New bithiazolyl hydrazones: Novel synthesis,characterization and antitubercular evaluation

New bithiazolyl hydrazones (6a–l) have been first time synthesized by carrying novel one pot cyclocondensation of 5-acyl thiazoles (1a–b), thiosemicarbazide (2) and substituted phenacyl chlorides (4a–f) in freshly prepared ionic liquid, diisopropyl ethyl ammonium acetate (DIPEAc) at room temperature. The newly synthesized compounds have been evaluated for their antitubercular activity and the compounds 3b, 6a, 6b, 6d, 6e, 6f, 6g, and 6l have displayed noticeable antitubercular activity compared to Rifampicin with tolerable cytotoxicity. All these compounds were also screened for their antibacterial activity and found that, compounds 6j and 6k have exhibited a very good antibacterial activity. Molecular docking study has shown better harmony with the evaluation trend shown by these compounds under in vitro antitubercular screening.     

Synthesis,antimicrobial, and mosquito larvicidal activity of 1-aryl-4-methyl-3,6-bis-(5-methylisoxazol-3-yl)-2-thioxo-2,3,6,10b-tetrahydro-1H-pyrimido[5,4-c]quinolin-5-ones

A series of 1-aryl-4-methyl-3,6-bis-(5-methylisoxazol-3-yl)-2-thioxo-2,3,6,10b-tetrahydro-1H-pyrimido[5,4-c]quinolin-5-ones (6a–h) have been synthesized by cyclization of ethyl-3-aryl-4-(2-chlorophenyl)-6-methyl-1-(5-methylisoxazol-3-yl)-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates 4a–h with 3-amino-5-methylisoxazole 5. Compounds 4a–h were obtained by Biginelli reaction, by condensation of aromatic aldehyde 1, ethyl acetoacetate 2, and isoxazolyl thioureas 3 in a one-pot reaction catalyzed by ceric ammonium nitrite (CAN). Compounds 6a–h were tested for their antibacterial and antifungal activities against various bacterial and fungal strains. The results showed that these compounds exhibited good antibacterial and antifungal activity compared with that of standard antibiotics. Mosquito larvicidal activity of the newly synthesized compounds 6a–h is also studied against fourth instar larvae Culex quinquefasciatus. Some of the compounds are proved to be lethal for mosquito larvae.     

Design,synthesis and evaluation of novel quinazoline-2,4-dione derivatives as chitin synthase inhibitors and antifungal agents

A series of novel 1-methyl-3-substituted quinazoline-2,4-dione derivatives were designed, synthesized, and characterized by ¹H NMR, ¹³C NMR and MS spectral data. Their inhibition against chitin synthase (CHS) and antifungal activities were evaluated in vitro. Results showed compounds 5b, 5c, 5e, 5f, 5j, 5k, 5l, and 5o had strong inhibitory potency against CHS. Compound 5c, which has the highest potency among these compounds, had a half-inhibition concentration (IC₅₀) of 0.08 mmol/L, while polyoxin B as positive drug had IC₅₀ of 0.18 mmol/L. These IC₅₀ values of compounds 5i, 5m, 5n, and 5s were greater than 0.75 mmol/L, which revealed that those compounds had weak inhibition activity against CHS. Moreover, most of these compounds exhibited moderate to excellent antifungal activities. In detail, to Candida albicans, the activities of compound 5g and 5k were 8-fold stronger than that of fluconazole and 4-fold stronger than that of polyoxin B; to Aspergillus flavus, the activities of 5g, 5l and 5o were16-fold stronger than that of fluconazole and 8-fold stronger than that of polyoxin B; to Cryptococcus neoformans, the minimum-inhibition-concentration (MIC) values of compounds 5c, 5d, 5e and 5l were comparable to those of fluconazole and polyoxin B. The antifungal activities of these compounds were positively correlated to their IC₅₀ values against CHS. Furthermore, these compounds had negligible actions to bacteria. Therefore, these compounds were promising selective antifungal agents.     

Synthesis and in vitro antitumor and antimicrobial activity of some 2,3-diaryl-7-methyl-4,5,6,7-tetrahydroindazole and 3,3a,4,5,6,7-hexahydroindazole derivatives

The synthesis of a series of 2,3-diaryl-7-methyl-4,5,6,7-tetrahydroindazole and 3,3a,4,5,6,7-hexahydroindazole derivatives substituted with various biologically-active function groups with anticipated chemotherapeutic activity is described. 4-(7-methyl-3-aryl-3,3a,4,5,6,7-hexahydro-indazol-2-yl)benzenesulfonamides 2a–c, which were employed as key intermediates in this study, were synthesized by cyclocondensation of 6-arylidene-2-methylcyclohexanones 1a–c with 4-hydrazinobenzenesulfonamide hydrochloride. A detailed discussion of the reactions utilized in the preparation of the intermediate and target compounds is reported, and the structures of the newly synthesized compounds were substantiated with IR, ¹H and ¹³C NMR spectral data and elementary microanalyses. Twenty of the newly synthesized compounds were selected by National Cancer Institute (NCI), Maryland, USA, to be evaluated for their antitumor activity and the results revealed that six compounds 3c, 4d,e, 5a,d and 8c exhibited broad spectrum of antitumor activity against most of the tested tumor cell lines. In addition, the in vitro antibacterial and antifungal activities of a number of the target compounds were also tested using the Agar-diffusion method. Some of these compounds have shown significant antibacterial and mild to moderate antifungal activities.     

Indolylmethylene benzo[h]thiazolo[2,3-b]quinazolinones: Synthesis,characterization and evaluation of anticancer and antimicrobial activities

A series of novel 10-((1H-indol-3-yl)methylene)-7-aryl-7,10-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-9(6H)-ones (8a–t) have been synthesized in good yields by the reaction of benzo[h]quinazoline-2(1H)-thiones (4a–f) with 2-chloro-N-phenylacetamide (5) followed by Knoevenagel condensation with various indole-3-carbaldehydes (7a–d) under conventional method. All the synthesized compounds were characterized by spectral studies and screened for their in vitro anticancer and antimicrobial activities. Compound 8c has exhibited excellent activity against MCF-7 (breast cancer cell line) than the standard drug Doxorubicin. Compound 8d against both the cancer cell lines, 8q against MCF-7 and 8c, 8h against HepG2 have also shown good activity. Remaining compounds have shown moderate activity against both the cell lines. Antimicrobial activity revealed that, the compound 8q and 8t against Staphylococcus aureus and 8i, 8k, 8l, 8q & 8t against Klebsiella pneumoniae have shown equipotent activity on comparing with the standard drug Streptomycin. Remaining compounds have shown significant antibacterial and comparable antifungal activities against all the tested microorganisms.     

Synthesis,cytotoxicity, DNA binding and topoisomerase II inhibition of cassiarin A derivatives

Four series of cassiarin A derivatives with alkanoyl (3a–3d), aroyl (4a–4d), hydroxy/amino-substituted ethylene glycol (5a–5c) and selenium-containing (6a) side chains were synthesized. Their antitumor activities were evaluated against BT474, CHAGO, HepG2, KATO-III, SW620 and CaSki cancer cell lines. Preliminary results demonstrated that 5b had moderate activities against HepG2 and KATO-III cell lines, while 5c showed moderate to high cytotoxicity against most tested cell lines. In addition, 6a exhibited moderate cytotoxicity against cervical cells, CaSki. DNA-binding and ethidium bromide displacement experiments suggested that 5c and 5b binds to DNA via an intercalative mode, whereas 6a did not. However, the selenium-containing cassiarin A derivative 6a inhibited topoisomerase II with more than 95% inhibition at the concentration of 50 μM. These cassiarin A derivatives showed lower toxicity to normal cells, WI-38 than amonafide therefore they are potential lead compounds to be further developed as new anticancer agents.     

Design,synthesis, molecular docking of new lipophilic acetamide derivatives affording potential anticancer and antimicrobial agents

Fifteen new substituted N-2-(2-oxo-3-phenylquinoxalin-1(2H)-yl) acetamides 5a-f, 6a-f, and 8a-c were synthesized by reacting ethyl 2-(2-oxo-3-phenylquinoxalin-1(2H)-yl)acetate with various primary amines including benzylamines, sulfonamides, and amino acids. The in vitro antimicrobial screening of the target compounds was screened to assess their antibacterial and antifungal activity. As a result, seven compounds namely; 5a, 5c, 5d, 6a, 6c, 8b and 8c showed a promising broad spectrum antibacterial activity against both Gram-positive and Gram-negative strains. Among these, the analogs 5c and 6d were nearly as equiactive as ciprofloxacin drug. Meanwhile, four compounds namely; 5c, 6a, 6f and 8c exhibited appreciable antifungal activity with MIC values range 33–40 mg/mL comparable with clotrimazole (MIC 25 mg/mL). In addition, the anticancer effects of the synthesized compounds were evaluated against three cancer lines. The data obtained revealed the benzylamines and sulpha derivatives were the most active compounds especially 5f and 6f ones. Further EGFR enzymatic investigation was carried out for these most active compounds 5f and 6f resulting in inhibitory activity by 1.89 and 2.05 µM respectively. Docking simulation was performed as a trial to study the mechanisms and binding modes of these compounds toward the enzyme target, EGFR protein kinase enzyme. The results revealed good compounds placement in the active sites and stable interactions similar to the co-crystallized reference ligand. Collectively, the analogs 5f and 6f could be further utilized and optimized as good cytotoxic agents.     

Design,synthesis and cytotoxic activities of scopoletin-isoxazole and scopoletin-pyrazole hybrids

12 novel scopoletin-isoxazole and scopoletin-pyrazole hybrids were designed, synthesized and their chemical structures were confirmed by HR-MS, IR, ¹H NMR and ¹³C NMR spectra. The anticancer activities of the newly synthesized compounds were evaluated in vitro against three human cancer cell lines including HCT-116, Hun7 and SW620 by MTT assay. The screening results showed that six compounds (9a, 9c, 9d, 12a, 18b and 18d) exhibited potent cytotoxic activities with IC₅₀ values below 20 μM. Besides, we have further evaluated the growth inhibitory activities of six compounds against the human normal tissue cell lines HFL-1. Especially, compound 9d displayed significant anti-proliferative activity with IC₅₀ values ranging from 8.76 μM to 9.83 μM and weak cytotoxicity with IC₅₀ value of 90.9 μM on normal cells HFL-1, which suggested that isoxazole-based hybrids of scopoletin were an effective chemical modification to improve the anticancer activity of scopoletin.     

Thermal solvent-free synthesis of novel pyrazolyl chalcones and pyrazolines as potential antimicrobial agents

A novel approach was adopted for the synthesis of series of new pyrazolyl chalcones (3a-c) by the reaction of 5-chloro-3-methyl-1-phenylpyrazole-4-carboxaldehyde (1) with different 5-acetylbarbituric acid derivatives (2a-c) under thermal solvent-free condition. The chalcones were then converted to the corresponding pyrazolines (4a-c) under the same condition in excellent yields. All the synthesized compounds were characterized using elemental analysis and spectral data (IR, ¹H NMR, and mass spectrometry). The synthesized compounds were tested for their antimicrobial activity by disk diffusion assay with slight modifications against Gram-positive, Gram-negative strains of bacteria as well as fungal strains. The investigation of antimicrobial screening revealed that compounds (3a-4c) showed good antibacterial and antifungal activities, respectively. Among the screened compounds, 3b showed more potent inhibitory activity (MIC = 12.5 μg/ml) nearly to that of standard antibiotics ciprofloxacin, griseofulvin and fluconazole.     

Synthesis,computational studies and antiproliferative activities of coumarin-tagged 1,3,4-oxadiazole conjugates against MDA-MB-231 and MCF-7 human breast cancer cells

A novel library of coumarin tagged 1,3,4 oxadiazole conjugates was synthesized and evaluated for their antiproliferative activities against MDA-MB-231 and MCF-7 breast cancer cell lines. The evaluation studies revealed that compound 9d was the most potent molecule with an IC₅₀ value of <5?µM against the MCF-7 cell line. Interestingly, compounds 10b and 11a showed a similar trend with lower inhibitory concentration (IC₅₀?=?7.07?µM), in Estrogen Negative (ER?) cells than Estrogen Positive (ER+) cells. Structure–activity relationship (SAR) studies revealed that conjugates bearing benzyl moieties (9b, 9c and 9d) had superior activities compared to their alkyl analogues. The most potent compound 9d showed ～1.4?times more potent activity than tamoxifen against MCF-7 cell line; while the introduction of sulfone unit in compounds 11a, 11b and 11c resulted in significant cytotoxicity against both MCF-7 and MDA-MB-231 cell lines. These results were further supported by docking studies, which revealed that the stronger binding affinity of the synthesized conjugates is due to the presence of sulfone unit attached to the substituted benzyl moiety in their pharmacophores.     

Synthesis and antimicrobial activity of novel fluorine containing 4-(substituted-2-hydroxybenzoyl)-1H-pyrazoles and pyrazolyl benzo[d]oxazoles

A series of fluorine containing 4-(substituted-2-hydroxybenzoyl) pyrazoles and pyrazolyl benzo[d]oxazoles were synthesized and evaluated for their antibacterial activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Bacillus subtilis and antifungal activity against Candida albicans. The antibacterial activities were expressed as the minimum inhibitory concentration (MIC₅₀) in μg/ml. The compounds 1-(3,4-difluorophenyl)-4-(5-fluoro-2-hydroxybenzoyl)-1H-pyrazole (4b), oxime derivatives such as 1-(3,4-difluorophenyl)-1H-pyrazol-4-yl)(2-hydroxy-4-methylphenyl)methanone oxime (5b) and (5-chloro-2-hydroxyphenyl)(1-(3,4-difluorophenyl)-1H-pyrazol-4-yl)methanone oxime (5e) exhibited promising activities against tested bacterial strains. Except compound 1-(3,4-difluorophenyl)-4-(2-hydroxybenzoyl)-1H-pyrazole (4d), none of the other compounds showed promising antifungal activity.     

Synthesis,and anti-proliferative,Pim-1 kinase inhibitors and molecular docking of thiophenes derived from estrone

Heterocyclization of steroids were reported to give biologically active products where ring D modification occured. Estrone (1) was used as a template to develop new heterocyclic compounds. Ring D modification of 1 through its reaction with cyanoacetylhydrazine and elemental sulfur gave the thiophene derivative 3. The latter compound reacted with acetophenone derivatives 4a-c to give the hydrazide-hydrazone derivatives 5a-c, respectively. In addition, compound 3 formed thiazole derivatives through its first reaction with phenylisothiocyanate to give the thiourea derivative 9 followed by the reaction of the later with α-halocarbonyl compounds. In the present work a series of novel estrone derivatives were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase, and six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG and SMMC-7721). The most promising compounds 5b, 5c, 11a, 13c, 15b, 15c, 15d, 17a and 17b were further investigated against the five tyrosine kinases c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR. Compounds 5b, 15d, 17a and 17b were selected to examine their Pim-1 kinase inhibition activity where compounds 15d and 17b showed high activities. Molecular docking of some of the most potent compounds was demonstrated.     

Solvent free synthesis,anti-inflammatory and anticancer activity evaluation of tricyclic and tetracyclic benzimidazole derivatives

Heterocyclic benzimidazole derivatives 3a–h, 5a–c and 7a–d have been synthesized by condensation of succinic acid (1) homophthalic acid (4) and 2,3-pyrazinedicarboxlic acid (6) with various substituted diamines under microwave irradiation in good yields. Structures assigned to 3a–h, 5a–c and 7a–d are fully supported by spectral data. All these compounds were screened for anti-inflammatory and anticancer activities. At a dose of 50 mg/kg po compounds 3b (39.4%) and 3c (39.2%) exhibited anti-inflammatory activity, comparable to standard ibuprofen which showed 39% activity at 50 mg/kg po and compound 7c exhibit good anticancer activity against ovary (IGR-OV-1), breast (MCF-7) and CNS(SF-295) human cancer cell lines.     

Synthesis and evaluation of antioxidant and antibacterial activities of new substituted bis(1,3,4-oxadiazoles), 3,5-bis(substituted) pyrazoles and isoxazoles

Two series of five membered heterocyclic bis(1,3,4-oxadiazole) derivatives 2(a-h) and 3,5-bis(substituted)pyrazoles, isoxazoles 3(a,b,d-i), 4(a-c) were synthesized via oxidative cyclization of some diaroylhydrazones using chloramine-T and cyclocondensation reaction with hydrazine hydrate and hydroxylamine hydrochloride, respectively. The newly synthesized compounds were screened for antioxidant and anti-microbial activities. Compounds 2(b), 3(b), and 4(a) showed higher antioxidant activity at 10 μg/ml while compounds 2(a), 3(a), 3(f), and 4(a) exhibited better anti-microbial activity at 100 μg/ml compared with standard vitamin C and ciprofloxacin, respectively. Structures of newly synthesized compounds were confirmed by elemental analysis and spectral IR, ¹H NMR, and ¹³C NMR data.     

Synthesis,antioxidant, antifungal,molecular docking and ADMET studies of some thiazolyl hydrazones

Some thiazolyl hydrazones were synthesized by one pot reaction of thiophene-2-carbaldehyde or 2, 4-dichlorobenzaldehyde, thiosemicarbazide and various phenacyl bromides which were preliminarily screened for in vitro antioxidant and antifungal activities. Excellent DPPH and H₂O₂ radical scavenged antioxidant activities were observed with almost all the tested compounds. Compounds 4a, 4b, 4c, 4e, 4f and 4i showed comparable DPPH scavenged antioxidant potential (90.26–96.56%) whereas H₂O₂ scavenged antioxidant activity (90.98–92.08%) was noticeable in case of 4a and 4f; showing significant antioxidant potential comparable with the standard ascorbic acid (95.3%). In vitro antifungal activity of synthesized compounds against fungal species Candida albicance, Aspergillus niger and Aspergillus flavus was found to be moderate to good as compared with the standard fluconazole and MIC values were found in the range of 3.12–25 μg/mL. Molecular docking studies revealed that the compounds 4a, 4b and 4c have a potential to become lead molecules in drug discovery process. In silico ADMET study was also performed for predicting pharmacokinetic and toxicity profile of the synthesized antioxidants which expressed good oral drug like behaviour and non-toxic nature.     

Synthesis and bio-evaluation of alkylaminoaryl phenyl cyclopropyl methanones as antitubercular and antimalarial agents

A series of 4-alkylaminoaryl phenyl cyclopropyl methanones (6a–6u and 8a–8c) were synthesized from 4-fluorochalcones (3a and 3b) by cyclopropanation of double bond followed by nucleophilic substitution of F with different amines. The compounds were screened for their antitubercular and antimalarial activities against Mycobacterium tuberculosis H37Rv and Plasmodium falciparum 3D7 strains in vitro respectively. Several compounds (6a, 6d–6h, 6p, 6q and 8a–8c) exhibited good in vitro antitubercular activities with MIC values 3.12–12.5 μg/mL and preferentially inhibited the growth of P. falciparum in vitro (4a, 4c, 6a–6d, 6f, 6s, 8a and 8c) with IC₅₀ as low as 0.080 and 0.035 μg/mL and SI values 4975 and 6948, respectively. Molecular docking studies and in vitro evaluation against FAS-II enzymes using reporter gene assays were carried out to elucidate the mode of action of these molecules. Two compounds 4a and 6g showed significant inhibition at 25 μM concentration of the compound.     

Synthesis,antimicrobial and anti-biofilm activities of novel Schiff base analogues derived from methyl-12-aminooctadec-9-enoate

A novel library of Schiff base analogues (5a–q) were synthesized by the condensation of methyl-12-aminooctadec-9-enoate and different substituted aromatic aldehydes. The synthesized compounds were thoroughly characterized by spectroscopic techniques (FT-IR, ¹H NMR, ¹³C NMR, ESI-MS and HRMS). The Schiff base analogues with different substitutions were screened for in vitro antibacterial activity against 7 different bacterial strains. Among these, the compounds with electron withdrawing substituent, namely chlorine (5a) and electron donating substituents, namely hydroxy (5n) and methoxy (5o), were found to exhibit excellent to good antimicrobial activities (MIC value 9–18 μM) against Staphylococcus aureus MTCC 96, Staphylococcus aureus MLS-16 MTCC 2940 and Bacillus subtilis MTCC 121. The products were also screened for anti-biofilm and MBC (Minimum Bactericidal Concentration) activities which exhibited promising activities.     

Efficient synthesis and antimicrobial activity of some novel S-β-d-glucosides of 5-aryl-1,2,4-triazole-3-thiones derivatives

A series of 3-S-β-d-glucosides-4-arylideneamino-5-aryl-1,2,4-triazoles were rationally designed and synthesized according to the principle of superposition of bioactive substructures by the combination of 1,2,4-triazole, Schiff base and glucosides. The structures of the target compounds have been characterized by ¹H NMR, ¹³C NMR, IR, MS and HRMS. All the newly synthesized compounds have been evaluated for their antimicrobial activities in vitro against Staphylococcus aureus (ATCC 6538), Escherichia coli (ATCC 8099) as well as Monilia albican (ATCC 10231). The bioactive assay showed that most of the tested compounds displayed variable inhibitory effects on the growth of the Gram-positive bacterial strain (Staphylococcus aureus), Gram-negative bacterial strains (Escherichia coli) and fungal strains (Monilia albican). All the target compounds exhibited better antifungal activity than antibacterial activity. Especially, compounds 6b, 6c, 6f, 6j, 6k and 6l showed excellent activity against fungus Monilia albican with MIC values of 16 μg/mL.     

Microwave-assisted synthesis of N-substituted cyclic imides and their evaluation for anticancer and anti-inflammatory activities

A number of N-substituted cyclic imides 3a–e, 5a–e, 7a–d, and 9a–e have been synthesized in very high yields, by condensation of various diacids 2, 4, 6, and 8 with different amines under microwave irradiation. These compounds were screened for anticancer and anti-inflammatory activities, and compounds 3c, 3e, 5c, 9c, and 9d exhibited anticancer activity against colon (COLO 205) cancer better than 5-fluorouracil and mitomycin-C, and compound 9b exhibited anti-inflammatory activity better than standard drug phenyl butazone.     

Synthesis,antimicrobial activity,structure-activity relationship and cytotoxic studies of a new series of functionalized (Z)-3-(2-oxo-2-substituted ethylidene)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-ones

A new series of functionalized (Z)-3-(2-oxo-2-substituted ethylidene)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-ones 23–26, incorporating pharmaceutically privileged substructures such as cyclopropyl, naphthyl, biphenyl and cyclohexylphenyl were synthesized in excellent yields. All the synthesized compounds were screened for their in vitro antibacterial activity against gram-(+)ve and gram-(?)ve bacterial species i.e. S. griseus, S. aureus, B. subtillis and E. coli as well as in vitro antifungal activity against fungal species i.e. F. oxysporium, A. niger, P. funiculosum and T. reesei, respectively. In this study, compounds containing cyclopropyl and cyclohexylphenyl substructures were identified as promising antimicrobial agents than standard drugs, ampicillin and chloramphenicol as well as ketoconazole. SAR study illustrates that electron-withdrawing groups increases the antibacterial as well as antifungal activity of 2-oxo-benzo[1,4]oxazines and vice versa. Compounds 23e and 26e, the most active compounds of the series, displayed promising antibacterial activity than Ampicillin and Chloramphenicol. Moreover, compound 26d showed promising antifungal potency as compared to Ketoconazole. Cytotoxic studies of the active compounds i.e. 23c–e, 24e, 25d and 26d–e found to be non-toxic in nature in 3T₃ fibroblast cell lines using MTT assay.