Design and synthesis of pyrazole/isoxazole linked arylcinnamides as tubulin polymerization inhibitors and potential antiproliferative agents

Abstract

As pyrazole and isoxazole based derivatives are well-known for displaying a considerable biological profile, an attempt has been made to unravel their cytotoxic potential. In this context, a number of pyrazole/isoxazole linked arylcinnamide conjugates (15a-o and 21a-n) have been synthesized by employing a straight forward route. The basic structure comprised three ring scaffolds (A, B and C): methoxyphenyl rings as A and C rings and a five membered heterocyclic ring (pyrazole or isoxazole) as the B-ring. To achieve clear understanding, these derivatives are categorized as pyrazole-phenylcinnamides (PP) and isoxazole-phenylcinnamides (IP). These compounds have been evaluated for their ability to inhibit the growth of various human cancer cell lines such as HeLa, DU-145, A549 and MDA-MB231 and most of them exhibit considerable cytotoxic effects. Some of them like 15a, 15b, 15e, 15i and 15l exhibit promising cytotoxicity in HeLa cells (IC50 = 0.4, 1.8, 1.2, 2.7 and 1.7 μM). Amongst them 15a, 15b and 15e were taken up for detailed biological studies, they were found to arrest the cells in the G2/M phase of the cell cycle. Moreover, they were investigated for their effect on the microtubular cytoskeletal system by using a tubulin polymerization assay, immunofluroscence and molecular docking studies; interestingly they demonstrate a significant inhibition of tubulin polymerization.

Isoxazole derivatives as new nitric oxide elicitors in plants

“…3,5-Disubstituted isoxazoles 6 , 7 , 9 and 10 (Table 1) have been previously prepared by different synthetic procedures, but compounds 6 [52], 7 [49] and 10 [53] have been only partly characterized, while for compound 9 [54] no characterization data have been reported.…”

“…The benzo[1,3]dioxole framework is a constituent of some fragrances and flavors [44], and several bioactive compounds with a broad spectrum of applications [45–48]. The thiophene is a core system of a large number of bioactive molecules such as antineoplastic agents [49], non-steroidal anti-inflammatory drugs [50] or compounds with antibacterial activities against several Gram-positive strains [51]. Thus, 3,5-disubstituted isoxazole derivatives were obtained by regioselective 1,3-dipolar cycloaddition reactions of aromatic nitrile oxides to non-symmetrical activated alkyne derivatives in the presence of catalytic amounts of copper(I) iodide.…”

Hybrid cis-stilbene Molecules: Novel Anticancer Agents

“…The exact location of these sites and the mechanism of MIA interactions with tubulin is still a subject of studies. Many natural MIAs have been identified, and still, new classes of potential MIAs are synthesized; among them, potent antitubulin agents are selected [24,25,26,27]. Combretastatins which show an affinity with the colchicine binding site draw our attention in the context of the search for potent remedies against cancer.…”

Synthesis of new bis‐pyrazole linked hydrazides and their in vitro evaluation as antimicrobial and anti‐biofilm agents: A mechanistic role on ergosterol biosynthesis inhibition in Candida albicans

“…Hydrazide has attracted attention of medicinal chemists in view of their diverse array of biological activities like antibacterial, antifungal (Figure v), anticonvulsant, anti‐inflammatory, antimalarial, and anti‐tuberculosis (Ajani, Obafemi, Nwinyi, & Akinpelu, ; Foroumadi, Kiani, & Soltani, ; Melnyk, Leroux, Sergheraert, & Grellier, ; Mohareb, Fleita, & Sakka, ; Short, ; Singh & Raghav, ; Xia et al., ; Zheng, Wu, Zhao, Dong, & Miao, ). Prompted by the aforementioned findings and in continuation of our ongoing research on the synthesis of bioactive conjugates (Kamal et al., ; Khan et al., ), we prepared hybrid derivatives comprising of two substituted pyrazole moieties joined through a hydrazide linker and later evaluated their antibacterial, anti‐ Candida, and anti‐biofilm activities. Further, mechanistic aspects of the promising leads on ergosterol biosynthesis inhibition in different C. albicans strains were demonstrated, which were further validated through molecular docking studies.…”