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23 pages, 3010 KB

Open AccessArticle

Hydroxamic Acids Containing a Bicyclic Pinane Backbone as Epigenetic and Metabolic Regulators: Synergizing Agents to Overcome Cisplatin Resistance

by Yulia Aleksandrova, Aldar Munkuev, Evgenii Mozhaitsev, Evgeniy Suslov, Konstantin Volcho, Nariman Salakhutdinov and Margarita Neganova

Cancers 2023, 15(20), 4985; https://doi.org/10.3390/cancers15204985 - 14 Oct 2023

Cited by 4 | Viewed by 2297

Abstract

Multidrug resistance is the dominant obstacle to effective chemotherapy for malignant neoplasms. It is well known that neoplastic cells use a wide range of adaptive mechanisms to form and maintain resistance against antitumor agents, which makes it urgent to identify promising therapies to solve this problem. Hydroxamic acids are biologically active compounds and in recent years have been actively considered to be potentially promising drugs of various pharmacological applications. In this paper, we synthesized a number of hydroxamic acids containing a p-substituted cinnamic acid core and bearing bicyclic pinane fragments, including derivatives of (−)-myrtenol, (+)-myrtenol and (−)-nopol, as a Cap-group. Among the synthesized compounds, the most promising hydroxamic acid was identified, containing a fragment of (−)-nopol in the Cap group 18c. This compound synergizes with cisplatin to increase its anticancer effect and overcomes cisplatin resistance, which may be associated with the inhibition of histone deacetylase 1 and glycolytic function. Taken together, our results demonstrate that the use of hydroxamic acids with a bicyclic pinane backbone can be considered to be an effective approach to the eradication of tumor cells and overcoming drug resistance in the treatment of malignant neoplasms. Full article

(This article belongs to the Special Issue Mechanisms of Cancer Cells Escape from Immune Surveillance: The Focus on Epigenetic and Pro-inflammatory Adaptations)

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16 pages, 2175 KB

Open AccessArticle

Synthesis, Antifungal Activity, and 3D-QSAR Study of Novel Nopol-Derived 1,3,4-Thiadiazole-Thiourea Compounds

by Ming Chen, Wen-Gui Duan, Gui-Shan Lin, Zhong-Tian Fan and Xiu Wang

Molecules 2021, 26(6), 1708; https://doi.org/10.3390/molecules26061708 - 18 Mar 2021

Cited by 34 | Viewed by 5068

Abstract

A series of novel nopol derivatives bearing the 1,3,4-thiadiazole-thiourea moiety were designed and synthesized by multi-step reactions in search of potent natural product-based antifungal agents. Their structures were confirmed by FT-IR, NMR, ESI-MS, and elemental analysis. Antifungal activity of the target compounds was preliminarily evaluated by in vitro methods against Fusarium oxysporum f. sp. cucumerinum, Cercospora arachidicola, Physalospora piricola, Alternaria solani, Gibberella zeae, Rhizoeotnia solani, Bipolaris maydis, and Colleterichum orbicalare at 50 µg/mL. All the target compounds exhibited better antifungal activity against P. piricola, C. arachidicola, and A. solani. Compound 6j (R = m, p-Cl Ph) showed the best broad-spectrum antifungal activity against all the tested fungi. Compounds 6c (R = m-Me Ph), 6q (R = i-Pr), and 6i (R = p-Cl Ph) had inhibition rates of 86.1%, 86.1%, and 80.2%, respectively, against P. piricola, much better than that of the positive control chlorothalonil. Moreover, compounds 6h (R = m-Cl Ph) and 6n (R = o-CF₃ Ph) held inhibition rates of 80.6% and 79.0% against C. arachidicola and G. zeae, respectively, much better than that of the commercial fungicide chlorothalonil. In order to design more effective antifungal compounds against A. solani, analysis of the three-dimensional quantitative structure–activity relationship (3D-QSAR) was carried out using the CoMFA method, and a reasonable and effective 3D-QSAR model (r² = 0.992, q² = 0.753) has been established. Furthermore, some intriguing structure–activity relationships were found and are discussed by theoretical calculation. Full article

(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds II)

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15 pages, 5013 KB

Open AccessArticle

Nopol-Based Quinoline Derivatives as Antiplasmodial Agents

by Rogers J. Nyamwihura, Huaisheng Zhang, Jasmine T. Collins, Olamide Crown and Ifedayo Victor Ogungbe

Molecules 2021, 26(4), 1008; https://doi.org/10.3390/molecules26041008 - 14 Feb 2021

Cited by 12 | Viewed by 3728

Abstract

Malaria remains a significant cause of morbidity and mortality in Sub-Saharan Africa and South Asia. While clinical antimalarials are efficacious when administered according to local guidelines, resistance to every class of antimalarials is a persistent problem. There is a constant need for new antimalarial therapeutics that complement parasite control strategies to combat malaria, especially in the tropics. In this work, nopol-based quinoline derivatives were investigated for their inhibitory activity against Plasmodium falciparum, one of the parasites that cause malaria. The nopyl-quinolin-8-yl amides (2–4) were moderately active against the asexual blood stage of chloroquine-sensitive strain Pf3D7 but inactive against chloroquine-resistant strains PfK1 and PfNF54. The nopyl-quinolin-4-yl amides and nopyl-quinolin-4-yl-acetates analogs were generally less active on all three strains. Interesting, the presence of a chloro substituent at C7 of the quinoline ring of amide 8 resulted in sub-micromolar EC₅₀ in the PfK1 strain. However, 8 was more than two orders of magnitude less active against Pf3D7 and PfNF54. Overall, the nopyl-quinolin-8-yl amides appear to share similar antimalarial profile (asexual blood-stage) with previously reported 8-aminoquinolines like primaquine. Future work will focus on investigating the moderately active and selective nopyl-quinolin-8-yl amides on the gametocyte or liver stages of Plasmodium falciparum and Plasmodium vivax. Full article

(This article belongs to the Collection Natural Products as Leads or Drugs against Neglected Tropical Diseases)

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21 pages, 390 KB

Open AccessArticle

Synthesis and Olfactory Evaluation of Bulky Moiety-Modified Analogues to the Sandalwood Odorant Polysantol^®

by Laura Chapado, Pablo J. Linares-Palomino, Concepción Badía, Sofía Salido, Manuel Nogueras, Adolfo Sánchez and Joaquín Altarejos

Molecules 2009, 14(8), 2780-2800; https://doi.org/10.3390/molecules14082780 - 28 Jul 2009

Cited by 4 | Viewed by 14940

Abstract

Five new bulky moiety-modified analogues of the sandalwood odorant Polysantol^® have been synthesized by aldol condensation of appropriate aldehydes with butanone, deconjugative α-methylation of the resulting α,β-unsaturated ketones, and reduction of the corresponding β,γ-unsaturated ketones. The final compounds were evaluated organoleptically and [...] Read more.

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