Series Of New Heterocyclic Compounds Research Articles

Synthesis, characterization, and biological activities of substituted pyridine-based azomethine scaffolds

The present research work describes the synthesis of a new series of heterocyclic compounds, namely, pyridine-based azomethine scaffolds. A total of eight derivatives were prepared, purified, and characterized by analytical methods such as 1H NMR, 13C NMR, and IR spectroscopic techniques. All compounds were used to investigate their alpha-amylase inhibition activity. We have also reported antimicrobial activity using a micro broth dilution assay, with microbial strains Pseudomonas aeruginosa (NCIM 5031), Escherichia coli (NCIM 2065), Bacillus subtilis (NCIM 2699), Aspergillus niger (NCIM 620), Aspergillus fumigatus (NCIM 902), and Aspergillus flavus (NCIM 549). Finally, we report the antioxidant activity of the synthesized derivatives using a DPPH free radical assay.

Design and synthesis of 4-nitroimidazole derivatives with potential antitubercular activity

Objectives. To develop the procedures for synthesis of hybrid molecules with potential anti-tubercular activity containing heterocyclic cores of 4-nitroimidazole and 1,3,4-thiadiazole within the framework of a double-drug strategy and predict bioactivity of target structures and drug-likeness physicochemical parameters.Methods. Target compounds were prepared by classical organic synthesis methods. The structure of the obtained compounds was characterized by melting points, 1H and 13C nuclear magnetic resonance spectroscopy, and high-resolution mass spectrometry. The calculation of the physicochemical parameters of the target compounds and prediction of their biological activity were carried out using publicly available software for cheminformatics and molecular modeling.Results. Acylation of propargylamine with (2-methyl-4-nitro-1H-imidazol-1-yl)acetic and (4-nitro-1H-imidazol-1-yl)acetic acids provided the corresponding amides, which were cyclized with seven different benzylamines in the presence of zinc triflate. In this way, seven new compounds were obtained at 20–30% yields. Ten arylamines were acylated with chloroacetyl chloride and the resulting chloroacetamides were converted into corresponding thio-oxahydrazides by the Willgerodt–Kindler reaction. Following acylation by (4-nitro-1H-imidazol-1-yl)acetic acid, these compounds were converted into the target hybrid imidazolyl-thiadiazoles at 29–54% yields.Conclusions. Two series of new heterocyclic compounds with a hybrid structure including a privileged 4-nitroimidazole moiety linked to the second heterocycle, imidazole, or thiadiazole, were obtained. The synthesis and characterization of compounds by physicochemical methods was aimed at searching for anti-tuberculosis activity. The bioactivity potential of target compounds was demonstrated by preliminary calculations performed using public prognostic programs.

Optical and Photovoltaic Properties of New Synthesized Quinoxaline-2,3 Dione Derivatives for Efficient Dye Sensitized Solar Cell Application

In this study, the synthesis of 4 new heterocyclic compounds derived from quinoxalinedione were presented, which have been characterized by 1H and 13C NMR spectroscopy. The solar cells’ photovoltaic properties based on these novels organic compounds donor-π-acceptor dyes were studied. Density functional theory DFT method is realized to optimize electronic parameters, optical and photovoltaic properties for some new 8-hydroxyquinoline derivatives based on quinoxaline-2,3-dione. The results have shown that time-dependent DFT (TDDFT) investigations with polarizable continuum model PCM were significantly able to foretell the excitation energy and the spectroscopy of the molecule. The highest occupied molecular orbital HOMO and the lowest unoccupied molecular orbital LUMO energy levels of these molecules can ensure a positive impact on the dye regeneration and electron injection process. Injection driving force ΔGinject, light-harvesting efficiency LHE, reorganization energy λtotal and open-circuit photovoltage Voc provide qualitative predictions on these dyes’ reactivity. Among these 4 molecules, the compounds which can be used as organic solar cells have determined.
 HIGHLIGHTS
 
 We presented the synthesis and the characterization of a new series of heterocyclic compounds obtained by association of 8-hydroxyquinoline with quinoxalindione derivatives.
 The synthesis of this series of compounds was carried out by simple conditions but with good yields and the characterization data shows that there is good consistency between the spectroscopic data and the proposed structures
 These new compounds were obtained according to simple procedures with good yields and they have been the subject of a theoretical study
 This investigated process can be employed to predict the optical and photovoltaics properties on the other compounds and polymers, and it encourages to synthesis the novel organic solar cell materials
 
 GRAPHICAL ABSTRACT

Green chemistry as efficient approache to achieve a new series of heterocyclic compounds

Solid phase one-pot Multicomponent reaction was used widely to achieved a board spectrum of heterocyclic compounds due to it’s supreme properties starting from four component mixture of piperonal binzil, p-phenylene diamine and ammonium acetate which was reacted directly through grinding then microwave irradiation at (270 watt) for (8 min) in a cidic media to afford 1-N(p-aminophenyl)-2-(piperonyl-5-yl)-5-hydroxy-4, 5-diphenyl-2H-imidazole (1) which then converted to its N'-aroyl derivatives (2-4) through it’s reaction with substituted benzoyl chloride in basic media terminated by direct reaction with acetic anhydride to obtained N'-acetyl-N'-aroyl derivative (5-7) followed by inter cyclization reaction with hydrazine hydrate (99%) to achieve 1,2,4-trizole derivatives (8-10) in basic media. The assigned structure of the prepared compounds were corroborated by the available physical and spectral methods.

Divergent Annulation of Spiro[indoline‐pyran] and Fused (Epoxyetheno)indeno‐Furan from 1,2‐Diketone and 1‐Cyanoketone

AbstractA simple and efficient method for the construction of spiro[indoline‐pyran] and fused (epoxyetheno)indeno[1,2‐b]furan compounds from 1‐cyanoketones and 1,2‐diketone has been developed. The synthesis proceeded via the Knoevenagel and Michael adduct through intramolecular/Paal‐Knorr cyclization under similar reaction condition. The less commonly used 1‐cyanoketones and active carbonyl compounds served as the indole containing pyran and bicyclic furan source for the preparation of a new series of heterocyclic compounds. This heterocyclic structure allows one and more than one tetra‐substituted carbon center and sequential hexa‐ and penta‐cyclic core under very mild conditions and shows excellent chemo and regioselectivity. In addition, the synthesis of spiro[indoline‐pyran] and (epoxyetheno)indeno[1,2‐b]furan was demonstrated in a gram scale.

Pyrazoles and Fused Pyrimidines: Synthesis, Structure Elucidation, Antitubercular Activity and Molecular Docking Study.

Synthesis of new heterocyclic drugs in short reaction time with sufficient quantity is considered as a target for several pharmaceutical scientists. Thus, organic reactions proceeded on the surface of nano-sized catalysts to speed up the stimulation process. <p Objective: We aimed in this research to synthesize a new series of heterocyclic compounds carrying pyrazole moiety in the presence of ZnO nano-catalyst to investigate their anti-tubercular activity. ZnO(NPs) were used in the synthesis of novel series of thienylpyrazolopyrimidines bearing arylazo group by the reaction of thiophene-enaminone and the amino-arylazopyrazoles in excellent yield. On the other hand, another series of theinyl-pyrazoles was synthesized through the reaction of the same enaminone with hydrazonoyl chlorides, but the usage of ZnO(NPs) failed in such reactions. The proposed structures of the products and the mechanistic pathways of the reactions were assured based on the spectral data and chemical evidences. Thienylpyrazole derivatives were assessed for their activity as Mycobacterium tuberculosis inhibitor and their results revealed that two thienylpyrazole derivatives 24d & 24f showed the most significant anti-mycobacterial activity with MIC values 0.70 & 1.29 μM/mL, respectively comparing with the MIC value = 0.60 μM/mL of the standard drug Rifampicin. Furthermore, the most active thienylpyrazole derivatives were investigated for their cytotoxic impact versus normal cells WI-38 (Normal human Lung fibroblast cells) using MTT assay. These thienylpyrazole derivatives exhibited good selective index profile. Moreover, 1,3,4-trisubstituted pyrazole analogs showed good interaction with the active site of enoyl-acyl carrier protein reductase (Mt InhA) through molecular docking studies. We synthesized a new series of heterocyclic compounds carrying pyrazole moiety in the presence of ZnO nano-catalyst as anti-tubercular agents.

Synthesis of substituted pyridine based sulphonamides as an antidiabetic agent

This research work describes the synthesis of a new series of heterocyclic compounds, namely sulfonamide derivatives. Sulfonamides are a diverse class of organic compounds having significant and potent biological activities. Diverse synthetic methods have been engaged to build up its various derivatives for different biological functions. In this study, the production of novel pyridine-based heterocyclic compounds having sulfonamide moieties has been elaborated. The obtained sulfonamide-based pyridine scaffold was used to investigate their alpha-amylase inhibition activity. The structures of freshly prepared compounds were described using 1H NMR, 13C NMR, and IR spectroscopic techniques. The molecular docking of sulfonamides performed against porcine pancreatic alpha-amylase using PDB file 1LP was used for generation of grid. All the new synthesized compounds were shown notable anti-diabetic activity.

Synthesis and antimicrobial activity evaluation of some new 7-substituted quinolin-8-ol derivatives: POM analyses, docking, and identification of antibacterial pharmacophore sites

Abstract Eight new 7-substituted quinolin-8-ol derivatives were synthesized moderate to good yields through quinolin-8-ol, and secondary amines as the starting reagents. The structures of the prepared compounds have been characterized by elemental analysis and 1H/13C NMR. The antimicrobial activity of this new series of heterocyclic compounds has been achieved in vitro against some bacterial strains by means of the disk method, and most of the tested compounds have shown comparable or greater antibacterial activity than nitroxoline (standard antibiotic). It was very motivating to observe that POM (Petra/Osiris/Molinspiration) bioinformatic analyses of compound 5 exhibited better antibacterial activity (MIC = 10 μg/mL against B. subtilis bacteria), and higher drug score (DS = 0.57) compared with Nitroxoline (DS = 0.47; MIC = 20 μg/mL). Molecular docking investigations were also conducted to investigate the binding affinities as well as interactions of some compounds with the target proteins.

Synthesis, Biological Evaluation and Docking Studies of 1,3,4-Oxadiazole Fused Benzothiazole Derivatives for Anticancer Drugs

Background: Hetero atom containing compounds are well studied class of organic compounds exhibits variety of properties and applications. Design and synthesis of new heterocyclic compounds are always of great interest in synthetic and medicinal organic chemistry. Benzothiazole or 2-aminobenzothiazole scaffold based derivatives were reported to display a wide range of biological activities including anticancer, anti-tubercular, antiviral, fungicidal, etc. On the other hand, 1,3,4-oxadiazoles were permit to increase their biological activities due to H-bonding with receptors. These derivatives possess diverse biological activities which include anticancer, antiviral, antifungal, antibacterial and antidepressant etc. Due to interesting biological activity information of about these hetero cyclic moieties, benzothiazole/2-aminobenzothiazole and 1,3,4-oxadiazoles moieties, we chose to design a new series of heterocyclic compounds by mimicking these two types of scaffolds in a single molecule for our study. Methods: The 1,3,4-oxadiazole linked benzothiazole derivatives were synthesized by condensation of, 2-(4-(5-(benzo[d]thiazol-2-yl)-1,3,4-thiadiazol-2-yl)-2,6-dimethoxyphenoxy)acetohydrazide and POCl3 under reflux conditions. All these ten compounds structures were confirmed by spectral data 1H &amp; 13C NMR, Mass, CHN analysis etc. Further, these compounds were evaluated for their anticancer activity against four human cancer cell lines, A549, MCF7, A375 and HT-29 in comparison to CA4 as a reference drug. We also carried out docking studies of these compounds in the Colchicines binding site of Tubulin (PDB_ID: 1SA0) using Glide docking tool indicated that the ligands show good interactions with active site residues. Results: A new series of 1,3,4-oxadiazole fused benzothiazole derivatives were synthesized successfully in totally six steps starting with 4-hydroxy-3,5-dimethoxybenzoyl chloride. All these newly synthesized compounds structures were confirmed by spectral studies and elemental analysis. As we designed for anticancer activity, they were assessed for their anticancer activity against four human cancer cell lines in comparison to a reference drug CA4. As expected, all the ten compounds exhibited anticancer activities against four cancer cell lines with half maximal inhibitory concentration (IC50) values ranging from 0.01 &amp;#181;M to 12.3 &amp;#181;M. The docking studies indicated all the compounds exhibited good binding energies with the receptor. Conclusion: In this study we designed a new series heterocyclic compounds by mimicking two types of scaffolds benzothiazole/2-aminobenzothiazole and 1,3,4-oxadiazoles moieties in a single molecule based on their biological activity in the literature. They were synthesized successfully and molecular structures were confirmed by spectral studies. As expected, all the compounds exhibited anticancer activities against four cancer cell lines. This study can provide a roadmap for design and synthesis of new drug molecules for antitumor and anticancer activity.

Novel synthesis, ring transformation and anticancer activity of 1,3-thiazine, pyrimidine and triazolo[1,5-a]pyrimidine derivatives

Synthesis, heterocyclization and anticancer activity of a new series of heterocyclic compounds are described. Aminothiazine 1 was obtained from the base induced condensation of thiourea, benzaldehyde and ethyl cyanoacetate. The synthesis of N-phenyl amino pyrimidine derivative 2 was obtained as a result of reaction of aniline with compound 1. Compound 2 underwent ring opening and recyclization upon reaction with HCl or H2O2/ NaOH to afford the acid derivative 3 or oxazine 4, respectively. Thiazine 1 undergoes ring transformation upon the effect of NH2OH.HCl to produce pyrimidine derivative 5. Heterocyclization of compound 1 with thiosemicarbazide followed by oxidation with I2/AcOH afforded triazolopyrimidine 6 and 7, respectively. Alkylation of compound 1 was promoted by reaction of 1 with ethyl iodide to give alkylated thiazine 8 which in turn undergo ring transformation when subjected to reaction with hydrazine hydrate to give pyrazole derivative 9. Refluxing of amino-1,3-thiazine derivative 1 with ethyl bromoacetate in the presence of Et3N produce the alkylated pyrimidine product 10. Hydrazonolysis of 1,3-thiazine 1 with hydrazine or phenyhydrazine gave pyrimidine derivatives 11a,b, respectively. Compound 11b was cyclized with carbon disulfide or formaldehyde to produce triazolopyrimidines 12 and 13, respectively. Some of the new compounds were screened for anticancer activity and significant results were found for some compounds. KEY WORDS: 1,3-Thiazine, Pyrimidine, Triazole, Pyrazole, Anticancer activity Bull. Chem. Soc. Ethiop. 2018, 32(3), 513-522.DOI: https://dx.doi.org/10.4314/bcse.v32i3.10

Synthesis and Analgesic Activity of 4,7-Dimethyl-3,4,4a,5,8,8a-Hexahydro-2-Chromen-4,8-Diols Containing Alkyl-Substituted Aromatic Moieties

A series of new heterocyclic compounds with the hexahydro-2H-chromene skeleton were prepared by reacting the monoterpenoid para-mentha-1,8-diene-5,6-diol with 4-alkyl-substituted aromatic aldehydes. Adding small alkyl substituents (methyl and ethyl) to the aldehyde aromatic ring increased the yields of hexahydrochromenes as compared with the analogous reaction with benzaldehyde. However, adding a branched substituent (isopropyl) and longer butyl and octyl moieties reduced the yields of the target compounds. The stereoselectivity of the reaction changed as the alkyl substituent lengthened. The analgesic activity of the obtained products was studied.

Design and Synthesis of Novel Oxadiazole and Diphenyl Ether Hydrazone Derivatives of Coumarin as Potential Antibacterial Agents

Background: Triazole based drugs are widely used in cancer patients for the treatment of life-threatening invasive fungal infections. A recent report on the usefulness of 1,2, 3- triazole scaffold for the inhibition of tyrosine kinases stimulated our curiosity to design new molecules based on this moiety. Methods: A series of new heterocyclic compounds containing 1,2,3 triazole moiety tethered to substituted vanillin or isovanillin were synthesized and analysed for their anticancer activity. The cyclopen-tyl/cyclohexyl ethers derived from vanillin and isovanillin were subsequently treated with MeMgI to give the carbinols. Reaction of these carbinols with TMSN 3 and ZrCl 4 as Lewis acid gave the desired azides. Click chemistry on azides with diverse acetylenes furnished the triazoles. The new triazole hybribs were screened o against 60 human cancer cell lines at a 10μM dose for their potential anticancer activity. Results: The two active compounds (8a, 10a) showed strong inhibitory effect against different cell lines, with highest inhibition against breast cancer panel. To elucidate the underlying molecular mechanisms, these compounds were examined for their clonogenic potential and anchorage-independent growth of estrogen receptor positive (MCF7 and T47D) and estrogen receptor negative (MDA-MB-231 and MDA-MB-468) breast cancer cells and investigated for induction apoptotic pathways. Conclusion: The outcomes from the current study will add much to the existing knowledge of the breast cancer research. This provides a rewarding conclusion and opens the way for future researchers to design and synthesize the novel active compounds against breast cancer.

Synthesis and Biological Evaluation of Triazole-Vanillin Molecular Hybrids as Anti-Cancer Agents

Background: Triazole based drugs are widely used in cancer patients for the treatment of life-threatening invasive fungal infections. A recent report on the usefulness of 1,2, 3- triazole scaffold for the inhibition of tyrosine kinases stimulated our curiosity to design new molecules based on this moiety. Methods: A series of new heterocyclic compounds containing 1,2,3 triazole moiety tethered to substituted vanillin or isovanillin were synthesized and analysed for their anticancer activity. The cyclopen-tyl/cyclohexyl ethers derived from vanillin and isovanillin were subsequently treated with MeMgI to give the carbinols. Reaction of these carbinols with TMSN 3 and ZrCl 4 as Lewis acid gave the desired azides. Click chemistry on azides with diverse acetylenes furnished the triazoles. The new triazole hybribs were screened o against 60 human cancer cell lines at a 10μM dose for their potential anticancer activity. Results: The two active compounds (8a, 10a) showed strong inhibitory effect against different cell lines, with highest inhibition against breast cancer panel. To elucidate the underlying molecular mechanisms, these compounds were examined for their clonogenic potential and anchorage-independent growth of estrogen receptor positive (MCF7 and T47D) and estrogen receptor negative (MDA-MB-231 and MDA-MB-468) breast cancer cells and investigated for induction apoptotic pathways. Conclusion: The outcomes from the current study will add much to the existing knowledge of the breast cancer research. This provides a rewarding conclusion and opens the way for future researchers to design and synthesize the novel active compounds against breast cancer.

Microwave‐Assisted Construction of Pyrrolopyridinone Ring Systems by Using an Ugi/Indole Cyclization Reaction

A series of pyrrolopyridinones were prepared by using N‐Boc‐pyrrole‐2‐carbaldehyde as a starting material in an Ugi reaction followed by an acid‐mediated indole cyclization to result in the formation of a new C–C bond. Changes to the other starting materials in this Ugi/indole cyclization reaction sequence extended the scope of this method to include a nucleophilic substitution reaction and an Ugi/deprotection/cyclization (UDC) strategy, which provided access to two new series of heterocyclic compounds. This method represents a facile and efficient one‐pot procedure for the preparation of pyrrolopyridinones under acidic conditions.

ChemInform Abstract: Synthesis of 5‐Cyano‐2‐carbethoxythieno[2,3‐b]thiophenyl‐3,4‐diisothiocyanates and Its Utility in Heterocyclic Synthesis under Phase Transfer Catalytic Technique.

Regarding to the importance of thieno[2,3-b]thiophens and isothiocyanaetes reactiveties in the physical, chemical and pharmaceutical fields, this study has been undertaken to prepare the target compound 5-cyano-2-carbethoxythieno[2,3-b]thiophenyl-3,4-diisothiocyanates via a safe method. The formed isothiocyanates derivative was reacted with aromatic amines, acid hydrazied and some active methylene groups, followed by cyclization reaction for the formed intermediates to give new series of heterocyclic compounds

Synthesis of 5‐Cyano‐2‐Carbethoxythieno[2,3‐b]thiophenyl‐3,4‐Diisothiocyanates and Its Utility IN Heterocyclic Synthesis under Phase Transfer Catalytic Technique

AbstractRegarding to the importance of thieno[2,3‐b]thiophens and isothiocyanaetes reactiveties in the physical, chemical and pharmaceutical fields, this study has been undertaken to prepare the target compound 5‐cyano‐2‐carbethoxythieno[2,3‐b]thiophenyl‐3,4‐diisothiocyanates via a safe method. The formed isothiocyanates derivative was reacted with aromatic amines, acid hydrazied and some active methylene groups, followed by cyclization reaction for the formed intermediates to give new series of heterocyclic compounds

Synthesis and biological evaluation of novel oxindole-based RTK inhibitors as anti-cancer agents

Given that receptor tyrosine kinases (RTKs) have emerged as key regulators of all aspects of cancer development, including proliferation, invasion, angiogenesis and metastasis, the RTK family represents an important therapeutic target for anti-cancer drug development. Oxindole structure has been used in RTK inhibitors such as SU4984 and intedanib. In this study, two series of new heterocyclic compounds containing oxindole scaffold have been designed and synthesized, and their inhibitory activity against the proliferation of nine cancer cell lines has been evaluated. Among them, compounds 9a and 9b displayed the strongest anti-proliferative activity with the IC50s below 10μM. Flow cytometric analysis showed that the compounds 9a and 9b dose-dependently arrested the cell cycle at G0/G1 phase. Although the leading compounds SU4984 and intedanib targets FGFR1, the kinase activity test revealed that these compounds only showed slight inhibitory activity on FGFR1 kinase. Further enzymatic test aided by molecular docking simulation in the ATP-binding site demonstrated that 9a and 9b are potent inhibitors of c-Kit kinase. These compounds are worthy of further evaluation as anticancer agents.

Synthesis and Crystal Structure of New Heterocyclic Compounds Containing 1,2,3-Triazole Moiety

A series of new heterocyclic compounds bearing 1,2,3-triazole moiety were synthesized using 4-acetyl-2-phenyl-1,2,3-triazole 1 as the starting material. The target compounds were prepared and the structures were characterized by IR, 1H NMR, MS and elemental analysis. Meanwhile, the crystal structures of the synthesized compounds were also furthered confirmed by X-ray diffraction analysis. Compound 3b crystallized in the monoclinic P2(1)/c space group with unit cell parameters a = 10.6974(17) A, b = 20.356(3) A, c = 7.8049(12) A, α = 90°, β = 102.840(3)°, γ = 90o, V = 1657.1(5) A3, Z = 4, T = 293(2) K. Compound 7c crystallized in the Triclinic P-1 space group with unit cell parameters a = 7.364(2) A, b = 7.366(2) A, c = 26.089(8)A, α = 87.114(7)°, β = 87.040(7) (3)°, γ = 82.337(7)°, V = 1399.2(7) A3, Z = 2, T = 293(2) K. Compound 10c crystallized in the Triclinic P-1 space group with unit cell parameters a = 9.8152(10) A, b = 10.0806(13) A, c = 11.1267(14) A, α = 100.344(3)°, β = 111.975(3)°, γ = 107.852(3)°, V = 916.18(19) A3, Z = 2, T = 293(2) K. New heterocyclic compounds bearing 1,2,3-triazole moiety were synthesized, which may have potential biological and medical applications.

ChemInform Abstract: Antiinflammatory, Analgesic, Anticonvulsant and Antiparkinsonian Activities of Some Pyridine Derivatives Using 2,6‐Disubstituted Isonicotinic Acid Hydrazides.

AbstractStarting from 2,6‐disubstituted isonicotinic acid hydrazides (I) or (XV) a series of new heterocyclic compounds is prepared and screened for their anti‐inflammatory, analgesic, anticonvulsant and antiparkinsonian activities.

Diversity Synthesis of Pyrimido[4,5-b][1,6]naphthyridine and Its Derivatives under Microwave Irradiation

A series of new heterocyclic compounds, involving pyrimido[4,5-b][1,6]-, benzo[b][1,6]-, pyrazolo[3,4-b][1,6]naphthyridine, and aza-benzo[b]fluorene skeletons were successfully synthesized via the reaction of structurally diverse 3,5-dibenzylidenepiperidin-4-one with various enamine-likes (2,6-diaminopyrimidin-4(3H)-one, 3-amino-5,5-dimethylcyclohex-2-enone, 3-methyl-1-phenyl-1H-pyrazol-5-amine and 1H-benzo[d]imidazol-2-amine) in glycol under microwave irradiation. This method has the advantages of short synthetic route, operational simplicity, and increased safety for small-scale fast synthesis for biomedical screening.