Synthesis of 5H‐indeno[1,2‐b]pyridine derivatives: Antiproliferative and antimetastatic activities against two human prostate cancer cell lines

Abstract

This study describes the direct synthesis of 2‐amino‐4‐(phenylsubstituted)‐5H‐indeno[1,2‐b]pyridine‐3‐carbonitrile derivatives 5–21, through sequential multicomponent reaction of aromatic aldehydes, malononitrile, and 1‐indanone in the presence of ammonium acetate and acetic acid (catalytic). The biological study showed that compound 10 significantly impeded proliferation of the cell lines PC‐3, LNCaP, and MatLyLu. The antimetastatic effects of compound 10 could be related with inhibition of MMP9 in the PC‐3 and LNCaP human cell lines. On the basis of a study of the structure–activity relationship of these compounds, we propose that the presence of two methoxy groups at positions 6 and 7 of the indeno nucleus and a 4‐hydroxy‐3‐methoxy phenyl substitution pattern at position 4 of the pyridine ring is decisive for these types of molecules to exert very good antiproliferative and antimetastatic activities.

One-Pot Multicomponent Synthesis of Methoxybenzo[h]quinoline-3-carbonitrile Derivatives; Anti-Chagas, X-ray, and In Silico ADME/Tox Profiling Studies

“…This literature reveals that 1,2-dihydro naphthalene and 1H-indene coupled heterocyclic compounds possess remarkable anticancer activity. On this basis, and as a continuation of previous work [15,19] we are reporting the synthesis, via a one-pot synthesis from elementary starting materials as methoxy substituted-1-tetralone, aromatic aldehydes substituted, malononitrile, ammonium acetate, acetic acid in toluene of 2-Amino-5,6-dihydro-4-(3 or 4-hydroxy-4 or 3-methoxyphenyl)methoxybenzo[h]-quinoline-3-carbonitrile derivatives and their in vitro evaluation against bloodstream trypomastigotes of T. cruzi (NINOA and INC-5 strains). A study in silico on absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) profiling to help to describe the molecular properties related to the pharmacokinetic aspects in the human body of these compounds is reported.…”

“…According to recent reports, it has been found that 2-amino-5,6-dihydro-4-phenylbenzo [h]quinoline-3-carbonitrile derivatives [15], 2-amino-4-benzylpyridine-3-carbonitrile derivatives [16], 2-amino-4-quinolinyl-naphthopyrane-3-carbonitrile derivatives [17], 6,7-Dimethyl-4-(3,4,5-trimethoxyphenyl)-3,4-dihydroquinolin-2(1H)-one (DTDQ) [18], and 2-Amino-4-(phenyl substituted)-5H-indeno[1,2-b]pyridine-3-carbonitrile derivatives [19] are particularly active as anticancer and MMPs inhibitors. This literature reveals that 1,2-dihydro naphthalene and 1H-indene coupled heterocyclic compounds possess remarkable anticancer activity.…”

“…However, the development of a general and efficient synthetic strategy to obtain 2-aminopyridine fused with a six-membered ring of the 1,2-dihydronaphthalene was still desired. As part of our ongoing program in this area [19], we now reported the preparation of a series of 2-amino-methoxybenzo[h]quinoline-3carbonitriles in less time from the reaction and with better yields than reported previously [15,20,21,23,24], through the sequential multicomponent reaction of benzaldehyde substituted 1 (1 mmol), malononitrile 2 (1 mmol), 1-tetralone substituted 3 (1 mmol), and ammonium acetate (1.5 mmol) in toluene, with a catalytic amount of acetic acid, reflux, and the system equipped with a Dean-Stark trap (Scheme 1). The resultant reaction may be assumed to proceed via the Knoevenagel reaction with the formation of arylidenemalononitrile, which then underwent the Michael addition with 1-tetralone respective 3, followed by cyclization, isomerization, and aromatization to obtain the final products 4-15 (Scheme 2).…”

Oxadiazole: A highly versatile scaffold in drug discovery

“…The common heterocycle pyridine possesses various activities like anticancer, antimicrobial, antimalarial, antitubercular, anti-inflammatory, antiproliferative, antiviral, and analgesic activities. [7][8][9][10][11][12][13][14] The other heterocycles like pyrimidine, furan, pyrrole, indole, oxadiazole, benzoxazole, azetidine, thiophene, coumarin, benzofuran, pyrazole, quinoline oxazole, quinazoline, pyrimidine, thiazole, quinoline, pyrazole, and isoxazole also possess various pharmacological activities. [8,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] The Food and Drug Administration (FDA)-approved drugs in recent years contain biologically active heterocycles in their structures.…”