Synthesis,crystal structure,and ADME prediction studies of novel imidazopyrimidines as antibacterial and cytotoxic agents

In the present study, a novel series of polyfunctionalized imidazopyrimidines 6a–u and 9a–d were efficiently constructed by a domino reaction between 2-imino-6-substituted-2,3-dihydropyrimidin-4(1H)-ones 4a–d or 8a–c and 2-bromoacetophenones 5a–i under mild basic conditions. The synthesized series were screened for their antibacterial activity against Staphylococcus aureus and Bacillus subtilis as Gram-positive (+) bacteria, as well as against Gram-negative (−) bacteria Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Salmonella typhi. Most of the synthesized derivatives of imidazopyrimidines 6 and 9 showed remarkable selectivity against Gram(−) bacteria over the Gram(+) ones. Compounds 6c , 6f , and 6g displayed potent and broad-spectrum antibacterial activity against all tested strains. Compounds 6f and 6g displayed promising inhibitory activity on GryB ATPase from E. coli with IC₅₀ = 1.14 and 0.73 μM, respectively. Simultaneously, some of the synthesized imidazopyrimidines were screened for their antiproliferative activity against 60 cancer cell lines at a concentration of 10 μM. Compound 9d showed potent activity against most of the tested cell lines, with a mean growth inhibition of 37%. The ADME (absorption, distribution, metabolism, and excretion) prediction study demonstrated that the synthesized hits have, in addition to their promising chemotherapeutic activity, acceptable pharmacokinetic properties, and a drug-likeness nature to be further developed.     

Synthesis and anti-BVDV activity of acridones as new potential antiviral agents

In this study we report the design, synthesis, and activity against bovine viral diarrhea virus (BVDV) of a novel series of acridone derivatives. BVDV is responsible for major losses in cattle. The virus is also considered to be a valuable surrogate for the hepatitis C virus (HCV) in antiviral drug studies. Some of the synthesized acridones elicited selective anti-BVDV activity with EC(50) values ranging from 0.4 to 4 microg/mL and were not cytotoxic at concentrations that were 25- to 200-fold higher (CC(50) >100 microg/mL). It was proven that the most potent acridone derivative 10 was able to not only protect cells from virus-induced cytopathic effect but also reduce the production of infectious virus and extracellular viral RNA. Furthermore, compound 10, as well as a number of other analogues, inhibited HCV replication to some extent. However, there was no direct correlation between anti-BVDV and anti-HCV activity. Thus, the acridone scaffold, when appropriately functionalized, can yield compounds with selective activity against pestiviruses and related viruses such as the HCV.     

Synthesis,characterization, and computational studies on phthalic anhydride-based benzylidene-hydrazide derivatives as novel,potential anti-inflammatory agents

A series of phthalic anhydride-based substituted benzylidene-hydrazide derivatives (3a–i) was synthesized. The synthesized derivatives were authenticated by TLC, UV–visible, FTIR, NMR, and mass spectroscopic techniques and further screened for in vivo anti-inflammatory and analgesic activities by carrageenan-induced rat paw oedema and tail immersion methods, respectively, using diclofenac sodium as standard drug. The derivatives 3d, 3e, and 3h were found to be most active anti-inflammatory and analgesic agents among all the synthesized derivatives. The physico-chemical similarity of the derivatives with standard drugs was assessed by calculating various physicochemical properties using software programs. The percent similarity of synthesized derivatives was found to be good except 3i. The derivatives were subjected to QSAR by multilinear regression using Analyze it version 3.0 software and two statistically sound models were developed with R ² (0.933–0.960), $ R_{{adj}}^{2} $ (0.595–0.762) and Q ² (0.999) with good F (2.76–4.84) values. Molecular docking studies were performed by MVD software (version 2012.5.0.0). The derivative 3h has emerged out as most potent anti-inflammatory agent with highest dock score, i.e., ?93.64.     

Synthesis of the acridone alkaloids glyfoline and congeners. Structure-activity relationship studies of cytotoxic acridones.

Glyfoline (4, 1,6-dihydroxy-10-methyl-2,3,4,5-tetramethoxyacridin-9-one) and its congeners were synthesized for evaluation of their cytotoxicity. A detailed structure-activity relationships (SAR) of these acridone derivatives were also studied. To study the SAR of glyfoline analogues, substituent(s) at C-1 and C-6 and at the heterocyclic nitrogen of glyfoline nucleus were modified. Nitro- and amino-substituted glyfoline analogues were also synthesized to study the effects of substituent(s) (electron-withdrawing vs electron-donating) on their cytotoxicity. These compounds were synthesized via the Ullmann condensation of anthranilic acids with iodobenzenes or 2-chlorobenzoic acids with aniline derivatives. The SAR studies showed that 1-hydroxy-9-acridones were more active than their 1-OMe derivatives against cell growth of human leukemic HL-60 cells in culture. Replacement of NMe of glyfoline with NH or N(CH2)2NEt2 resulted in either total loss or dramatic reduction of cytotoxicity. Glyfoline congeners with nitro function at the A-ring were inactive, while compounds with amino substituent were shown to be cytotoxic in vitro.     

Synthesis, characterization and cytotoxic activity of new salicylaldehyde benzoylhydrazone derivatives as potential anti-proliferative agents

Three new hydrazones, derivatives of salicylaldehyde benzoylhydrazone, were synthesized as potential anti-proliferative compounds. The structure of the new compounds was characterized by elemental and thermo-gravimetric analyses, IR, 1H and 13C-NMR spectroscopy and quantum chemical calculations. The cytotoxic effects of new hydrazones were examined on a wide spectrum of human tumor cell lines. The obtained results revealed that all compounds proved to be equipotent or moreactive than cisplatin, and far more activethan another utilized anticancer drug, melphalan. On the basis of IC50 values the compound 3-methoxy-salicylaldehyde isonicotinoylhydrazone (mSIH) was found to be the most active cytotoxic agent at all cell lines.     

Synthesis,characterization, biological evaluation,and in silico studies of novel 1,3-diaryltriazene-substituted sulfathiazole derivatives

In the present study, a series of eleven novel 1,3-diaryltriazene-substituted sulfathiazole moieties ( ST1 – 11 ) was synthesized by the reaction of diazonium salt of sulfathiazole with substituted aromatic amines and their chemical structures were characterized by Fourier transform infrared, ¹H-NMR (nuclear magnetic resonance), ¹³C-NMR, and high-resolution mass spectroscopy methods. These synthesized novel derivatives were found to be effective inhibitor molecules for α-glycosidase (α-GLY), human carbonic anhydrase (hCA), and acetylcholinesterase (AChE), with K_I values in the range of 426.84 ± 58.42–708.61 ± 122.67 nM for α-GLY, 450.37 ± 50.35–1,094.34 ± 111.37 nM for hCA I, 504.37 ± 57.22–1,205.36 ± 195.47 nM for hCA II, and 68.28 ± 10.26–193.74 ± 19.75 nM for AChE. Among the synthesized novel compounds, several lead compounds were investigated against the tested metabolic enzymes. More specifically, ST11 (4-[3-(perfluorophenyl)triaz-1-en-1-yl]-N-(thiazol-2-yl)benzenesulfonamide) showed a highly efficient inhibition profile against hCA I, hCA II, and AChE, with K_I values of 450.37 ± 50.35, 504.37 ± 57.22, and 68.28 ± 10.26 nM, respectively. Due to its significant biological inhibitory potency, this derivative may be considered as an interesting lead compound against these enzymes.     

Synthesis, characterization and their anticonvulsant, anti-inflammatory studies of some novel chromeno oxadiazoles

In this study, a series of new 1,2,4-oxadiazole derivatives containing 3,4-dihydro-2H-chromen-2-amine moiety were synthesized by efficient microwave reaction of 2-amino-N′-hydroxychroman-3-carboxamidine and suitable aldehyde. Structures of all the synthesized compounds were confirmed by spectral studies and C, H, N analyses. Newly synthesized compounds were screened for their anticonvulsant and anti-inflammatory properties. Few of the compounds exhibited excellent anticonvulsant activity as compared to the standard drug Diazepam. Also compounds have exhibited moderate anti-inflammatory activity as compared to the standard drug Diclofenac sodium.     

Synthesis and characterization of HPMC derivatives as novel duodenum-specific coating agents

HPMC (Hydroxypropyl methylcellulose) was chemically modified, using maleic anhydrides, to obtain pH-sensitive HPMCAM (Hydroxypropyl methylcellulose acetate maleate) polymers for use as novel duodenum-specific coating agents. The pharmaceutical properties of HPMCAM, such as film forming, acid values, pH-sensitive values, water vapor permeability, tensile strength and Tg, were investigated, and found to show good film forming properties. The pH-sensitive values were 3.0 to 3.7. In vitro results demonstrate that HPMCAM could completely suppress drug release within 2h in a simulated gastric fluid (pH 1.2) and rapidly release the drug in a simulated pathological duodenal fluid (pH 3.4). These results indicate that HPMCAM might be a useful material for a duodenum-specific drug delivery system.     

Synthesis, biological evaluation and molecular docking studies of 1,3-benzoxazine derivatives as potential anticancer agents

A series of 6 and/or 8-substituted derivatives of 1,3-benzoxazines, having flavone moiety at 3-position, have been synthesized. For synthesis of the compounds, 6 or/and 8-substituted saliscylaldehydes were reacted with aminoflavone followed by reduction, and CHCl₃/HCHO promoted cyclization to give corresponding aminoflavone precursors which provided the desired 1,3-benzoxazine skeleton. Cytotoxic effects of the synthesized compounds were investigated in vitro against human breast cancer (MCF-7) cell lines. Among the compounds tested, methyl (3f and 6f), methoxy (3h, 3i, and 6h), and chloro (3d) derivatives were found to be most potent with IC₅₀ values of 14.3, 14.9, 17.1, 8.03, 12.1, and 12.03 μM, respectively. Molecular docking studies of most active compounds of the series revealed that they bind to a narrow hydrophobic pocket of the N-terminal chain in the ATP binding site of EGFR.     

Synthesis of 1,3-thiazine derivatives and their evaluation as potential antimycobacterial agents.

A series of eight 5,6-dihydro-4H-1,3-thiazine derivatives was synthesized by the BF3 x Et2O-catalyzed reaction of selected alpha,beta-unsaturated ketones with thiobenzamide at room temperature. The antimycobacterial activities of these compounds were determined against Mycobacterium tuberculosis H37Rv (ATCC 27294) using the Alamar blue susceptibility assay. Three compounds, 5-hydroxy-3-phenyl-4-aza-2-thiabicyclo[3.3.1]none-3-ene 3a, 4-hydroxy-4-methyl-6-pentyl-2-phenyl-5,6-dihydro-4H-1,3-thiazine 3b, and 4-ethyl-4-hydroxy-2-phenyl-5,6-dihydro-4H-1,3-thiazine 3c exhibited inhibitory activities of 97, 77 and 76%, respectively, at a concentration of 6.25 microg/ml. The actual MIC99 for the most active of these compounds, 3a, was also determined to be >6.25 microg/ml. These results, and especially those for 3a, suggest that 1,3-thiazines are potential lead compounds in the search for new antitubercular agents.     

Synthesis,characterization of 4,6-disubstituted aminopyrimidines and their sulphonamide derivatives as anti-amoebic agents

The present study describes the synthesis and anti-amoebic activity of 4,6-disubstituted aminopyrimidines (1b–10b) and their sulphonamide derivatives (1–20). All the desired compounds were characterized by spectral data and their purity was confirmed by elemental analysis. The aim of the study was to explore the effect of the target compounds on in vitro growth of HM1:IMSS strain of Entamoeba histolytica. In vitro anti-amoebic activity was performed by microdilution method and the results were compared with standard drug metronidazole. The results revealed that sulphonamide derivatives (1–20) showed better activity than 4,6-disubstituted aminopyrimidines (1b–10b). 5 pyrimidine and 12 sulphonamide derivatives were better inhibitors of the growth of E. histolytica than the reference drug metronidazole (IC₅₀ = 1.80 μM). The promising in vitro anti-amoebic activity of the compounds make them promising molecules for further lead optimization in the development of novel anti-amoebic agents, therefore, it is hoped that these preliminary results could help in designing better molecules with an enhanced anti-amoebic activity.     

Synthesis and biological evaluation of novel hydrazide based cytotoxic agents

Recently, we designed and synthesized a series of pyrroloquinoxaline compounds with hydrazine moiety linking a nitrogen-containing polycyclic group to a heteroaroyl system. Several derivatives, with attractive drug-like properties, were identified as promising cytotoxic agents, showing excellent potency in a panel of cancer cell lines. In the current study, we synthesized a further 19 new analogues to optimize their physicochemical properties and assess a coherent mechanism of action. Several chemical modifications were made to the reference compounds by varying the fused-ring system and/or the heteroacyl moiety. To evaluate their in vitro activity, we tested these compounds in six human cancer cell lines derived from different origins. Among them, two compounds ( and ) showed similar potency as the reference compounds with IC₅₀ values in the sub-micromolar range in all cell lines tested. Furthermore, compound showed excellent in vivo efficacy in our preliminary human ovarian cancer mouse xenograft studies. Flow cytometric studies indicated that both derivatives interrupted cell cycle progression in colorectal cancer HCT116 cell lines and ovarian cancer SKOV-3 cells. Further mechanistic studies revealed that and were able to induce reactive oxygen species in SKOV-3 cells with apparently different kinetic patterns. Considering their cytotoxicity profiles in a variety of in vitro and in vivo cancer models, these hydrazide based compounds seem to have considerable potentials as novel chemotherapeutics.     

Synthesis, biological evaluation, and molecular modeling studies of novel heterocyclic compounds as anti-proliferative agents

Two novel series of heterocyclic compounds have been synthesized. In first series, isatin was allowed to react with substituted aromatic/cyclic carbonyl compounds to get desired mannich bases (2a–e). In second series, 4,5-disubstituted oxazoles (6a–p) were synthesized. Eight compounds (2c, 6a, 6e, 6f, 6i, 6j, 6m, and 6n) were screened for anticancer activity in 60 cell lines. Compound 2c, 1-[(4,7,7-trimethyl-3-oxobicyclo[2.2.1]heptan-2-yl)methyl]indoline-2,3-dione, showed maximum activity and thus, selected for further evaluation at five dose level screening. Furthermore, molecular docking studies of compounds 2c into the colchicine-binding site of tubulin, revealed possible mode of inhibition by the compound.     

Synthesis,biological evaluation,and molecular docking studies of pyrazolyl-acylhydrazone derivatives as novel anticancer agents

A series of pyrazolyl-acylhydrazone derivatives (1e–20e) have been designed and synthesized and their biologic activities were also evaluated for telomerase inhibition and tumor cell antiproliferation. Among all the compounds, 12e showed the most potent activity in vitro, which inhibited the growth of MCF-7 and B16-F10 cell lines with IC₅₀ values of 0.57 ± 0.03 and 0.49 ± 0.07 μM, respectively. Compound 12e also exhibited significant telomerase inhibitory activity (IC₅₀ = 1.9 ± 0.43 μM). The result of flow cytometry demonstrated that compound 12e induced cell apoptosis. Docking simulation was performed to insert compound 12e into the crystal structure of telomerase at ATP binding site to determine the probable binding model. Based on the preliminary results, compound 12e with potent inhibitory activity in tumor growth may be a potential anticancer agent.     

Synthesis and evaluation of curcumin analogues as cytotoxic agents

Seventeen curcumin analogues were prepared and evaluated for in vitro and in vivo cytotoxicity against an Ehrlich ascites carcinoma (EAC). In vitro results revealed that compounds 10, 7, and 12 were the most potent analogues against EAC respectively. However, in vivo evaluation of compound 10 proved its capability to normalize the blood picture compared with 5-fluorouracil, a well-known anticancer drug.     

Natural and synthetic acridines/acridones as antitumor agents: their biological activities and methods of synthesis

Acridine derivatives constitute a class of compounds that are being intensively studied as potential anticancer drugs. Acridines are well-known for their high cytotoxic activity; however, their clinical application is limited or even excluded because of side effects. Numerous synthetic methods are focused on the preparation of target acridine skeletons or modifications of naturally occurring compounds, such as acridone alkaloids, that exhibit promising anticancer activities. They have been examined in vitro and in vivo to test their importance for cancer treatment and to establish the mechanism of action at both the molecular and cellular level, which is necessary for the optimization of their properties so that they are suitable in chemotherapy. In this article, we review natural and synthetic acridine/acridone analogs, their application as anticancer drugs and methods for their preparation.     

Synthesis and characterization of novel benzimidazole bearing pyrazoline derivatives as potential antimicrobial agents

A new series of compounds N-(4-(2-(3-(1H-benzo[d]imidazol-2-yl)-5-(aryl)-4,5-dihydro-1H-pyrazol-1-yl)-2-oxoethoxy)phenyl)acetamides (5a–u) were synthesized and structures of these compounds were elucidated by spectral (IR, ¹H NMR, ¹³C NMR, and mass spectra) analysis. Antimicrobial activity was measured against Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 1688), Staphylococcus aureus (MTCC 96), Streptococcus pyogenes (MTCC 442), Candida albicans (MTCC 227), Aspergillus niger (MTCC 282), and Aspergillus clavatus (MTCC 1323) by serial broth dilution method. Evaluation of antimicrobial activity revealed that compounds 5f, 5i, 5q, and 5t were the most active antibacterial, while compounds 5e, 5g, 5h, 5j, 5p, 5r, and 5u were the most potent antifungal agents as compared to standard drugs and thus could be promising new lead molecules.