Anti-influenza activity of diazaadamantanes combined with monoterpene moieties

Суслов, Е. В.; Zarubaev, Vladimir V.; Slita, Alexander V.; Ponomarev, Konstantin; Корчагина, Д. В.; Ayine-Tora, Daniel Moscoh; Reynisson, Jóhannes; Волчо, К. П.; Salakhutdinov, N. F.

doi:10.1016/j.bmcl.2017.08.062

Cited by 21 publications

(14 citation statements)

References 40 publications

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“…The introduction of two nitrogen atoms and two methyl groups in compound ( 4 ) ( Fig. 2 ) made it possible to partially overcome the resistance of the A/California/07/09 (H1N1)pdm09 influenza virus strain to rimantadine and increased the selectivity index SI to 13, compared with SI = 5 for rimantadine (SI = CC 50 /IC 50 , where CC 50 is the concentration causing the death of 50% of cells and IC 50 is the half-maximal inhibitory concentration) [ 30 ]. The addition of citronellal, the fragment of the monoterpenoid, to aminodiazaadamantane ( 4 ), followed by subsequent reduction led to the formation of amine ( 5 ), which demonstrated the high SI value of 30 at the IC 50 value of 8 µM [ 31 ].…”

Section: Biological Activity Of Azaadamantanesmentioning

confidence: 99%

“…The introduction of the citronellal residue into 1- or 2-aminoadamantanes that do not contain nodal nitrogen atoms (compounds ( 6 ) and ( 7 )) also led to an increase, although less significant, in the activity against the influenza virus (SI = 22) [ 32 ]. The results of computer modeling [ 30 ] suggest that diazaadamantane ( 5 ) can bind to the M2 protein channel, although its effect on other molecular targets cannot be excluded.…”

Section: Biological Activity Of Azaadamantanesmentioning

confidence: 99%

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Azaadamantanes, a New Promising Scaffold for Medical Chemistry

et al. 2021

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Azaadamantanes are nitrogen-containing analogs of adamantane, which contain one or more nitrogen atoms instead of carbon atoms. This substitution leads to several specific chemical and physical properties. The azaadamantane derivatives have less lipophilicity compared to their adamantane analogs, which affects both their interaction with biological targets and bioavailability. The significant increase in the number of publications during the last decade (2009–2020) concerning the study of reactivity and biological activity of azaadamantanes and their derivatives indicates a great theoretical and practical interest in these compounds. Compounds with pronounced biological activity have been already discovered among azaadamantane derivatives. The review is devoted to the biological activity of azaadamantanes and their derivatives. It presents the main methods for the synthesis of di- and triazaadamantanes and summarizes the accumulated data on studying the biological activity of these compounds. The prospects for the use of azaadamantanes in medical chemistry and pharmacology are discussed.

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Section: Biological Activity Of Azaadamantanesmentioning

confidence: 99%

Section: Biological Activity Of Azaadamantanesmentioning

confidence: 99%

Azaadamantanes, a New Promising Scaffold for Medical Chemistry

et al. 2021

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“…Adamantane and its derivatives have fascinating structures due to their various physiological, pharmaceutical, and medical activities [1][2][3][4][5][6]. It consists of a polycyclic cage molecule with high symmetry representing diamondoids-hydrogen-terminated hydrocarbons with a diamond-like structure [7][8].…”

Section: ■ Introductionmentioning

confidence: 99%

Theoretical Study on Molecular Structure and Electronic Properties of New 1,3-Diaza-adamantan-6-ones Derivatives

2020

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In this study, the structural geometry and vibrational frequencies (IR) of 1,3-Diaza-adamantane-6-ones derivatives including Adamantane (A), 1,3-Diaza-adamantan (D), 1,3-Diaza-adamantan-6-one (DO), 5-Benzyl-1,3-diaza-adamantan-6-one (BD), 5-(4-Hydroxybenzyl)-1,3-diaza-adamantan-6-one (HBD), 5-(4-Methoxybenzyl)-1,3-diaza-adamantan-6-one (MBD), and 5-(4-Hydroxy-3-methoxybenzyl)-1,3-diaza-adamantan-6-one (HMBD) were theoretically studied. In addition, molecular orbital energies, including the highest occupied molecular orbitals (HOMOs), and lowest unoccupied molecular orbitals (LUMOs), and electronic properties of the titled molecules were theoretically studied using the computational method. Optimized molecular structures were obtained by DFT method with the hybrid B3LYP functional at a relatively small basis set of 6-31G. The calculated vibrational wavenumbers were obtained using the same level of the theory mentioned above. The contributions to the molecular orbitals of adamantane and substituted-phenyl groups in the title compounds were determined. Moving from A to HMBD, a decrease in the value of LUMO and total energy are noticed, while an increase in the value of HOMO is noted. These findings are supported by the decreasing in the EHOMO-LUMO gap values. Furthermore, a decrease in the value of ionization potential (IP) is obtained, while an increase in the electronegativity (EA) is observed.

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“…1). Recently, a diazaadamantane derivative 6 has been reported as an inhibitor of the rimantadineresistant strain of the influenza A/Puerto Rico/8/34 (H1N1) virus [27]. It is noteworthy that although methenamine is clinically used to prevent urinary tract infections [28], the tetrazaadementane skeleton is barely utilized to design small drug-like molecules except in synthesizing the crucial reaction intermediate phenacyl amines [29e31].…”

Section: Introductionmentioning

confidence: 99%

ASR352, A potent anticancer agent: Synthesis, preliminary SAR, and biological activities against colorectal cancer bulk, 5-fluorouracil/oxaliplatin resistant and stem cells

Narayan

Ramisetti

Jaiswal

et al. 2019

European Journal of Medicinal Chemistry

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a b s t r a c tDespite new agent development and short-term benefits in patients with colorectal cancer (CRC), metastatic CRC cure rates have not improved due to high rates of 5-fluorouracil (5-FU)/leucovorin/ oxaliplatin (FOLFOX)-resistance and a clinical therapeutic plateau. At the same time, this treatment regime leads to significant toxicity, cost, and patient inconvenience. Drug-resistance is linked to CRC stem cells, which are associated with the epidermal-to-mesenchymal transition (EMT) pathway. Thus, to optimally treat CRC, a therapy that can target the cell survival and EMT pathways in both CRC bulk and stem cell populations is critical. We recently identified a novel small molecule NSC30049 (7a) that is effective alone, and in combination potentiates 5-FU-mediated growth inhibition of CRC bulk, FOLFOXresistant, and CRC stem cells both in vitro and in vivo models. In the present study, we report the synthesis and anti-CRC evaluation of several stable and effective 7a analogs. ASR352 (7b) was identified as one of the equipotent 7a analogs that inhibited the growth of CRC bulk cells, sensitized FOLFOX-resistant cells, and reduced the sphere formation capacity of CRC stem cells. It appears that the complex mechanism of cytotoxicity for 7b includes abrogation of 5-FU-induced the S phase, reduction of the phosphorylation of Chk1 at S317P, S345P and S296P, increased gH2AX staining, activation of caspase 3/PARP1 cleavage, and enhancement of Bax/Bcl2 ratio. Further 7b-mediated reduced phosphorylation of Chk1 was an indirect effect, since it did not inhibit Chk1 activity in an in vitro kinase assay. Our findings suggest that 7b as a single agent, or in combination with 5-FU can be developed as a therapeutic agent in CRC bulk, FOLFOX-resistant, and CRC stem cell populations for unmanageable metastatic CRC conditions.

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Anti-influenza activity of diazaadamantanes combined with monoterpene moieties

Cited by 21 publications

References 40 publications

Azaadamantanes, a New Promising Scaffold for Medical Chemistry

Azaadamantanes, a New Promising Scaffold for Medical Chemistry

Theoretical Study on Molecular Structure and Electronic Properties of New 1,3-Diaza-adamantan-6-ones Derivatives

ASR352, A potent anticancer agent: Synthesis, preliminary SAR, and biological activities against colorectal cancer bulk, 5-fluorouracil/oxaliplatin resistant and stem cells

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