Discovery and synthesis of 2-amino-1-methyl-1H-imidazol-4(5H)-ones as GPCR ligands; an approach to develop breast cancer drugs via GPCR associated PAR1 and PI3Kinase inhibition mechanism.

Efforts were taken to synthesis and characterize 2-amino-1-methyl-1H-imidazole-4(5H)-one derivatives (4a-u) through a four-step reaction. The achieved compounds in remarkable yield have characterized through standard analytical techniques such as FTIR, LC-MS, NMR, HRMS, and elemental analysis. Present study mainly aimed to evaluate 4a-u as G protein-coupled receptors (GPCR). In the mechanism, stimulation of phosphoinositide 3-kinase (PI3K) and Akt (protein kinase B) is a general reaction activated by a series of membrane-bound receptors such as GPCR. Protease-activated receptor-1 (PAR1) is a subfamily of related GPCR, which triggered by the division of fragment of its extracellular domain. Therefore, molecular docking is done to ensure the inhibition of PAR1 and PI3Kinase. PI3Kinase is a chief enzyme in the development of breast cancer via the Akt/mTOR pathway. Thus, in vitro PI3Kinase inhibition and anti-breast cancer studies has also done to screen medicinally important compounds among (4a-u). Based on the best binding affinity, in vitro relative % activity and IC50 values, compounds 4a, 4g, 4i, 4n, and 4u were screened for further preclinical studies in animal model evaluations.

Synthesis characterization and anticancer activity studies on some Mannich bases derived from 1,2,4-triazoles.

A series of 3-substituted 4-[5-(4-methoxy-2-nitrophenyl)-2-furfurylidene] amino-5-mercapto-1,2,4-triazoles (3) were synthesized. Aminomethylation of compounds 3 with formaldehyde and various secondary amines furnished Mannich bases 4 and 5. These compounds were characterized on the basis of IR, 1H-NMR, mass spectral data and elemental analysis. The newly synthesized compounds were screened for their anticancer activity against a panel of 60 cell lines derived from seven cancer types namely, lung, colon, melanoma, renal, ovarian, CNS and leukemia. Some of the compounds were slightly more potent.

New bis-aminomercaptotriazoles and bis-triazolothiadiazoles as possible anticancer agents.

A series of bis-phenoxyacetic acids 2 were prepared starting from corresponding unsubstituted/substituted 1,4-quinols 1. The fusion of bis-phenoxyacetic acids 2 with thiocarbohydrazide gave the corresponding bis-[4-amino-5-mercapto-1,2,4-triazol-3-yl-methyleneoxy]phenylenes (3) in a one pot reaction. The reaction of bis-triazoles 3 with various reagents afforded N-bridged heterocycles 4-6 in good yields. The newly synthesised compounds were screened for their anticancer activity against a panel of 60 cell lines derived from seven cancer types namely, lung, colon, melanoma, renal, ovarian, CNS and leukemia. Some of the tested compounds showed promising anticancer properties.

Studies on nitrophenylfuran derivatives part Xii. synthesis, characterization, antibacterial and antiviral activities of some nitrophenylfurfurylidene-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines.

Synthesis of four 1-aryl-3-[5-(p-nitrophenyl)-2-furyl]-2-propen-1-ones starting from substituted acetophenones and p-nitrophenylfurfuraldehyde is described. These propenones were then converted into corresponding dibromo derivatives which on dehydrobromination afforded alpha-bromopropenones rather than acetylenic ketones. Condensation of these dibromopropanones with 4-amino-5-mercapto-1,2,4-triazoles yielded a new class of nitrophenylfurfurylidene-1,2,4-triazolothiadiazines. The structures of nitrophenylfurfurylidene-1,2,4-triazolothiadiazines were established on the basis of analytical, IR, NMR and mass spectral studies. The formation of 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines rather than 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazepines in the above condensation was unambiguously confirmed by X-ray crystallographic analysis of one of them. A possible mechanism is proposed to account for the formation of nitrophenylfurfurylidene-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines. Some of the newly synthesized triazolothiadiazines were screened for their antibacterial and antiviral properties.

Studies on arylfuran derivatives: part X. Synthesis and antibacterial properties of arylfuryl-delta2-pyrazolines.

Arylfurylpropenones 3 were synthesized by Claisen-Schmidt condensation of arylfurfurals 1 with various substituted acetophenones 2. Cyclocondensation of these arylfurylpropenones 3 with hydrazine hydrate and phenylhydrazine furnished 1H-pyrazolines 4 and N-phenylpyrazolines 6, respectively. In order to study the structure-activity relationships, pyrazolines 4 were converted into their N-acetyl derivatives 5. The antibacterial properties of the new pyrazoline derivatives were studied.

Studies on arylfuran derivatives- Part VIII. Synthesis, characterization and antibacterial activities of some 1-aminomethyl-3-substituted-4-[5-(4-nitrophenyl-2-furfurylidene)] amino-1,2,4-triazole-5-thiones.

A series of 4-[5-(4-nitrophenyl-2-furfurylidene)]amino-5- mercapto-3-substituted-s-triazoles (3) and their Mannich bases (4) are synthesized. The structures of these compounds are established on the basis of elemental analysis, IR, NMR and mass spectral data. The newly synthesized compounds are screened for their antibacterial activities.

Studies on arylmethyltriazinone derivatives-Part II. Synthesis and antifungal properties of 2-aminomethyl-4-(arylidene)amino-6-arylmethyl- 3-mercapto-1,2,4-triazin-5(4H)-ones.

The preparation of twenty new 2-aminomethyl-4-(arylidene)amino- 6-arylmethyl-3-mercapto-1,2,4-triazin-5(4H)-ones(4) is described. The structural elucidation of all the compounds is carried out on the basis of analytical and spectral data. The newly synthesized compounds are evaluated for their antifungal activity against Candida albicans and Paecileomyces variotti.

Studies on arylfuran derivatives. Part VII. Synthesis and characterization of some Mannich bases carrying halophenylfuryl moieties as promising antibacterial agents.

A series of 4-[5-(halophenyl)-2-furfurylidene)] amino-3-mercapto-5-substituted-1,2,4-triazoles (3) were synthesized. Aminomethylation of 3 with formaldehyde and a secondary amine furnished Mannich bases, 4. Both Schiff bases and Mannich bases were characterized on the basis of IR, NMR, mass spectral data and elemental analysis. All the newly synthesized compounds were tested for their antibacterial activities. Some of them carrying morpholino and N-methylpiperazino residues were found to be promising antibacterial agents.

Studies on arylfuran derivatives-Part VI. Synthesis, characterization and antibacterial activities of some 6-(5-aryl-2-furyl)-1,2,4-triazolo [3,4-b]-1,3,4-thiadiazoles and 6-(5-nitro-2-furyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles.

A series of 4-[5-aryl-2-furfurylidene]amino-3-mercapto-5-substituted-1,2,4-tri azoles and 4-[5-Nitro-2-furfurylidene]amino-3-mercapto-5-substituted-1,2,4-tr iazoles have been synthesized and were converted into 1,2,4-triazolo [3,4-b]-1,3,4-thiadiazoles. These triazolothiadiazoles are also synthesized by an alternative method in better yields employing arylfuroic acids and s-triazoles in the presence of phosphorus oxychloride. The newly synthesized compounds are screened for their antibacterial properties.

Studies on arylfuran derivatives--Part V. Synthesis and antibacterial properties of 7H,6-[5-(4-nitrophenyl)-2-furyl]-1,2,4-triazolo [3,4-b]-1,3,4-thiadiazines.

The preparation of fifteen new 7H, 6-[5-(4-nitrophenyl)-2-furyl]-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine is described. The structural elucidation of all the compounds is carried out on the basis of analytical and spectral data. The newly synthesized compounds are evaluated for their antibacterial activity against both Gram-positive and Gram-negative bacteria.

Studies on arylfuran derivatives--Part IV. Synthesis and antibacterial properties of arylfurylvinylquinazolinones.

A number of arylfurylvinylquinazolinones were prepared as possible antibacterial agents. The structural elucidations of all the compounds were carried out on the basis of analytical and spectral data. The newly synthesised compounds were screened for their antibacterial properties against both Gram-positive and Gram-negative bacteria.