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New chemical agents based on adamantane-monoterpene conjugates against orthopoxvirus infections.

ABSTRACT: Currently, the spectrum of agents against orthopoxviruses, in particular smallpox, is very narrow. Despite the fact that smallpox is well controlled, there is, for many reasons, a real threat of epidemics associated with this or a similar virus. In order to search for new low molecular weight orthopoxvirus inhibitors, a series of amides combining adamantane and monoterpene moieties were synthesized using 1- and 2-adamantanecarboxylic acids as well as myrtenic, citronellic and camphorsulfonic acids as acid components. The produced compounds exhibited high activity against the vaccinia virus (an enveloped virus belonging to the poxvirus family), which was combined with low cytotoxicity. Some compounds had a selectivity index higher than that of the reference drug cidofovir; the highest SI = 1123 was exhibited by 1-adamantanecarboxylic acid amide containing the (-)-10-amino-2-pinene moiety. The produced compounds demonstrated inhibitory activity against other orthopoxviruses: cowpox virus (SI = 30-406) and ectromelia virus (mousepox virus, SI = 39-707).

SUBMITTER: Suslov EV

PROVIDER: S-EPMC7651861 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Novel Tdp1 Inhibitors Based on Adamantane Connected with Monoterpene Moieties via Heterocyclic Fragments.

Project description:Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a promising target for anticancer therapy due to its ability to counter the effects topoisomerase 1 (Top1) poison, such as topotecan, thus, decreasing their efficacy. Compounds containing adamantane and monoterpenoid residues connected via 1,2,4-triazole or 1,3,4-thiadiazole linkers were synthesized and tested against Tdp1. All the derivatives exhibited inhibition at low micromolar or nanomolar concentrations with the most potent inhibitors having IC50 values in the 0.35-0.57 µM range. The cytotoxicity was determined in the HeLa, HCT-116 and SW837 cancer cell lines; moderate CC50 (µM) values were seen from the mid-teens to no effect at 100 µM. Furthermore, citral derivative 20c, α-pinene-derived compounds 20f, 20g and 25c, and the citronellic acid derivative 25b were found to have a sensitizing effect in conjunction with topotecan in the HeLa cervical cancer and colon adenocarcinoma HCT-116 cell lines. The ligands are predicted to bind in the catalytic pocket of Tdp1 and have favorable physicochemical properties for further development as a potential adjunct therapy with Top1 poisons.

| S-EPMC8197275 | biostudies-literature

Orthopoxvirus targets for the development of new antiviral agents.

Project description:Investments in the development of new drugs for orthopoxvirus infections have fostered new avenues of research, provided an improved understanding of orthopoxvirus biology and yielded new therapies that are currently progressing through clinical trials. These broad-based efforts have also resulted in the identification of new inhibitors of orthopoxvirus replication that target many different stages of viral replication cycle. This review will discuss progress in the development of new anti-poxvirus drugs and the identification of new molecular targets that can be exploited for the development of new inhibitors. The prototype of the orthopoxvirus group is vaccinia virus and its replication cycle will be discussed in detail noting specific viral functions and their associated gene products that have the potential to serve as new targets for drug development. Progress that has been achieved in recent years should yield new drugs for the treatment of these infections and might also reveal new approaches for antiviral drug development with other viruses.

| S-EPMC3773844 | biostudies-literature

New Myrtenal-Adamantane Conjugates Alleviate Alzheimer's-Type Dementia in Rat Model.

Project description:Alzheimer's disease (AD) is a neurodegenerative disease associated with memory impairment and other central nervous system (CNS) symptoms. Two myrtenal-adamantane conjugates (MACs) showed excellent CNS potential against Alzheimer's models. Adamantane is a common pharmacophore for drug design, and myrtenal (M) demonstrated neuroprotective effects in our previous studies. The aim of this study is to evaluate the MACs' neuroprotective properties in dementia.MethodsScopolamine (Scop) was applied intraperitoneally in Wistar rats for 11 days, simultaneously with MACs or M as a referent, respectively. Brain acetylcholine esterase (AChE) activity, noradrenaline and serotonin levels, and oxidative brain status determination followed behavioral tests on memory abilities. Molecular descriptors and docking analyses for AChE activity center affinity were performed.ResultsM derivatives have favorable physicochemical parameters to enter the CNS. Both MACs restored memory damaged by Scop, showing significant AChE-inhibitory activity in the cortex, in contrast to M, supported by the modeling analysis. Moderate antioxidant properties were manifested by glutathione elevation and catalase activity modulation. MACs also altered noradrenaline and serotonin content in the hippocampus.ConclusionFor the first time, neuroprotective properties of two MACs in a rat dementia model were observed. They were stronger than the natural M effects, which makes the substances promising candidates for AD treatment.

| S-EPMC9457974 | biostudies-literature

Ciprofloxacin-Tethered 1,2,3-Triazole Conjugates: New Quinolone Family Compounds to Upgrade Our Antiquated Approach against Bacterial Infections.

Project description:A newer ciprofloxacin series containing 1,2,3-triazole conjugates of ciprofloxacin was designed, synthesized, and well characterized using modern analytical techniques by reacting diversified anilines with ciprofloxacin obtained from ciprofloxacin hydrochloride. The newer conjugates were evaluated for their antimicrobial activity against various strains, viz. Staphylococcus aureus (ATCC25923), Enterococcus faecalis (clinical isolate), Staphylococcus epidermidis (ATCC3594), Escherichia coli (ATCC25922), Pseudomonas aeruginosa (ATCC27853), Salmonella typhi (clinical isolate), Salmonella typhimurium (clinical isolate), Acinetobacter baumannii (ATCC19606), Aeromonas hydrophila (ATCC7966), Plesiomonas shigelloides (ATCC14029), and Sphingo biumpaucimobilis (MTCC6362) in vitro. Interestingly, some of the conjugates showed superior antimicrobial activity as compared to the control drug ciprofloxacin. The three compounds 4i, 4j, and 4n showed strong activity with minimum inhibitory concentration (MIC) 0.78 μM, while the compound 4g showed MIC 1.56 μM against S. typhi (clinical). The compound 4a showed good efficacy against S. aureus (ATCC25923) and S. typhi (clinical) with MIC 3.12 μM, while the compound 4b exhibited efficacy with MIC 3.12 μM against S. aureus (ATCC25923) and the control drug ciprofloxacin showed MIC 6.25 μM. Among all of the synthesized compounds, 4e, 4f, 4g, 4h, 4p, 4q, 4t, and 4u displayed less than 20% hemolysis, while the rest of the compounds showed hemolysis in the range of 21-48%. Moreover, the structure of compound 4b was also established by single-crystal X-ray diffraction studies.

| S-EPMC8793084 | biostudies-literature

New Conjugates of Quinoxaline as Potent Antitubercular and Antibacterial Agents.

Project description:Considering quinoxaline as a privileged structure for the design of potent intercalating agents, some new sugar conjugates of quinoxaline were synthesized and characterized by IR, (1)HNMR, (13)C NMR, and mass spectral data. In vitro testing for antitubercular and antimicrobial activities was performed against Mycobacterium tuberculosis H 37 Rv and some pathogenic bacteria. Results revealed that conjugate containing ribose moiety demonstrated the most promising activity against Mycobacteria and bacteria with minimum inhibitory concentrations (MIC) of 0.65 and 2.07??M, respectively. Other conjugates from xylose, glucose, and mannose were moderately active whilst disaccharides conjugates were found to be less active. In silico docking analysis of prototype compound revealed that ATP site of DNA gyrase B subunit could be a possible site for inhibitory action of these synthesized compounds.

| S-EPMC4802037 | biostudies-literature

New 3-(Dibenzyloxyphosphoryl)isoxazolidine Conjugates of N1-Benzylated Quinazoline-2,4-diones as Potential Cytotoxic Agents against Cancer Cell Lines

Project description: Not available

| S-EPMC11243672 | biostudies-literature

Orthopoxvirus

Project description:Orthopoxvirus and human sequences raw sequence reads

| PRJNA286208 | ENA

New Multifunctional Agents Based on Conjugates of 4-Amino-2,3-polymethylenequinoline and Butylated Hydroxytoluene for Alzheimer's Disease Treatment.

Project description:New hybrids of 4-amino-2,3-polymethylenequinoline with different sizes of the aliphatic ring linked to butylated hydroxytoluene (BHT) by enaminoalkyl (7) or aminoalkyl (8) spacers were synthesized as potential multifunctional agents for Alzheimer's disease (AD) treatment. All compounds were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. Lead compound 8c, 2,6-di-tert-butyl-4-{[2-(7,8,9,10- tetrahydro-6H-cyclohepta[b]quinolin-11-ylamino)-ethylimino]-methyl}-phenol exhibited an IC50(AChE) = 1.90 ± 0.16 µM, IC50(BChE) = 0.084 ± 0.008 µM, and 13.6 ± 1.2% propidium displacement at 20 ?M. Compounds possessed low activity against carboxylesterase, indicating likely absence of clinically unwanted drug-drug interactions. Kinetics were consistent with mixed-type reversible inhibition of both cholinesterases. Docking indicated binding to catalytic and peripheral AChE sites; peripheral site binding along with propidium displacement suggest the potential of the hybrids to block AChE-induced ?-amyloid aggregation, a disease-modifying effect. Compounds demonstrated high antioxidant activity in ABTS and FRAP assays as well as inhibition of luminol chemiluminescence and lipid peroxidation in mouse brain homogenates. Conjugates 8 with amine-containing spacers were better antioxidants than those with enamine spacers 7. Computational ADMET profiles for all compounds predicted good blood-brain barrier distribution (permeability), good intestinal absorption, and medium cardiac toxicity risk. Overall, based on their favorable pharmacological and ADMET profiles, conjugates 8 appear promising as candidates for AD therapeutics.

| S-EPMC7763995 | biostudies-literature

Triazole-diindolylmethane conjugates as new antitubercular agents: synthesis, bioevaluation, and molecular docking.

Project description:We describe the synthesis of novel triazole-incorporated diindolylmethanes (DIMs) using a molecular hybridization approach. The in vitro antitubercular activity of the DIMs against Mycobacterium tuberculosis H37Ra (ATCC 25177) was tested in the active and dormant state. Among all the synthesized conjugates, the compounds 6b, 6f, 6l, 6n, 6q, 6r, and 6s displayed good antitubercular activity against both the active and dormant Mtb H37Ra strain. The compound 6l exhibited good antitubercular activity against dormant Mtb H37Ra with an IC50 value of 1 μg mL-1 and IC90 (MIC) value of 3 μg mL-1. The compounds 6b, 6l, and 6r displayed good antitubercular activity against active Mtb H37Ra with IC50 values of 2.19, 1.52, and 0.22 μg mL-1, respectively. The compounds 6b, 6h, 6l, and 6s displayed more than 70% inhibition against the Gram-positive Bacillus subtilus strain at 3 μg mL-1. The molecular docking study showed the binding modes of the titled compounds in the active site of the DprE1 enzyme and assisted with elucidating a structural basis for the inhibition of Mycobacteria.

| S-EPMC6072531 | biostudies-literature

Adamantane-Monoterpenoid Conjugates Linked via Heterocyclic Linkers Enhance the Cytotoxic Effect of Topotecan.

Project description:Inhibiting tyrosyl-DNA phosphodiesterase 1 (TDP1) is a promising strategy for increasing the effectiveness of existing antitumor therapy since it can remove the DNA lesions caused by anticancer drugs, which form covalent complexes with topoisomerase 1 (TOP1). Here, new adamantane-monoterpene conjugates with a 1,2,4-triazole or 1,3,4-thiadiazole linker core were synthesized, where (+)-and (-)-campholenic and (+)-camphor derivatives were used as monoterpene fragments. The campholenic derivatives 14a-14b and 15a-b showed activity against TDP1 at a low micromolar range with IC50 ~5-6 μM, whereas camphor-containing compounds 16 and 17 were ineffective. Surprisingly, all the compounds synthesized demonstrated a clear synergy with topotecan, a TOP1 poison, regardless of their ability to inhibit TDP1. These findings imply that different pathways of enhancing topotecan toxicity other than the inhibition of TDP1 can be realized.

| S-EPMC9182348 | biostudies-literature

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