Design, synthesis, and biological activity of novel 4-(3,4-dimethoxyphenyl)-2-methylthiazole-5-carboxylic acid derivatives

Novel 4-(3,4-dimethoxyphenyl)-2-methylthiazole-5-carboxylic acid derivatives (11-23) were synthesized from 3,4-dimethoxyacetophenone (5) in six-step procedure. Their biological activities were evaluated in the greenhouse. Some of the compounds had shown fungicidal and insecticidal activities at 375 g ai/ha and 600 g ai/ha, respectively.     

Synthesis of 5-arylidene-2-amino-4-azolones and evaluation of their anticancer activity

Series of novel 5-arylidene-2-arylaminothiazol-4(5H)-ones and 2-aryl(benzyl)amino-1H-imidazol-4(5H)-ones were synthesized from appropriate 2-alkylthioazol-4-ones using nucleophilic substitution in position 2 by various anilines and benzylamines and Knoevenagel reaction. X-ray structural studies of 22 revealed the structure to be intermediate between amino and imino tautomeric forms. All the target compounds were evaluated for the anticancer activity in vitro in standard National Cancer Institute 60 cancer cell lines assay. Majority of compounds showed significant antitumor cytotoxicity effect at micromolar and submicromolar level (Mean Log GI₅₀ ranges ?5.77 to ?4.35). Some of the most potent compounds, namely 10 and 13, possessed selectively high effect on all leukemia cell lines at submicromolar level (Mean Log GI₅₀ [leukemia lines], respectively, ?6.41 and ?6.29), which are probably associated with immunosuppressive activity. Individual cancer cell lines sensitivity to synthesized compounds and SAR studies are discussed. COMPARE analysis allowed to disclose probable modes of anticancer action for synthesized compounds, in particular showed number of high correlations with activity patterns of alkylating agents (PCC ～ 0.606–0.731).     

Inhibitors of the tissue factor/factor VIIa-induced coagulation: synthesis and in vitro evaluation of novel specific 2-aryl substituted 4H-3,1-benzoxazin-4-ones

The synthesis of a series of novel 2-aryl substituted 4H-3,1-benzoxazin-4-ones and their evaluation as specific inhibitors of the Tissue Factor (TF)/Factor VIIa (FVIIa)-induced pathway of coagulation is reported. Inhibitory activities (IC50 values) in the range 0.17 to > 40 microM on the activation of Factor X (FX) by the TF/FVIIa complex were found for compounds having one or two electronegative substituents such as F, Cl and NO2 in the 2-aryl substituent. Different substitutions both electron-attracting and donating groups were allowed in the 5, 6, 7 and 8 positions. Several of the compounds showed a selectivity ratio towards FX and thrombin of > 50, thus being the first small molecules described as potential drugs for oral antithrombotic treatment without side effects such as bleeding which is observed especially with thrombin inhibitors. The best substituent pattern being the 2-aryl group substituted with: 2-F; 2,6-F2; or 2-FX; 6-Cl; together with electronegative substitution in the 5, 6, 7, or 8 positions. 2-Heteroaryl substituents like thienyl and furanyl were of low activity while some 2-(2-chloro-3-pyridyl) derivatives had inhibitory activity < 10 microM and a good selectivity.     

4-Aryl/cycloalkyl-5-phenyloxazole derivatives as selective COX-2 inhibitors.

A series of 4-aryl/cycloalkyl-5-phenyloxazole derivatives was synthesized and evaluated for their ability to inhibit cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1). These compounds were found to be potent and selective COX-2 inhibitors.     

Design,synthesis, in silico and in vitro studies of novel 4-methylthiazole-5-carboxylic acid derivatives as potent anti-cancer agents

Since inhibitors of mucin onco proteins are potential targets for breast cancer therapy, a series of novel 4-methylthiazole-5-carboxylic acid (1) derivatives 3a–k were synthesized by the reaction of 1 with SOCl₂ followed by different bases/alcohols in the presence of triethylamine. Once synthesized and characterized, their binding modes with MUC1 were studied by molecular docking analysis using Aruglab 4.0.1 and QSAR properties were determined using HyperChem. All synthesized compounds were screened for in vitro anti-breast cancer activity against MDA-MB-231 breast adenocarcinoma cell lines by Trypan-blue cell viability assay and MTT methods. Compounds 1, 3b, 3d, 3e, 3i and 3f showed good anti-breast cancer activity. Since 1 and 3d exhibited high potent activity against MDA-MB-231 cell lines, they show could be effective mucin onco protein inhibitors.     

Synthesis of Some New Fluorine Containing 2-(N-Arylamino)/2-methyl-4-aryl Thiazoles and Their Bactericidal Activity

Sixteen fluorine containing 2-(N-arylamino)/2-methyl-4-aryl thiazoles have been synthesised and characterized by spectral (IR and NMR) studies. Some representative compounds have also been screened for their bactericidal activity.     

Synthesis and in vitro antitubercular activity of 4-aryl/alkylsulfonylmethylcoumarins as inhibitors of Mycobacterium tuberculosis

A series of 4-aryl/alkylsulfonylmethylcoumarins have been synthesized and screened for in vitro antitubercular activity against Mycobacterium tuberculosis H(37)Rv (MTB). Four of the compounds showed MIC in the range of 0.78-3.13 μg/mL proving their potential activity.     

C-aryl glucosides substituted at the 4'-position as potent and selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes

A series of C-aryl glucosides with various substituents at the 4′-position of the distal aryl ring have been synthesized and evaluated for inhibition of hSGLT1 and hSGLT2. Introduction of alkyl or alkoxy substituents at the 4′-position was found to improve SGLT2 potency, whereas introduction of a hydrophilic group at this position was deleterious. Compounds with alkoxy-, cycloalkoxy- or cycloalkenyloxy-ethoxy scaffolds exhibited good inhibitory activity and high selectivity toward SGLT2. Selected compounds were investigated for in vivo efficacy.     

Inhibitors of the tissue factor/factor VIIa-induced coagulation: synthesis and in vitro evaluation of novel 2-aryl substituted pyrid

The synthesis of a series of 2-aryl substituted hetero annulated 1,3-oxazin-4-ones and their evaluation as specific inhibitors of the tissue factor (TF)/factor VIIa (FVIIa)-induced pathway of coagulation is reported. Inhibitory activities (IC₅₀ values) in the range 0.64 to >40 μM on the activation of factor X (FX) by the TF/FVIIa complex were found for compounds having one or two electronegative substituents such as F and NO₂ in the 2-aryl substituent. Some of the compounds showed a selectivity ratio towards FX and thrombin of >50, thus being similar in specificity to 2-aryl substituted 4H-3,1-benzoxazin-4-ones described as potential drugs for oral antithrombotic treatment without side effects, such as bleeding, which is observed especially with thrombin inhibitors.     

The synthesis of 2- and 3-aryl indoles and 1,3,4,5-tetrahydropyrano[4,3-b]indoles and their antibacterial and antifungal activity

A series of 2- and 3-aryl substituted indoles and two 1,3,4,5-tetrahydropyrano[4,3-b]indoles were synthesized from indole and 5-methoxyindole. The 2-aryl indoles were synthesized from the 1-(phenylsulfonyl)indole derivatives using magnesiation followed by iodination. The 2-iodinated compounds were then subjected to Suzuki–Miyaura reactions. In addition, the 3-aryl indoles were made from the corresponding 3-bromoindoles using Suzuki–Miyaura reactions. The 1,3,4,5-tetrahydropyrano[4,3-b]indoles were also synthesized from 1-(phenylsulfonyl)indole by magnesiation followed by treatment with allylbromide. The product was then converted into [2-allyl-1-(phenylsulfonyl)-1H-indol-3-yl]methanol which upon exposure to Hg(OAc)₂ and NaBH₄ afforded tetrahydropyrano[4,3-b]indoles. A number of the 2- and 3-aryl indoles displayed noteworthy antimicrobial activity, with compound 13a displaying the most significant activity (3.9 μg/mL) against the Gram-positive micro-organism Bacillus cereus.     

Synthesis, anti-inflammatory, analgesic and antioxidant activities of some tetrasubstituted thiophenes

Sets of tetrasubstituted thiophene esters 4a-4g, 5a-5f and 6a-6e were synthesized by reaction of 1-(alpha-Carbomethoxy-beta-aminothiocrotonoyl)-aryl/aroyl amines (3) with 3-(bromoacetyl)coumarin, 1,4-dibromodiacetyl and chloroacetone respectively. The compound 3 were synthesized by nucleophilic addition of aryl/aroylisothiocyanate and enamine (2). The synthesized targeted compounds (4a-4g, 5a-5f and 6a-6e) were evaluated for their in vivo anti-inflammatory activity in carrageenin-induced rat hind paw oedema model at three graded doses employed at 10, 20 and 40 mg/kg body weight using mefanamic acid, ibuprofen and in vivo analgesic activity in acetic acid induced writhing response model at 10 mg/kg dose using ibuprofen as standard drug. The compounds 4a-4f, 5c, 5f, 6c and 6e were evaluated for their in vitro antioxidant nitric oxide radical scavenging assay at the concentrations of 5, 10, 15, 20, 25, 30 and 35 microg/mL using ascorbic acid as standard drug. Among all the targeted compounds 4c showed maximum anti-inflammatory activity of 71% protection at 10 mg/kg and 77% protection at 20 mg/kg to inflamed paw and analgesic activity of 56% inhibition and also maximum in vitro nitric oxide radical scavenging activity having IC(50) value 31.59 microg/mL.     

Discovery of benzimidazole derivatives as novel multi-target EGFR, VEGFR-2 and PDGFR kinase inhibitors

Multi-target EGFR, VEGFR-2 and PDGFR inhibitors are highly useful anticancer agents with improved therapeutic efficacies. In this work, we used two virtual screening methods, support vector machines (SVM) and molecular docking, to identify a novel series of benzimidazole derivatives, 2-aryl benzimidazole compounds, as multi-target EGFR, VEGFR-2 and PDGFR inhibitors. 2-Aryl benzimidazole compounds were synthesized and their biological activities against a tumor cell line HepG-2 and specific kinases were evaluated. Among these compounds, compounds 5a and 5e exhibited high cytotoxicity against HepG-2 cells with IC?? values at ～2 μM. Further kinase assay study showed that compound 5a have good EGFR inhibitory activity and moderate VEGFR-2 and PDGFR inhibitory activities, while 5e have moderate EGFR inhibitory activity and slightly weaker VEGFR-2 and PDGFR inhibitory activities. Molecular docking analysis suggested that compound 5a more tightly interacts with EGFR and PDGFR than compound 5e. Our study discovered a novel series of benzimidazole derivatives as multi-target EGFR, VEGFR-2 and PDGFR kinases inhibitors.     

Synthesis and in vitro cytotoxicity of 5-substituted 2-cyanoimino-4-imidazodinone and 2-cyanoimino-4-pyrimidinone derivatives

A series of 5-substituted 2-cyanoimino-4-imidazodinone and 2-cyanoimino-4-pyrimidinone derivatives were synthesized and their anticancer cytotoxicity were evaluated in in vitro assay. It was found that the bulky aryl functionality in the 5-position of the 2-cyanoimino-4-imidazolidinone compounds was essential for the cytotoxicity of these heterocyclic compounds. Some of the derivatives exhibited modest cytotoxicity against a variety of cancer cell lines. One of the derivatives, [1-[6-(4-chlorophenoxy)hexyl]-5-oxo-4-phenyl-3-(4-pyridyl)tetrahydro-1H-2-imidazolyliden]aminomethanenitrile (Compound 11), exhibited the most potent cytotoxic activity with IC(50) in the nanomolar range. The cytotoxicity of these derivatives was selection with no apparent toxic effect toward normal fibroblasts.     

Synthesis and antituberculosis activity of new 3-alkylsulfanyl-1,2,4-triazole derivatives

The increasing clinical importance of drug-resistant mycobacterial pathogens has lent additional urgency to microbiological research and new antimycobacterial compound development. For this purpose, new alkylsulfanyltriazoles were synthesized and evaluated for antituberculosis activity. The reaction of thienyl-2-acetic acid with thiocarbohydrazide gave the mercaptotriazoles (II). The 4-amino-5-(2-thienylmethyl)-3-[1-(2-thienyl)-3-aryl) propion-3-yl] sulfanyl-4H-1,2,4-triazole (III) derivatives were synthesized by reacting the mercaptotriazoles with chalcones (I). Antituberculosis activities of the synthesized compounds were determined by broth microdilution assay, the Microplate Alamar Blue Assay, in BACTEC 12B medium and results were screened in-vitro, using BACTEC 460 Radiometric System against Mycobacterium tuberculosis H37Rv (ATCC 27294) at 6.25 microg/ml and the tested compounds showed considerable inhibition ranging from 58-84%.     

Synthesis,identification and in vitro biological evaluation of some novel quinoline incorporated 1,3-thiazinan-4-one derivatives

The present study describes the synthesis of two new series of 3-hydroxy-N-(4-oxo-2-phenyl-1,3-thiazinan-3-yl)-8-(trifluoromethyl)quinoline-2-carboxamide derivatives (4a–j) and 3-((7-chloroquinolin-4-ylamino)methyl)-2-phenyl-1,3-thiazinan-4-one derivatives (5a–7j). All the compounds were synthesized in moderate to good yield by one-pot three component cyclo-condensation reaction. The newly synthesized compounds were characterized by FT-IR, ¹H, ¹³C NMR and elemental analysis. The compounds were screened for their in vitro antibacterial activity against a panel of pathogenic bacterial strains, antitubercular activity against Mycobacterium tuberculosis H₃₇Rv and also for their in vitro antimalarial activity against Plasmodium falciparum. Among the synthesized compounds two of them (4f and 5f) showed excellent antibacterial activity against C. tetani at 15.6 μg/mL. Some of them exhibited excellent antitubercular (4f & 5f) and good antimalarial (4f, 5f & 6f) activity compared with the first line drugs.     

Synthesis and pharmacological screening: Sulfa derivatives of 2-pipecoline-bearing 1,3,4-oxadiazole core

An electrophile, 1-(4-(bromomethylbenzenesulfonyl)-2-methylpiperidine, was synthesized by the reaction of 2-methylpiperidine (2-pipecoline) and 4-bromomethylbenzenesulfonyl chloride in a weak basic medium under pH control. A series of nucleophiles, 5-aryl/aralkyl-1,3,4-oxadiazol-2-thiols, were synthesized from corresponding carboxylic acids in three steps. The title molecules were synthesized by coupling the electrophile to nucleophiles in an aprotic medium using LiH as an activator. The structures of all synthesized compounds were corroborated through IR, ¹H NMR, and EI-MS techniques. All the compounds were screened for their pharmacological behavior, particularly, antibacterial and enzyme inhibitory activities. Notably efficient results were obtained against both gram-positive and gram-negative bacterial strains. Regarding enzyme inhibition, compounds were efficient against acetylcholinesterase and butyrylcholinesterase.     

Synthesis,characterization, anticancer,antimicrobial and carbonic anhydrase inhibition profiles of novel (3aR,4S,7R,7aS)-2-(4-((E)-3-(3-aryl)acryloyl) phenyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione derivatives

In the present study, a series of new hybrid compounds containing chalcone and methanoisoindole units 7a-n ((3aR,4S,7R,7aS)-2-(4-((E)-3-(3-aryl)acryloyl) phenyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione) were synthesized, characterized and investigated for their anticancer activity against C6 gliocarcinoma cell in rats, and antimicrobial activity against some human pathogen microorganisms. The compounds 7e, 7h, 7j, 7k, 7L and 7n showed very high anticancer activity with the inhibition range of 80.51–97.02% compared to 5-FU. Some of the compounds exhibited anti-microbial activity. Also, they evaluated for inhibition effects against human carbonic anhydrase I, and II isoenzymes (hCA I and II) with Ki values in the range of 405.26–635.68 pM for hCA I, and 245.40–489.60 pM for hCA II, respectively. These results demonstrated that 3aR,4S,7R,7aS)-2-(4-((E)-3-(3-aryl)acryloyl)phenyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione derivatives could be used in different biomedical applications.     

Synthesis and antimycobacterial activity of 4-(5-substituted-1,3,4-oxadiazol-2-yl)pyridines

4-(5-Substituted-1,3,4-oxadiazol-2-yl)pyridine derivatives 1-12 were synthesized and evaluated for their in vitro antimycobacterial activity. Some compounds showed an interesting activity against Mycobacterium tuberculosis H(37)Rv and five clinical isolates (drug-sensitive and -resistant strains). Compound 4 [4-(5-pentadecyl-1,3,4-oxadiazol-2-yl)pyridine] was 10 times more active than isoniazid, 20 times more active than streptomycin, and 28 times more potent than ethambutol against drug-resistant strain CIBIN 112. Compound 5 [4-(5-heptadecyl-1,3,4-oxadiazol-2-yl)pyridine] showed the same behavior as compound 4. Both of the above structures bear a high lipophilic chain bonded to the 5-position of the oxadiazole moiety. This fact implies that there exists a contribution of lipophilicity, which could facilitate the entrance of these molecules through lipid-enriched bacterial cell membrane.     

Synthesis and biological evaluation of arylhydrazinocyanoacrylates and N-aryl pyrazolecarboxylates

A series of arylhydrazino-substituted cyanoacrylates 3 and N-aryl pyrazolecarboxylates 6 were synthesized and their bioactivities were evaluated. Though compounds 3 were designed as herbicide, some of them showed fungicidal activity and anti-tumor activity. Some of the compounds 6 exhibited plant growth regulatory activity.