Multistep synthesis and screening of heterocyclic tetrads containing furan,pyrazoline, thiazole and triazole (or oxadiazole) as antimicrobial and anticancer agents

In the present study novel heterocyclic tetrads containing furan, pyrazoline, thiazole and triazole (or oxadiazole) (1, 2, 3, 4a-e and 5a-e) were designed and synthesized and investigated for their antimicrobial (against selected bacteria and fungi) and anticancer potential. The molecules 4e and 5e containing 4-fluoro phenyl and 4-fluoro benzyl substituents showed promising antimicrobial (antibacterial and antifungal activities with MICs ranging between 0.5 and 8 µg/mL. Compounds 3 exhibited potent anticancer activity with an IC₅₀ value of 0.49 ± 1.45 µM against the human gastric cancer cell line (BGC-823) whereas compound 4e displayed an IC₅₀ value of 0.65 ± 0.53 µM against breast cancer (MCF-7) cell line respectively. All compounds showed selective toxicity against the cancer cell lines compared to human normal liver cell lines. Molecular docking studies of the most potent compounds (3 and 4e) against selected microbial and cancer proteins revealed the crucial binding interactions of the potent compounds with the target enzymes. Compounds 3 and 4e are promising lead molecules to be developed as potential drug candidates.     

Design,synthesis and docking studies of new hydrazinyl-thiazole derivatives as anticancer and antimicrobial agents

Increase in the number of infections caused by pathogenic microbes in cancer patients has prompted the searcher to invest in the development of agents having dual anticancer and antimicrobial properties. The present study is concerned with synthesis and screening for anticancer and antimicrobial activity of a series of 5-hydrazinyl-2-(2-(1-(thien-2-yl)ethylidene)hydrazinyl)thiazole derivatives. The structure elucidation of the synthesized hydrazinyl thiazole derivatives was illustrated by spectroscopic and elemental analysis. All the newly synthesized compounds 5a-p were evaluated for in-vitro cytotoxic activity against breast carcinoma (MCF-7 cell line), hepatocellular carcinoma (HePG-2) and colorectal cancer (HCT-116) cell lines using MTT assay method. Compounds 5 g, 5h showed broad spectrum activity against three cancer cell lines with IC₅₀ ranged from 3.81 to 11.34 µM in compared to the reference drug Roscovitine (IC₅₀ = 9.32 to 13.82 µM), while compounds 5 l and 5 m were found to be more selective against HePG-2 and HCT-116 cell line (IC₅₀ = 9.29 and 8.93 µM respectively) and compound 5j was more selective against HePG-2 and MCF-7 cell lines (IC₅₀ = 6.73 and 10.87 µM respectively). The inhibitory activity of the most promising compounds was tested against the EGFR and ARO enzymes and were further tested for apoptosis and Annexin V/PI staining. The results of enzyme-based tests revealed that the tested compound 5j has a dual inhibitory effect on the EGFR and ARO enzymes with IC₅₀ = 82.8 and 98.6 nM respectively in compared to the reference drugs Erlotinib and Letrozole (IC₅₀ = 62.4 and 79 nM respectively). Furthermore, the majority of the tested hydrazinyl thiazole derivatives exhibited significant antimicrobial activity against the used pathogenic microbes species. Compounds 4b, 5h, 5j and 5 m exerted a good antibacterial and antifungal activity against all tested pathogenic microbes. Therefore, it was concluded that compounds 5 h, 5j and 5 m proved to possess dual anticancer and antimicrobial agent and may serves as a useful lead compounds in search for further modification or derivatization to give more potent and selective agents.     

Synthesis,characterization and antimicrobial activities of new bis-hydrazonothioxothiazolidinone derivatives

New bis-hydrazonothioxothiazolidinone derivatives based on 2-thioxothiazolidin-4-one were synthesized in good yields using a simplified experimental condition. The structure of synthesized compounds was established with the help of common physico-chemical analysis and various spectroscopic techniques like FT-IR, mass and ¹H NMR. The results of characterizations are in good agreement with the proposed structure of all the synthesized compounds. Further, the antimicrobial (antibacterial and antifungal) activities of all the synthesized derivatives were carried out against various species like Bacillus subtilis, Escherichia coli, Aspergillous niger and Aspergillous flavus by using agar-cup method. The results of antimicrobial screening showed that all the compounds have mild to moderate activity. However, some of the compounds (3a, 3b, 3d, 3e, 3f, 3g, 3i and 3j) have shown better activity than the other.     

Synthesis and biological evaluation of newer analogues of 2,5-disubstituted 1,3,4-oxadiazole containing pyrazole moiety as antimicrobial agents

A series of 2,5-disubstituted-1,3,4-oxadiazole derivatives bearing pyrazole moiety were synthesized by reacting various substituted pyrazole-4-carboxylic acids with different hydrazides in POCl₃. All the synthesized compounds (4a–n) were characterized by IR, NMR, mass spectra and elemental analyses. Synthesized 1,3,4-oxadiazole derivatives were screened for their antibacterial activity against three different strains, namely Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa, while antifungal activity was determined against three different strains Aspergillus flavus, Chrysosporium keratinophilum and Candida albicans. The investigation of antimicrobial screening revealed that compounds 4i and 4j exhibited excellent activity when compared with the standard drugs.     

Anticancer and antimicrobial evaluation of newly synthesized steroidal 5,6 fused benzothiazines

A series of new 5α-cholestano [5,6-b] benzothiazines (4–6) has been synthesized by the reaction of 5α-cholestan-6-one (1–3) with 2-aminothiophenol in the presence of iodine. The structures of newly synthesized compounds have been established on the basis of spectral and analytical data. Compounds (1–6) were screened for in vitro anticancer activity against the human cancer cell lines; SW480 (colon adenocarcinoma cells), A549 (lung carcinoma cells), HepG2 (hepatic carcinoma cells) and HeLa (cervical cancer cells) using MTT assay during which the products (4–6) showed marked increase in anticancer activity and in particular, compound 6 showed IC₅₀ = 13.73 μmol L⁻¹ against HeLa cells, being more effective than Doxorubicin against the same cells. Compounds 4 and 6 also showed minimum IC₅₀ of 15.83 μmol L⁻¹ and 16.89 μmol L⁻¹ against HepG2 and A549 cells, respectively. Compounds (1–6) were also tested for in vitro antimicrobial activity against different bacterial as well as fungal strains during which newly synthesized compounds (4–6) were found more potent than starting compounds (1–3). Compound 4 was found to be more potent than the reference drug, Chloramphenicol, in the case of Escherichia coli while compound 5 was found almost equally potential antifungal agent against P. marneffei in comparison with the reference drug, Nystatin.     

A Facial Synthesis and Anticancer Activity of (Z)‐2‐((5‐(4‐nitrobenzylidene)‐4‐oxo‐4,5‐dihydrothiazol‐2‐yl)amino)‐substituted Acid

In order to explore the anticancer and antimicrobial activity associated with the thiazole framework, we synthesized the new series (Z )‐2‐((5‐(4‐nitrobenzylidene)‐4‐oxo‐4,5‐dihydrothiazol‐2‐yl)amino)‐substituted acid derivatives 6a – l . All the synthesized compounds were evaluated for anticancer and antimicrobial activity in vitro. Among these, the compounds 6a , 6b, 6c , 6e , 6f , 6g , 6h , 6i , 6j , and 6k showed highest antibacterial and antifungal activity. The compound 6a exhibited significant antibacterial activity against Bacillus subtilis , whereas compound 6j displays significant antifungal activity against fungal strains, that is, A. oryzae . The in vitro anticancer studies revealed that 6e , 6g , 6h , 6k , and 6l are the most active compounds against MCF‐7 and BT‐474 human breast cancer cell lines, which can be regarded as the promising drug candidate for development of anticancer drugs.     

Isomannide monoundecenoate-based 1,2,3-triazoles: Design,synthesis, and in vitro bioactive evaluation

A new series of isomannide monoundecenoate-based 1,2,3-triazole analogs 6a–e were designed by employing click chemistry in good yields. in vitro bioactive assay manifested that the several target compounds exhibited promising antibacterial and antifungal activities. Notably, compounds having phenyl substituted triazole 6a , and hydroxy phenyl substituted triazole 6b possessed highly selective promising inhibition towards Gram-positive bacterial strains namely Bacillus subtilis and Staphylococcus aureus with MIC value of 3.9 μg/mL. Further, these potential hybrids ( 6a and 6b) also exhibited highly impressive antifungal activity against the tested panel of Candida strains with MIC value of 3.9 μg/mL. Based on our in vitro preliminary antimicrobial study, these two compounds 6a and 6b have been identified as potential antimicrobial lead compounds. Moreover, all prepared derivatives were also evaluated for their in vitro cytotoxic activities against A549, MCF7, DU145 and HeLa cancer cell lines. The results indicated that only the hydroxy phenyl substituted triazole analog 6b displayed good cytotoxic activity towards all tested human cancer cell lines without any significant effects on normal cell line (HUVEC).     

Synthesis and antimicrobial screening of 1,3,4-oxadiazole and clubbed thiophene derivatives

In the present study, a novel series of 2-{5-[4-(1-aza-2-(2-thienyl)vinyl)phenyl](1,3,4-oxadiazol-2-ylthio)}-N-arylacetamides (IV)_1–12 were synthesized and tested for their antimicrobial activity. Newly synthesized compounds were screened for their antibacterial and antifungal activities on Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Staphylococcus pyogenes, Candida albicans, Aspergillus niger and Aspergillus clavatus. The chemical structures of newly synthesized compounds were elicited by IR, ¹H NMR, ¹³C NMR and mass spectral data. The synthesized bio-active compounds exhibited excellent to moderate antimicrobial activity. Compounds (IV)₅, (IV)₆ and (IV)₇ possess excellent antibacterial activity whereas compounds (IV)₆, (IV)₉ and (IV)₁₁ possess excellent antifungal activity.     

Synthesis and evaluation of antiproliferative activity of substituted N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamides

Several novel N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamide derivatives were prepared as potential antiproliferative agents. The in vitro antiproliferative activity of the synthesized compounds was investigated against a panel of tumor cell lines including breast cancer cell lines (MDA-MB-231, T-47D) and neuroblastoma cell line (SK-N-MC) using MTT colorimetric assay. Etoposide, a well-known anticancer drug, was used as a positive standard drug. Among synthesized compounds, 4-methoxy-N-(9-oxo-9H-xanthen-4-yl)benzenesulfonamide (5i) showed the highest antiproliferative activity against MDA-MB-231, T-47D, and SK-N-MC cells. Furthermore, pentafluoro derivatives 5a and 6a exhibited higher antiproliferative activity than doxorubicin against human leukemia cell line (CCRF-CEM) and breast adenocarcinoma (MDA-MB-468) cells. Structure–activity relationship studies revealed that xanthone benzenesulfonamide hybrid compounds can be used for the development of new lead anticancer agents.     

Design and synthesis of some novel pyridothienopyrimidine derivatives and their biological evaluation as antimicrobial and anticancer agents targeting EGFR enzyme

A new series of pyridothienopyrimidine derivatives was designed and evaluated as antimicrobial and anticancer agents. The target compounds were synthesized starting with 3-aminothieno[2,3-b]pyridine-2-carboxamide derivative 1 which underwent cyclocondensation reaction with aromatic aldehydes to give the key intermediates 2a,b. By further treatment of 2a,b with various reagents, the target 2,4-disubstituted-pyrido[3′,2′:4,5]thieno[2,3-d]pyrimidines 3a,b–11a,b were obtained. To evaluate the antimicrobial activity of the new compounds, they were tested against five bacterial and five fungal strains. Compounds 6c, 8b, 9a and 9b revealed the most significant antimicrobial activity against the tested microorganisms with MIC values range (4–16 μg/mL). Also, compounds 2a,b–11a,b were screened for their in vitro cytotoxic activity against HepG-2 and MCF-7 cancer cell lines compared with doxorubicin and cisplatin as references drugs. Moreover, compounds (2b, 4a, 6a, 7b, 7c and 9a) which exhibited the most potent anticancer activity, were further subjected to EGFR^WT enzyme inhibition assay utilizing erlotinib as a standard drug. The compounds 6a, 7b, 7c and 9a which showed the most promising suppression effects were also evaluated as inhibitors against the mutant forms EGFR^L858R and EGFR^T790M. The 4-aminopyrazolone analogue 9a showed superior anticancer activity against both HepG-2 and MCF-7 cell lines (IC50 = 1.27, 10.80 μM, respectively) and more potent enzymatic inhibition activity against EGFR^WT and its mutant forms EGFR^L858R and EGFR^T790M than that obtained by erlotinib (IC₅₀ = 0.021, 0.053, 0.081 µM, respectively, IC_50erlotinib; 0.027, 0.069, 0.550 µM, respectively). Finally, the molecular docking study showed good binding patterns of the most active compounds with the prospective target EGFR^WT.     

Synthesis,characterization and antimicrobial evaluation of novel halopyrazole derivatives

Two novel halopyrazole derivatives (3, 5) were synthesized from 5-chloro-3-methyl-1-phenylpyrazole-4-carboxaldehyde (1) using appropriate synthetic routes. Newly synthesized compounds were characterized using elemental analysis, spectral data (IR, ¹H NMR, ¹³C NMR and mass spectrometry) and were evaluated for their in vitro antimicrobial activity. The minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and minimum fungicidal concentration (MFC) were determined for the test compounds as well as for reference standards. The investigation of antimicrobial screening revealed that compounds (3, 5) showed good antibacterial and antifungal activities, respectively.     

Bioactive Fluorenes. Part II. Unprecedented biologically active thiazole derivatives based-2,7-dichlorofluorene as competent DHFR inhibitors: Design,synthesis, and molecular docking approaches

In this study, a new series of (4-(2,7-dichloro-9H-fluoren-4-yl)thiazol-yl)acetamide derivatives was synthesized, and the new heterocycles were completely characterized, evaluated for their antimicrobial activity, and screened for cytotoxic activity against human lung carcinoma (A-549) and human breast carcinoma (MCF-7) cell lines. A molecular docking study was undertaken to identify the possible mode of action of the synthesized compounds, which suggested binding interactions with the dihydrofolate reductase (DHFR) active sites.Most of the synthesized compounds displayed meaningful activity against A-549 and MCF-7 cell lines when compared to 5-fluorouracil (5-FU), which was used as a reference drug. Furthermore, some of the prepared compounds exhibited potent antibacterial and antifungal activities. The highly pronounced biological activities of the compounds under investigation offer such species as promising future drug prospects which may find applications in the fields of biological and medicinal sciences.     

Thiazolidin-4-Ones as Potential Antimicrobial Agents: Experimental and In Silico Evaluation

Herein, we report computational and experimental evaluations of the antimicrobial activity of twenty one 2,3-diaryl-thiazolidin-4-ones. All synthesized compounds exhibited an antibacterial activity against six Gram-positive and Gram-negative bacteria to different extents. Thus, the MIC was in the range of 0.008–0.24 mg/mL, while the MBC was 0.0016–0.48 mg/mL. The most sensitive bacterium was S. Typhimurium, whereas S. aureus was the most resistant. The best antibacterial activity was observed for compound 5 (MIC at 0.008–0.06 mg/mL). The three most active compounds 5, 8, and 15, as well as compound 6, which were evaluated against three resistant strains, MRSA, P. aeruginosa, and E. coli, were more potent against all bacterial strains used than ampicillin. The antifungal activity of some compounds exceeded or were equipotent with those of the reference antifungal agents bifonazole and ketoconazole. The best activity was expressed by compound 5. All compounds exhibited moderate to good drug-likeness scores ranging from −0.39 to 0.39. The docking studies indicated a probable involvement of E. coli Mur B inhibition in the antibacterial action, while CYP51 inhibition is likely responsible for the antifungal activity of the tested compounds. Finally, the assessment of cellular cytotoxicity of the compounds in normal human MRC-5 cells revealed that the compounds were not toxic.     

Design,synthesis and biological evaluation of novel N1,N8-bis(((4-((5-aryl-1,3,4-oxadiazol-2-yl)methoxy)phenyl)amino)oxy)-1-naphthamide derivatives

A new series of 1,8-bis(4-((5-phenyl-1,3,4-oxadiazol-2-yl) methoxy)-substituted aryl) naphthalene-1,8-dicarboxamide derivatives (6a–j) were synthesized in the presence of POCl₃ and obtained good yields. All the synthesized novel compounds were characterized by IR, ¹H NMR, ¹³C NMR, HRMS spectroscopic data and elemental analysis. All the synthesized compounds evaluated for their antibacterial and antifungal activities. The antibacterial activity screened against Gram-positive bacteria Staphylococcus aureus and Gram-negative bacteria Escherichia coli and used standard reference drug ciprofloxacin. The antifungal activity screened against two pathogenic fungal strains Aspergillus niger and Candida albicans used a reference standard drug Voriconazole. All these compounds (6a–j) demonstrate good antibacterial and antifungal activity. Among them, compounds 6h and 6c show highest antibacterial and antifungal activity.     

Synthesis,spectral characterization,and biological studies of 3,5-disubstituted-1,3,4-oxadiazole-2(3H)-thione derivatives

The reaction of 3,4-dichlorophenyl-1,3,4-oxadiazole-2( 3H )-thione with piperidine derivatives via Mannich reaction was used to generate eleven novel compounds in moderate to good yields. Synthesized molecules were characterized according to their structure with ¹H NMR, ¹³C NMR and FT-IR spectral foundations, which were compatible with literature informations. Antimicrobial activity and cytotoxicity studies were done by disc diffusion and NCI-60 sulphordamine B assay methods. The antimicrobial test results revealed that synthesized compounds have better activity against gram-positive species than gram-negative ones. A total analysis of the antibacterial, antifungal, and antiyeast activity revealed that newly synthesized compounds were really active against Bacillus cereus , Bacillus ehimensis, and Bacillus thuringiensis species . For cytotoxicity, among three different cancer cell lines (HCT116, MCF7, HUH7) compounds 5c, 5d, 5e, 5f, 5g, 5i, 5j and 5k were seemed especially effective on HUH7 cancer cell line via moderate to good activity. More significantly, against liver carcinoma cell line (HUH7) most of the compounds of the series ( 5c-5g and 5i-5j ) have better IC₅₀ values (IC₅₀= 18.78 µM) than 5-Florouracil (5-FU) and also compound 5d possessed 10.1 µM value, which represents good druggable cytotoxic activity. Further, the molecules were also screened for in silico chemoinformatic and toxicity data to gather the predicted bioavailibity and safety measurements.     

Janoxepin and brevicompanine B: antiplasmodial metabolites from the fungus Aspergillus janus

Two compounds janoxepin (1) and brevicompanine B (2) were isolated from the fungus Aspergillus janus and the structures elucidated by one- and two-dimensional NMR spectroscopic methods and mass spectrometry. Janoxepin is a novel oxepin derivative with a rare d-leucine incorporated. Brevicompanine B has previously only been isolated from Penicillium brevicompactum. Both compounds were tested in antimicrobial assays and found to be active against the malaria parasite Plasmodium falciparum 3D7 (IC₅₀-values of 28 and 35 mg/ml, respectively). However, no activity was observed in antifungal or antibacterial assays.     

Synthesis,characterization and antimicrobial activity evaluation of new 2,4-Thiazolidinediones bearing imidazo[2,1-b][1,3,4]thiadiazole moiety

The synthesis and antimicrobial activity of 2,4-thiazolidinedione derivatives 5a–g and 6a–g are described. The structures of the newly synthesized compounds were confirmed by IR, NMR, mass and elemental analyses. All compounds were evaluated for their preliminary in vitro antibacterial and antifungal activity. The results revealed that most of the compounds showed high or moderate biological activity against tested microorganisms.     

N'-(1-([1,1'-biphenyl]-4-yl)ethylidene)-2-cyanoacetohydrazide as scaffold for the synthesis of diverse heterocyclic compounds as prospective antitumor and antimicrobial activities

In this article, the main target was to study the antitumor and antimicrobial efficacy of new heterocycles conjugated with biphenyl moiety in-vitro. This was implemented by utilizing N'-(1-([1,1'-biphenyl]-4-yl)ethylidene)-2-cyanoacetohydrazide 3 as a material for the synthesis of various heterocyclic compounds. Among of them, some compounds were selected and assayed against two antitumor cell lines as (HepG2) and (HCT-116). Conspicuously, the achieved results showed that compounds 6, 13, and 23 possess significant potency against both cancer cell lines. Particularly, compound 13 exhibited a remarkable efficacy, similar to the standard anticancer drug (doxorubicin), against both cancer cell lines. Noteworthy, compound 13 may serve as a potential anticancer therapeutic drug in the future. On the other hand, In-vitro antifungal and antibacterial activities of selected compounds were assayed and the results indicated that the compound 6 exhibited significant potency against Candida albicans, while compounds 6 and 8 displayed spectacular results for the antibacterial study.     

Synthesis of hydrazone derivatives of benzofuran and their antibacterial and antifungal activity

A series of benzofuran hydrazones 6a–6n were synthesized from benzofuran aldehyde and substituted aromatic hydrazides 5a–5n. Structures of all compounds were confimed by IR, ¹H and ¹³C NMR, and Mass spectral data. These compounds were evaluated for their antibacterial activity against gram-negative bacteria (Escherichia coli, –ve), gram-positive bacteria (Bacillus Subtillis, +ve), and antifungal activity against Candida albicans. All compounds demonstrated considerable activity against bacteria and fungi.     

Novel aromatic carboxamides from dehydroabietylamine as potential fungicides: Design,synthesis and antifungal evaluation

The present study was carried out to design and synthesize a number of novel aromatic carboxamide derivatives of dehydroabietylamine. The preliminary antifungal assay indicated that most of title compounds displayed moderate to good antifungal activity toward the six fungal strains in vitro. Compounds 3i, 3q, 4b and 4d showed significant antifungal activity against Sclerotinia sclerotiorum, with EC₅₀ values ranging from 0.067 ～ 0.393 mg/L. Compounds 3i, 4b and 4d also showed pronounced mycelial growth inhibition activities against B. cinerea and A. solani. Furthermore, in the in vivo assay, compound 4b exhibited brilliant protective activity against S. sclerotiorum-infected rape leaves. Meanwhile, the in vivo bioassay on tomato plants infected by B. cinerea showed that compound 3i and 4d displayed excellent protective activity at 200 mg/L, which were near to boscalid. Primary mechanistic study revealed that 4b could inhibit sclerotia formation as well as reduce the exopolysaccharide level. SEM and TEM analysis indicated that 4b possessed a strong ability to destroy the surface morphology of mycelia, cell structure and seriously interfere with the growth of the fungal pathogen. In addition, 4b exhibited good inhibitory activity (IC₅₀ = 23.3 ± 1.6 μM) toward succinate dehydrogenase (SDH). Molecular modeling study confirmed the binding modes between compound 4b and SDH. The above antifungal results and fungicidal mechanism study revealed that this class of dehydroabietylamine derivatives could be potential SDH inhibitors and lead compounds for novel fungicides development.