycles, Quinazolinone and Quinazoline Derivatives, Drug Development

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Novel Indole‐Quinazolinone Based Amides as Cytotoxic Agents

Abstract: Indole‐quinazolinone hybrids with active amides were synthesized, characterized, and assessed for their cytotoxicity. Two molecules displayed substantial activity in sulphorhodamine B assay method.

Cited by 8 publications

References 40 publications

Design, Synthesis, and Biological Evaluation of New 8‐Trifluoromethylquinoline Containing Pyrazole‐3‐carboxamide Derivatives

Design, Synthesis, and Biological Evaluation of New 8‐Trifluoromethylquinoline Containing Pyrazole‐3‐carboxamide Derivatives

Design, synthesis, in vitro antiproliferative activity and apoptosis-inducing studies of 1-(3′,4′,5′-trimethoxyphenyl)-3-(2′-alkoxycarbonylindolyl)-2-propen-1-one derivatives obtained by a molecular hybridisation approach

Nanocatalyzed Synthetic Approach for the Quinazolinone and Quinazoline Derivatives: A Review (2015 – Present)

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