Design and synthesis of hybrid compounds as novel drugs and medicines

Alkhzem, Abdulaziz H.; Woodman, Timothy J.; Blagbrough, Ian S.

doi:10.1039/d2ra03281c

Cited by 90 publications

(60 citation statements)

References 84 publications

(129 reference statements)

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“…Methylene groups in α position to an amide (11‐CH 2 for compound 14 , 12‐CH 2 for 15 , 11‐CH 2 , 18‐CH 2 for compounds 16 ) are more de‐shielded, and therefore have the highest chemical shift. The protonation of primary and secondary amine functional groups causes a de‐shielding of the methylene functional group α to the nitrogen atom, causing a downfield shift by ≈1 ppm [9] . Therefore, CH 2 groups located next to an amine are more de‐shielded than those located further away, (1‐CH 2 , 3‐CH 2 , 5‐CH 2 , 7‐CH 2 , 9‐CH 2 for 14 , 1‐CH 2 , 3‐CH 2, 5‐CH 2 , 8‐CH 2, 10‐CH 2 for 15 , and 1‐CH 2 , 3‐CH 2 , 5‐CH 2 , 7‐CH 2 , 9‐CH 2 , 20‐CH 2 , 22‐CH 2 , 25‐CH 2 , 27‐CH 2 , 29‐CH 2 for 16 ).…”

Section: Resultsmentioning

confidence: 99%

“… [8] Such hybrids were created by joining various biologically active agents into a single heteromeric unit with the aim of retaining the pharmacological actions of each component. [9] The aim of this research project is to link two biologically active linear polyamines by an appropriately chosen/designed linker (Figure 1 ). This approach might improve their affinity and potency.…”

Section: Introductionmentioning

confidence: 99%

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Practical Synthesis of Polyamine Succinamides and Branched Polyamines

et al. 2022

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Antibiotic resistance is now a growing threat to human health, further exacerbated by the lack of new antibiotics. We describe the practical synthesis of a series of substituted polyamine succinamides and branched polyamines that are potential new antibiotics against both Gram‐positive and Gram‐negative bacteria, including MRSA and Pseudomonas aeruginosa. They are prepared via 1,4‐Michael addition of acrylonitrile and then hydrogenation of the nitrile functional groups to primary amines. They are built upon the framework of the naturally occurring polyamines thermine (3.3.3, norspermine) and spermine (3.4.3), homo‐ and heterodimeric polyamine succinic amides. Linking two of the same or different polyamines together via amide bonds can be achieved by introducing a carboxylic acid group on the first polyamine, then coupling that released carboxylic acid to a free primary amine in the second polyamine. If the addition of positive charges on the amino groups along the polyamine chains are a key factor in their antimicrobial activity against Gram‐negative bacteria, then increasing them will increase the antimicrobial activity. Synthesising polyamine amide dimers will increase the total net positive charge compared to their monomers. The design and practical synthesis of such homo‐ and hetero‐dimers of linear polyamines, spermine and norspermine, are reported. Several of these compounds do not display significant antibacterial activity against Gram‐positive or Gram‐negative bacteria, including MRSA and Pseudomonas aeruginosa. However, the most charged analogue, a branched polyamine carrying eight positive charges at physiological pH, displays antibiofilm activity with a 50 % reduction in PAO1 at 16–32 μg mL−1.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Practical Synthesis of Polyamine Succinamides and Branched Polyamines

et al. 2022

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“…To overcome the phenomenon of drug resistance developed by infectious agents, a new approach is conceived in the design of biomolecules endowed with high efficiency and low toxicity. − This concept is based on the combination of two or more bioactive molecules in order to produce new hybrid structures, retaining or not the properties of the starting molecules. ,− A single-molecule drug that acts on multiple targets is much more attractive in terms of therapeutic efficacy and economic efficiency. , Most significantly, molecular hybridization as a novel approach has proven to be very helpful in creating new drugs with increased and specific affinity. These hybrid drugs could be able to act on two or more targets as well as to reduce undesirable side effects.…”

Section: Introductionmentioning

confidence: 99%

“…These hybrid drugs could be able to act on two or more targets as well as to reduce undesirable side effects. Moreover, this kind of drugs could be considered as a magic solution to overcome the emergence of drug resistance. ,− In addition, the synergistic and additive effect of a hybrid drug against the same target provides a beneficial pathway for the treatment of a variety of complex diseases, including cancer, malaria, bacterial infections, etc. − ,− …”

Section: Introductionmentioning

confidence: 99%

Synthesis, Characterization, DFT Mechanistic Study, Antimicrobial Activity, Molecular Modeling, and ADMET Properties of Novel Pyrazole-isoxazoline Hybrids

et al. 2022

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A series of new heterocycle hybrids incorporating pyrazole and isoxazoline rings was successfully synthesized, characterized, and evaluated for their antimicrobial responses. The synthesized compounds were obtained utilizing N-alkylation and 1,3-dipolar cycloaddition reactions, as well as their structures were established through spectroscopic methods and confirmed by mass spectrometry. To get more light on the regioselective synthesis of new hybrid compounds, mechanistic studies were performed using DFT calculations with B3LYP/6-31G(d,p) basis set. Additionally, the results of the preliminary screening indicate that some of the examined hybrids showed potent antimicrobial activity, compared to standard drugs. The results confirm that the antimicrobial activity is strongly dependent on the nature of the substituents linked pyrazole and isoxazoline rings. Furthermore, molecular docking studies were conducted to highlight the interaction modes between the investigated hybrid compounds and the Escherichia coli and Candida albicans receptors. Notably, the results demonstrate that the investigated compounds have strong protein binding affinities. The stability of the formed complexes by the binding between the hybrid compound 6c, and the target proteins was also confirmed using a 100 ns molecular dynamics simulation. Finally, the prediction of ADMET properties suggests that almost all hybrid compounds possess good pharmacokinetic profiles and no signs of observed toxicity, except for compounds 6e, 6f, and 6g.

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“…aureus (MRSA), potentially primarily acting by depolarization of the cytoplasmic membrane and permeabilization of the bacterial outer membrane. , Linking two of the same or different polyamines via amide bonds can be achieved by introducing a carboxylic acid group on the first polyamine, then coupling to a free primary amine in the second polyamine. If the addition of positive charges − increases the antimicrobial activity of linear polyamines, − synthesizing homo- or heterodimeric polyamines will increase the total net charge compared to their monomeric counterparts …”

Section: Introductionmentioning

confidence: 99%

Practical Synthesis of Antimicrobial Long Linear Polyamine Succinamides

Alkhzem

Wonfor

et al. 2022

ACS Bio Med Chem Au

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There are many severe bacterial infections notorious for their ability to become resistant to clinically relevant antibiotics. Indeed, antibiotic resistance is a growing threat to human health, further exacerbated by the lack of new antibiotics. We now describe the practical synthesis of a series of substituted long linear polyamines that produce rapid antibacterial activity against both Gram-positive and Gram-negative bacteria, including meticillin-resistant Staphylococcus aureus. These compounds also reduce biofilm formation in Pseudomonas aeruginosa. The most potent analogues are thermine, spermine, and 1,12-diaminododecane homoand heterodimeric polyamine succinic acid amides. They are of the order of activity of the aminoglycoside antibiotics kanamycin and tobramycin as positive controls. Their low human cell toxicity is demonstrated in ex vivo hemolytic assays where they did not produce even 5% hemolysis of human erythrocytes. These long, linear polyamines are a new class of broad-spectrum antibacterials active against drug-resistant pathogens.

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Design and synthesis of hybrid compounds as novel drugs and medicines

Abstract: Hybrid compounds (L1–L2) possess potential advantages over mixtures used in combination therapies.

Cited by 90 publications

References 84 publications

Practical Synthesis of Polyamine Succinamides and Branched Polyamines

Practical Synthesis of Polyamine Succinamides and Branched Polyamines

Synthesis, Characterization, DFT Mechanistic Study, Antimicrobial Activity, Molecular Modeling, and ADMET Properties of Novel Pyrazole-isoxazoline Hybrids

Practical Synthesis of Antimicrobial Long Linear Polyamine Succinamides

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