Molecular Hybridization Approach Research Articles

Design and synthesis of anti-breast cancer agents from 4-piperazinylquinoline: A hybrid pharmacophore approach

A novel class of 4-piperazinylquinoline derivatives based on the isatin scaffold were designed by molecular hybridization approach and synthesized for biological evaluation. Subsequently, the compounds were examined for their cytotoxic effects on two human breast tumor cell lines, MDA-MB468 and MCF7, and two non-cancer breast epithelial cell lines, 184B5 and MCF10A. Although all compounds examined were quite effective on the breast cancer cell lines examined, the compound 4-bromo-1-[4-(7-chloro-quinolin-4-yl)-piperazin-1-ylmethyl]-1H-indole-2,3-dione (5b) and N1-[4-(7-trifluoromethyl-quinolin-4-yl)]-piperazin-1-ylmethyl-4-chloro-1H-indole-2,3-dione-3-thiosemicarbazone (8a) emerged as the most active among this series. It appeared that both 5b and 8a caused apoptosis to MCF7 cancer cells, but not MCF10A non-cancer cells. Thus, 4-piperazinylquinoline linked isatin analog can serve as the prototype molecule for further development of a new class of anti-breast cancer agents.

Leishmanicidal Activity of New Megazol Derivatives

A series of thirteen new megazol derivatives, designed exploring the molecular hybridization approach between megazol (3) and heterocombretastatins (2), was synthesized. These new compounds were tested for in vitro antiparasitic activity upon axenic amastigotes of Leishmania donovani. Biological results led us to identify a new potent megazol derivative (4g), which presents an IC(50) = 0.081microg/mL, more active tham the reference drug miltefosine (IC(50) = 0.131microg/mL).

Drug hybridization strategies: before or after lead identification?

The molecular hybridization approach is one of the most valuable structural modification tools useful for the discovery of ligands and prototypes presenting either optimized affinity for one bioreceptor or the ability to modulate more than one bioreceptor associated with the target disease. The growing efforts to discover hybrid drugs resulting from the combination of pharmacophoric moieties of different known lead compounds have brought a new hope for the treatment of multifactorial diseases in recent years. This editorial describes possible ways of exploring molecular hybridization strategies to plan new effective dual or symbiotic drug candidates.

Novel 6-methanesulfonamide-3,4-methylenedioxyphenyl- N-acylhydrazones: Orally effective anti-inflammatory drug candidates

We described herein the molecular design of novel in vivo anti-inflammatory 6-methanesulfonamide-3,4-methylenedioxyphenyl- N-acylhydrazone derivatives ( 1) planned by applying the molecular hybridization approach. This work also points out to the discovery of LASSBio-930 ( 1c) as a novel anti-inflammatory and anti-hyperalgesic prototype, which was able to reduce carrageenan-induced rat paw edema with an ED 50 of 97.8 μmol/kg, acting mainly as a non-selective COX inhibitor.

Synthesis and antimycobacterial evaluation of new trans-cinnamic acid hydrazide derivatives

In this work, we report the synthesis and the antimycobacterial evaluation of new trans-cinnamic acid derivatives of isonicotinic acid series ( 5) and benzoic acid series ( 6), designed by exploring the molecular hybridization approach between isoniazid ( 1) and trans-cinnamic acid derivative ( 3). The minimum inhibitory concentration (MIC) of the compounds 5a– d and 6c exhibited activity between 3.12 and 12.5 μg/mL and could be a good start point to find new lead compounds against multi-drug resistant tuberculosis.

Design and synthesis of 3,4-methylenedioxy-6-nitrophenoxyacetylhydrazone derivatives obtained from natural safrole: New lead-agents with analgesic and antipyretic properties

In this work, we reported the synthesis and evaluation of the analgesic, anti-inflammatory, and antipyretic properties of new 2-(6-nitro-benzo[1,3]dioxol-5-yloxy)-acetylhydrazone derivatives (3), designed exploring molecular hybridization and isosteric replacement approaches between nimesulide (1) and carbanalogue NAH series (2) developed at LASSBio. Target compounds were synthesized in very good yields exploiting abundant Brazilian natural product safrole (4) as starting material. The evaluation of the antinociceptive properties of this series led us to discover a new potent prototype of analgesic and antipyretic agent, that is, NAH derivative 3c, named LASSBio-891, which showed to be more potent than dipyrone used as standard.

Synthesis and Antitrypanosomal Profile of New Functionalized 1,3,4‐Thiadiazole‐2‐arylhydrazone Derivatives, Designed as Non‐mutagenic Megazol Analogues.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Rapid, species-specific detection of uropathogen 16S rDNA and rRNA at ambient temperature by dot-blot hybridization and an electrochemical sensor array

Development of rapid molecular approaches for pathogen detection is key to improving treatment of infectious diseases. For this study, the kinetics and temperature-dependence of DNA probe hybridization to uropathogen species-specific sequences were examined. A set of oligonucleotide probes were designed based on variable regions of the 16S gene of the Escherichia coli, Proteus mirabilis, Klebsiella oxytoca, and Pseudomonas aeruginosa. A universal bacterial probe and probes-specific for gram-positive and gram-negative organisms were also included. The oligonucleotide probes discriminated among 16S genes derived from 11 different species of uropathogenic bacteria applied to nylon membranes in a dot-blot format. Significant binding of oligonucleotide probes to target DNA and removal of nonspecific binding by membrane washing could both be achieved rapidly, requiring as little as 10 min. An oligonucleotide probe from the same species-specific region of the E. coli 16S gene was used as a capture probe in a novel electrochemical 16-sensor array based on microfabrication technology. Sequence-specific hybridization of target uropathogen 16S rDNA was detected through horseradish peroxidase acting as an electrochemical transducer via a second, detector probe. The sensor array demonstrated rapid, species-specific hybridization in a time course consistent with the rapid kinetics of the dot-blot hybridization studies. As in the dot-blot hybridization studies, species-specific detection of bacterial nucleic acids using the sensor array approach was demonstrated both at 65 °C and at room temperature. These results demonstrate that molecular hybridization approaches can be adapted to rapid, room temperature conditions ideal for an electrochemical sensor array platform.

Synthesis and antitrypanosomal profile of new functionalized 1,3,4-thiadiazole-2-arylhydrazone derivatives, designed as non-mutagenic megazol analogues

In this work we reported the synthesis and the trypanocidal profile of new 1,3,4-thiadiazole-2-arylhydrazone derivatives of nitroimidazole series ( 4) or phenyl series ( 5), designed by exploring the molecular hybridization approach between megazol ( 2) and guanyl hydrazone derivative ( 3). The evaluation of the activity against bloodstream trypomastigote forms of Trypanosoma cruzi forms lead us to identify a new potent trypamomicide prototype, that is, brazilizone A ( 4k), which present an IC 50/24 h = 5.3 μM.

New class of potent antinociceptive and antiplatelet 10H-phenothiazine-1-acylhydrazone derivatives

The synthesis and pharmacological evaluation of new 10 H -phenothiazine-1-acylhydrazone derivatives ( 6 ) is reported. In this work, we reported the synthesis and evaluation of the analgesic, antiinflammatory, and antiplatelet properties of new phenothiazine-attached acylhydrazone derivatives ( 6 ), designed exploring the molecular hybridization approach between antipsychotic chlorpromazine ( 4 ) and other heterocyclic derivatives ( 3 ) and ( 5 ) developed at LASSBio. Target compounds were synthesized in very good yields exploiting diphenylamine ( 7 ) as starting material, through regioselective functionalization of the C-1 position of 10 H -phenothiazine ring. The evaluation of platelet antiaggregating profile lead us to identify a new potent prototype of antiplatelet derivative, that is ( 6a ) (IC 50 =2.3 μM), which acts in arachidonic acid pathway probably by inhibition of platelet COX-1 enzyme. Additionally, the change of para -substituent group of acylhydrazone framework permitted us to identify hydrophilic carboxylate derivative ( 6g ) and hydrophobic bromo derivative ( 6b ) as two new leads of analgesics more active than dipyrone used as standard and with selective peripheral or central mechanism of action.

New class of potent antinociceptive and antiplatelet 10 H-phenothiazine-1-acylhydrazone derivatives

In this work, we reported the synthesis and evaluation of the analgesic, antiinflammatory, and antiplatelet properties of new phenothiazine-attached acylhydrazone derivatives ( 6), designed exploring the molecular hybridization approach between antipsychotic chlorpromazine ( 4) and other heterocyclic derivatives ( 3) and ( 5) developed at LASSBio. Target compounds were synthesized in very good yields exploiting diphenylamine ( 7) as starting material, through regioselective functionalization of the C-1 position of 10 H-phenothiazine ring. The evaluation of platelet antiaggregating profile lead us to identify a new potent prototype of antiplatelet derivative, that is ( 6a) (IC 50=2.3 μM), which acts in arachidonic acid pathway probably by inhibition of platelet COX-1 enzyme. Additionally, the change of para-substituent group of acylhydrazone framework permitted us to identify hydrophilic carboxylate derivative ( 6g) and hydrophobic bromo derivative ( 6b) as two new leads of analgesics more active than dipyrone used as standard and with selective peripheral or central mechanism of action.

RNA editing in wheat mitochondria proceeds by a deamination mechanism

Most if not all mitochondrial messenger RNAs from seed plants undergo a post-transcriptional modification (RNA editing) involving the conversion of some cytidine residues to uridine. Using a molecular hybridization approach, an in vitro RNA editing system, able to faithfully reproduce the in vivo observed C to U changes of subunit 9 ( atp9) of wheat mitochondrial ATP synthase mRNA, has been described [Araya et al. (1992) Proc. Natl. Acad. Sci. USA 89, 1040–1044]. In this work we extend these studies to better understand the biochemical mechanism of this process. RNA editing was analysed by P1 nuclease digestion of the reaction product followed by thin layer chromatography. Experiments performed with unedited [ 3H]RNA labelled on the base and with unedited [ 32P]RNA labelled at the α-phosphate of cytidine residues, indicate that plant mitochondrial RNA editing operates through a deamination mechanism.

Detection and mapping of homologous, repeated and amplified DNA sequences by DNA renaturation in agarose gels.

A new molecular hybridization approach to the analysis of complex genomes has been developed. Tracer and driver DNAs were digested with the same restriction enzyme(s), and tracer DNA was labeled with 32P using T4 DNA polymerase. Tracer DNA was mixed with an excess amount of driver, and the mixture was electrophoresed in an agarose gel. Following electrophoresis, DNA was alkali-denatured in situ and allowed to reanneal in the gel, so that tracer DNA fragments could hybridize to the driver only when homologous driver DNA sequences were present at the same place in the gel, i.e. within a restriction fragment of the same size. After reannealing, unhybridized single-stranded DNA was digested in situ with S1 nuclease. The hybridized tracer DNA was detected by autoradiography. The general applicability of this technique was demonstrated in the following experiments. The common EcoRI restriction fragments were identified in the genomes of E. coli and four other species of bacteria. Two of these fragments are conserved in all Enterobacteriaceae. In other experiments, repeated EcoRI fragments of eukaryotic DNA were visualized as bands of various intensity after reassociation of a total genomic restriction digest in the gel. The situation of gene amplification was modeled by the addition of varying amounts of lambda phage DNA to eukaryotic DNA prior to restriction enzyme digestion. Restriction fragments of lambda DNA were detectable at a ratio of 15 copies per chicken genome and 30 copies per human genome. This approach was used to detect amplified DNA fragments in methotrexate (MTX)-resistant mouse cells and to identify commonly amplified fragments in two independently derived MTX-resistant lines.

A Molecular Hybridization Approach for the Determination of the Immunoglobulin V‐Gene Pool Size

A Molecular Hybridization Approach for the Determination of the Immunoglobulin V‐Gene Pool Size