Synthesis of New Hybrid Derivatives from Metronidazole and Eugenol Analogues as Trypanocidal Agents

Background: The search for new drug compounds is always challenging and there are several different strategies that involve the most varied and creative approaches in medicinal chemistry. One of them is the technique of molecular hybridisation: forming a hybrid compound from two or more pharmacophoric subunits. These hybrids may maintain the characteristics of the original compound and preferably show improvements to its pharmacological action, with reduced side effects and lower toxicity when compared to the original components. This study specifically focuses on synthesising hybrid molecules which demonstrate trypanocidal activity against the epimastigote and trypomastigote forms of Trypanosoma cruzi. Methods: In this context, this study centres on the synthesis of a novel structural scaffold via molecular hybridisation; by using a triazole species to link a metronidazole unit to a eugenol analogue unit, the objective being to combine their therapeutic properties into a new molecular structure. The resulting hybrid molecules were evaluated against T. cruzi which is responsible for high incidences of trypanosomiasis in tropical countries such as Brazil. Results: The results of this study showed an improvement in the anti-parasitic activity of the hybrid compounds with the best result coming from hybrid compounds [8] and [9], which present an activity similar to the control drug benznidazole. The new compounds, utilising a triazole species as a coupling connector, demonstrated promising results and has highlighted the path for planning similar structural patterns to investigate new compounds. Conclusions: In summary, we can conclude that the synthesised hybrid compounds demonstrate that using a triazole to link metronidazole with natural phenols, produces hybrid molecules that are promising as a new class of compounds of therapeutic interest for further investigation.

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Dual-acting of Hybrid Compounds - A New Dawn in the Discovery of Multi-target Drugs: Lead Generation Approaches

Current Topics in Medicinal Chemistry ◽

10.2174/1568026616666160927151144 ◽

2017 ◽

Vol 17 (9) ◽

pp. 1096-1114 ◽

Cited By ~ 11

Author(s):

Azizeh Abdolmaleki ◽

Jahan B. Ghasemi

Keyword(s):

Drug Discovery ◽

Structural Biology ◽

Design And Synthesis ◽

Hybrid Compounds ◽

Target Drug ◽

Hybrid Molecules ◽

Lead Generation ◽

Multiple Ligands ◽

New Compounds ◽

Screening Approaches

Finding high quality beginning compounds is a critical job at the start of the lead generation stage for multi-target drug discovery (MTDD). Designing hybrid compounds as selective multitarget chemical entity is a challenge, opportunity, and new idea to better act against specific multiple targets. One hybrid molecule is formed by two (or more) pharmacophore group’s participation. So, these new compounds often exhibit two or more activities going about as multi-target drugs (mtdrugs) and may have superior safety or efficacy. Application of integrating a range of information and sophisticated new in silico, bioinformatics, structural biology, pharmacogenomics methods may be useful to discover/design, and synthesis of the new hybrid molecules. In this regard, many rational and screening approaches have followed by medicinal chemists for the lead generation in MTDD. Here, we review some popular lead generation approaches that have been used for designing multiple ligands (DMLs). This paper focuses on dual- acting chemical entities that incorporate a part of two drugs or bioactive compounds to compose hybrid molecules. Also, it presents some of key concepts and limitations/strengths of lead generation methods by comparing combination framework method with screening approaches. Besides, a number of examples to represent applications of hybrid molecules in the drug discovery are included.

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Recent Advances in 1,3,5-Triazine Derivatives as Antibacterial Agents

Mini-Reviews in Organic Chemistry ◽

10.2174/1570193x17666200129094032 ◽

2020 ◽

Vol 17 (8) ◽

pp. 991-1041

Author(s):

Divya Utreja ◽

Jagdish Kaur ◽

Komalpreet Kaur ◽

Palak Jain

Keyword(s):

Antibacterial Activity ◽

Heterocyclic Compounds ◽

Antibacterial Agents ◽

Rapid Development ◽

Pharmacological Action ◽

Biological Properties ◽

Vast Array ◽

Bacterial Diseases ◽

New Class ◽

Triazine Derivatives

Triazine, one of the nitrogen containing heterocyclic compounds has attracted the considerable interest of researchers due to the vast array of biological properties such as anti-viral, antitumor, anti-convulsant, analgesic, antioxidant, anti-depressant, herbicidal, insecticidal, fungicidal, antibacterial and anti-inflammatory activities offered by it. Various antibacterial agents have been synthesized by researchers to curb bacterial diseases but due to rapid development in drug resistance, tolerance and side effects, there had always been a need for the synthesis of a new class of antibacterial agents that would exhibit improved pharmacological action. Therefore, this review mainly focuses on the various methods for the synthesis of triazine derivatives and their antibacterial activity.

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Thiazole Analogues of the Marine Alkaloid Nortopsentin as Inhibitors of Bacterial Biofilm Formation

Molecules ◽

10.3390/molecules26010081 ◽

2020 ◽

Vol 26 (1) ◽

pp. 81

Author(s):

Anna Carbone ◽

Stella Cascioferro ◽

Barbara Parrino ◽

Daniela Carbone ◽

Camilla Pecoraro ◽

...

Keyword(s):

Biofilm Formation ◽

Bacterial Biofilm ◽

Thiazole Derivatives ◽

Gram Positive ◽

Lead Compounds ◽

New Class ◽

Marked Selectivity ◽

Global Threat ◽

New Compounds ◽

Reference Strains

Anti-virulence strategy is currently considered a promising approach to overcome the global threat of the antibiotic resistance. Among different bacterial virulence factors, the biofilm formation is recognized as one of the most relevant. Considering the high and growing percentage of multi-drug resistant infections that are biofilm-mediated, new therapeutic agents capable of counteracting the formation of biofilms are urgently required. In this scenario, a new series of 18 thiazole derivatives was efficiently synthesized and evaluated for its ability to inhibit biofilm formation against the Gram-positive bacterial reference strains Staphylococcus aureus ATCC 25923 and S. aureus ATCC 6538 and the Gram-negative strain Pseudomonas aeruginosa ATCC 15442. Most of the new compounds showed a marked selectivity against the Gram-positive strains. Remarkably, five compounds exhibited BIC50 values against S. aureus ATCC 25923 ranging from 1.0 to 9.1 µM. The new compounds, affecting the biofilm formation without any interference on microbial growth, can be considered promising lead compounds for the development of a new class of anti-virulence agents.

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Zhaoshumycins A and B, Two Unprecedented Antimycin-Type Depsipeptides Produced by the Marine-Derived Streptomyces sp. ITBB-ZKa6

Marine Drugs ◽

10.3390/md19110624 ◽

2021 ◽

Vol 19 (11) ◽

pp. 624

Author(s):

Zhikai Guo ◽

Shiying Ma ◽

Salman Khan ◽

Hongjie Zhu ◽

Bo Zhang ◽

...

Keyword(s):

Toxicity Tests ◽

Marine Actinomycetes ◽

Human Breast ◽

Mcf7 Cells ◽

Imino Group ◽

Streptomyces Sp ◽

New Class ◽

Relationship Analysis ◽

Disubstituted Benzene ◽

New Compounds

Marine actinomycetes are prolific chemical sources of complex and novel natural products, providing an excellent chance for new drug discovery. The chemical investigation of the marine-derived Streptomyces sp. ITBB-ZKa6, from Zhaoshu island, Hainan, led to the discovery of two unique antimycin-type depsipeptides, zhaoshumycins A (1) and B (2), along with the isolation of the four known neoantimycins A (3), F (4), D (5), and E (6). The structures of the new compounds 1 and 2 were elucidated on the basis of the analysis of diverse spectroscopic data and biogenetic consideration. Zhaoshumycins A (1) and B (2) represent a new class of depsipeptides, featuring two neoantimycin monomers (only neoantimycin D or neoantimycins D and E) linked to a 1,4-disubstituted benzene ring via an imino group. Initial toxicity tests of 1–6 in MCF7 human breast cancer cells revealed that compounds 5 and 6 possess weak cytotoxic activity. Further structure–activity relationship analysis suggested the importance of the NH2 group at C-34 in 5 and 6 for cytotoxicity in MCF7 cells.

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Crystal structure, Hirshfeld surface analysis and contact enrichment ratios of 1-(2,7-dimethylimidazo[1,2-a]pyridin-3-yl)-2-(1,3-dithiolan-2-ylidene)ethanone monohydrate

Acta Crystallographica Section E Crystallographic Communications ◽

10.1107/s2056989019015755 ◽

2019 ◽

Vol 75 (12) ◽

pp. 1934-1939 ◽

Cited By ~ 1

Author(s):

Yvon Bibila Mayaya Bisseyou ◽

Mahama Ouattara ◽

Pénétjiligué Adama Soro ◽

R. C. A. Yao-Kakou ◽

Abodou Jules Tenon

Keyword(s):

Hydrogen Bonds ◽

Surface Analysis ◽

Crystal Packing ◽

Hirshfeld Surface ◽

Hirshfeld Surface Analysis ◽

Enrichment Ratio ◽

Water Molecules ◽

Hybrid Compound ◽

Compound C ◽

Hybrid Molecules

In the title hydrated hybrid compound C14H14N2OS2·H2O, the planar imidazo[1,2-a]pyridine ring system is linked to the 1,3-dithiolane moiety by an enone bridge. The atoms of the C—C bond in the 1,3-dithiolane ring are disordered over two positions with occupancies of 0.579 (14) and 0.421 (14) and both disordered rings adopt a half-chair conformation. The oxygen atom of the enone bridge is involved in a weak intramolecular C—H...O hydrogen bond, which generates an S(6) graph-set motif. In the crystal, the hybrid molecules are associated in R 2 2(14) dimeric units by weak C—H...O interactions. O—H...O hydrogen bonds link the water molecules, forming infinite self-assembled chains along the b-axis direction to which the dimers are connected via O—H...N hydrogen bonding. Analysis of intermolecular contacts using Hirshfeld surface analysis and contact enrichment ratio descriptors indicate that hydrogen bonds induced by water molecules are the main driving force in the crystal packing formation.

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New N-(oxazolylmethyl)-thiazolidinedione Active against Candida albicans Biofilm: Potential Als Proteins Inhibitors

Molecules ◽

10.3390/molecules23102522 ◽

2018 ◽

Vol 23 (10) ◽

pp. 2522 ◽

Cited By ~ 9

Author(s):

Gabriel Marc ◽

Cătălin Araniciu ◽

Smaranda Oniga ◽

Laurian Vlase ◽

Adrian Pîrnău ◽

...

Keyword(s):

Biofilm Formation ◽

Infection Prevention ◽

Public Health Problem ◽

Opportunistic Pathogen ◽

Surface Proteins ◽

Form Complex ◽

New Approach ◽

New Class ◽

New Compounds

C. albicans is the most frequently occurring fungal pathogen, and is becoming an increasing public health problem, especially in the context of increased microbial resistance. This opportunistic pathogen is characterized by a versatility explained mainly by its ability to form complex biofilm structures that lead to enhanced virulence and antibiotic resistance. In this context, a review of the known C. albicans biofilm formation inhibitors were performed and a new N-(oxazolylmethyl)-thiazolidinedione scaffold was constructed. 16 new compounds were synthesized and characterized in order to confirm their proposed structures. A general antimicrobial screening against Gram-positive and Gram-negative bacteria, as well as fungi, was performed and revealed that the compounds do not have direct antimicrobial activity. The anti-biofilm activity evaluation confirmed the compounds act as selective inhibitors of C. albicans biofilm formation. In an effort to substantiate this biologic profile, we used in silico investigations which suggest that the compounds could act by binding, and thus obstructing the functions of, the C. albicans Als surface proteins, especially Als1, Als3, Als5 and Als6. Considering the well documented role of Als1 and Als3 in biofilm formation, our new class of compounds that target these proteins could represent a new approach in C. albicans infection prevention and management.

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The Chemical Bonding of Organic-Inorganic in Hybrid Compounds

MRS Proceedings ◽

10.1557/proc-848-ff9.31 ◽

2004 ◽

Vol 848 ◽

Author(s):

Yadong Dai ◽

Liling Guo ◽

Minjie Hu ◽

Kunyu Shi ◽

Xinmin Min ◽

...

Keyword(s):

Electronic Structure ◽

Energy Density ◽

Chemical Bonding ◽

Fermi Energy ◽

Energy Band Structure ◽

Bond Orders ◽

Density Of State ◽

Hybrid Compound ◽

Hybrid Compounds ◽

Calculation Results

ABSTRACTAs has been discussed, research on the electronic structure between organic and inorganic atoms in hybrid compounds has become important. In our study, DV—Xα method was employed to calculate the electronic structure of the hybrid compound. The information obtained from the calculation included orbit charge, bonding order, Fermi energy, density of the state, etc. The influence of organic and inorganic parts on the energy band structure of the hybrid compound was discussed based on the calculation results of Fermi energy and density of state. The chemical bonding between organic and inorganic parts in the hybrid compound was also analyzed in detail according to the orbital charges and bond orders.

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Synthesis, Antimicrobial and Antitumor Evaluations of a New Class of Thiazoles Substituted on the Chromene Scaffold

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557519666190722123422 ◽

2019 ◽

Vol 19 (20) ◽

pp. 1717-1725 ◽

Cited By ~ 4

Author(s):

Dina H. Elnaggar ◽

Naglaa A. Abdel Hafez ◽

Huda R.M. Rashdan ◽

Nayera A.M. Abdelwahed ◽

Hanem M. Awad ◽

...

Keyword(s):

Human Cell Line ◽

Diffusion Method ◽

Cytotoxic Activities ◽

Antitumor Activities ◽

Reference Drug ◽

New Class ◽

Excellent Activity ◽

Thiosemicarbazide Derivatives ◽

New Compounds

Background & Objective: A new series of thiazoles substituted on the chromene scaffold were prepared by facial approaches starting from (E)-1-(2,3-Dihydrochromen-4-ylidene)thiosemicarbazide derivatives (2a,b). The thiosemicarbazides (2a,b) were reacted with a series of α-halo carbonyl compounds to give the corresponding rhodanine analogues and reacted also with C-acetyl-or Cethoxy- N-hydrazonoyl chlorides to afford the corresponding tri- and tetra-substituted hybrid hydrazinyl thiazole substituted chromenes. Methods: The newly synthesized compounds were screened for their in vitro antimicrobial and antitumor activities by agar diffusion method and MTT assay, respectively. Results: The results of the antimicrobial activity revealed that some of the new compounds exhibited excellent activity against pathogenic microorganism; Candida albicans compared with Ciprofloxacin and nystatin, as the reference drugs. : All of the tested compounds exhibited significant cytotoxic activities comparable to that of the reference drug; Doxorubicin® (on HCT116 (colorectal carcinoma human cell line).

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Synthesis and Anti Cervical Cancer Activity of Novel 5H-Thiochromeno [4,3-d]pyrimidines

Letters in Organic Chemistry ◽

10.2174/1570178616666190705152116 ◽

2020 ◽

Vol 17 (4) ◽

pp. 294-302

Author(s):

Dhananjay Pandya ◽

Yogesh Naliapara

Keyword(s):

Cervical Cancer ◽

13C Nmr ◽

Positive Control ◽

Pyrimidine Derivatives ◽

Control Drug ◽

Cervical Cell ◽

Cell Line Hela ◽

New Compounds ◽

Line Hela ◽

Cancer Activity

A series of novel 5H-Thiochromeno[4,3-d]pyrimidine derivatives were synthesized, purified and characterized by different spectroscopy techniques such as 1H NMR, 13C NMR, Mass and Elemental Analysis. The new compounds were evaluated for their anti-cervical cancer activity on Human Cervical Cell Line HeLa. They were found to be potent anti-cervical cancer agents with GI50 values less than 10 μg/mL with respect to positive control drug Adriamycin.

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Progress and development of C-3, C-6, and N-9 position substituted carbazole integrated molecular hybrid molecules as potential anticancer agents

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557521666210521221808 ◽

2021 ◽

Vol 21 ◽

Author(s):

Pratibha Mehta Luthra ◽

Nitin Kumar

Keyword(s):

Biological Activity ◽

Side Effects ◽

Anticancer Agents ◽

Biological Activities ◽

Structural Motif ◽

Hybrid Compounds ◽

Hybrid Molecules ◽

Anticancer Mechanism ◽

Pharmacologically Active

Abstract: The carbazole skeleton, a key structural motif occurring naturally or chemically synthesized, have shown various biological activities. Molecular hybridization based on the combination of two or more bioactive pharmacophores has been an important tool to convert the potent structural leads to form new hybrid compounds with improved biological activity. In recent years, modifications/substitutions of the carbazole motif at C3, C6, N9 position have been carried to develop novel carbazole based potential anticancer agents in the cancer therapy. In the last fifteen years, several compounds based on carbazole core integrated to pharmacologically active molecular hybrid having active pharmacophore such as 1,3,4-thiadiazole, thiazole, guanidine, sulfonamides, glyoxamides, imidazole, phenanthrene, rhodamine, chalcones, imidazopyridine, platinum 2H-chromen-2-one, hydrazones, piperazine, Isoxazole-thiadiazole, pyrazole etc. have been synthesized showing anticancer profile at sub-micromolar to nano-molar concentrations. We have thoroughly reviewed the design, progress and development of C-3, C-6, and N-9 position substituted carbazole derivatives integrated with various medicinally active pharmacophore as potential anticancer agents evaluated against various cancer cell lines. Additionally, the anticancer mechanism and in vivo activity of the reported compounds have been discussed. This study will support in designing of a new pharmacophore that can be linked to carbazole motif for development for new, potent and target specific anticancer drugs with improved pharmacokinetics and minimal side effects.

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