Scalable synthesis and antibacterial evaluation of 2‐(3‐(N‐(substituted phenyl)sulfamoyl)ureido)benzothiazoles

A new series of 2‐(3‐(N‐(substituted phenyl)sulfamoyl)ureido)benzothiazoles was synthesized via a one‐pot efficient and scalable method, involving the condensation of 2‐aminobenzothiazoles derivatives, substituted anilines, and chlorosulfonyl isocyanate. The products were obtained in good yield with a simple workup, and their structures were confirmed from their spectral analyses. The synthesized compounds were further screened for their antibacterial activity against Gram‐positive and Gram‐negative pathogenic strains. The molecules show promising activity in the MIC value range of 2–0.25 µg/ml against selected bacterial strains, especially against nonfermentative carbapenem‐resistant bacteria (Pseudo VIM‐2 and Acinetobacter baumanni).     

Synthesis of cyclic peptides from unprotected precursors using removable Nα‐(1‐(4‐methoxyphenyl)‐2‐mercaptoethyl) auxiliary

Abstract: A new method to cyclize unprotected peptides is presented. The method involves the use of a 1‐phenyl‐2‐mercaptoethyl derivative on the N‐terminal glycine. This template acts as an auxiliary thiol‐containing group in order to drive cyclization with a counterpart thioester moiety on the same molecule. Subsequent facile removal of the derivative generates products with only native peptide structure. The successful, high‐yield cyclization of the peptide GSPYSSDTTPA is described.     

Design and synthesis of 4′‐((5‐benzylidene‐2,4‐dioxothiazolidin‐3‐yl)methyl)biphenyl‐2‐carbonitrile analogs as bacterial peptide deformylase inhibitors

Herein, we report the synthesis and screening of 4′‐((5‐benzylidene‐2,4‐dioxothiazolidin‐3‐yl)methyl)biphenyl‐2‐carbonitrile analogs 11(a–j) as bacterial peptide deformylase (PDF) enzyme inhibitors. The compounds 11b (IC₅₀ value = 139.28 μm ), 11g (IC₅₀ value = 136.18 μm ), and 11h (IC₅₀ value = 131.65 μm ) had shown good PDF inhibition activity. The compounds 11b (MIC range = 103.36–167.26 μg/mL), 11g (MIC range = 93.75–145.67 μg/mL), and 11h (MIC range = 63.61–126.63 μg/mL) had also shown potent antibacterial activity when compared with standard ampicillin (MIC range = 100.00–250.00 μg/mL). Thus, the active derivatives were not only PDF inhibitors but also efficient antibacterial agents. To gain more insight on the binding mode of the compounds with PDF enzyme, the synthesized compounds 11(a–j) were docked against PDF enzyme of Escherichia coli and compounds exhibited good binding properties. The results suggest that this class of compounds has potential for development and use in future as antibacterial drugs.     

Stereoselective Synthesis and Antiviral Activity of (1E,2Z,3E)‐1‐(Piperidin‐1‐yl)‐1‐(arylhydrazono)‐2‐[(benzoyl/benzothiazol‐ 2‐oyl)hydrazono]‐4‐(aryl1)but‐3‐enes

The reaction of benzoyl hydrazine 1a or benzothiazole‐2‐carbohydrazide 1b with 2‐oxo‐N‐arylpropanehydrazonoyl chlorides 2a–d yielded (1Z,2E)‐2‐[(benzoyl/benzothiazol‐2‐oyl)hydrazono]‐N‐(aryl)propanehydrazonoyl chlorides 3a–e . The reaction of 3a–c with sodium benzenesulphinate furnished sulphones 5a–c while the reaction of 5d , e with hydroxyl amine afforded hydroxomoyl derivatives 6a , b . The one‐pot sterioselective reaction of N‐(aryl)propanehydrazonoyl chlorides 3 with certain aromatic aldehydes in the presence of piperidine resulted in the formation of (1E,2Z,3E)‐1‐(piperidin‐1‐yl)‐1‐(arylhydrazono)‐2‐[(benzoyl/benzothiazol‐2‐oyl)hydrazono]‐4‐(aryl¹)‐but‐3‐enes 7a–g . X‐ray analysis of piperidinyl amidrazone 7g showed a conversion of its geometrical structure with respect to that of compound 3 and confirmed the stereoselectivity of the latter reaction. The piperidinyl amidrazones 7a–g possessed a significant antiviral activity against herpes simplex viruses (HSV‐1). Compound 7d reduced the number of viral plaques of herpes simplex type‐1 (HSV‐1) by 67%, with respect to the effect of reference drug Aphidicolin.     

Synthesis of (R)‐ and (S)‐[O‐methyl‐11C]N‐[2‐[3‐(2‐cyano‐phenoxy)‐2‐hydroxy‐propylamino]‐ethyl]‐N′‐(4‐methoxy‐phenyl)‐urea as candidate high affinity β1‐adrenoceptor PET radioligands

Molecular imaging and quantification of myocardial β₁‐adrenoceptor (AR) rather than total β‐AR density is of great clinical interest since cardiac biopsy studies suggest that myocardial β₁‐AR density is reduced in patients with chronic heart failure whereas cardiac β₂‐AR density may vary. Positron emission tomography (PET), with appropriate radioligands, offers the possibility to assess β‐AR density non‐invasively in humans. However, no PET radioligand for the selective imaging of cardiac β₁‐ARs is clinically available. Here some derivatives of the well characterized β₁‐AR selective antagonist, ICI 89,406, namely the enantiomers of N‐[2‐[3‐(2‐cyano‐phenoxy)‐2‐hydroxy‐propylamino]‐ethyl]‐N′‐(4‐hydroxy‐phenyl)‐urea ( 5a and 5b ) were synthesized and evaluated in vitro. The (R)‐isomer 5a was more β₁‐selective but has lower affinity than its (S)‐enantiomer 5b (β₁‐AR selectivity: 6100 vs 1240; β₁‐affinity: K₁ = 0.288 nM vs K₁ = 0.067 nM). Etherification of the analogous desmethyl precursors, 5e and 5f , respectively, with [¹¹C]iodomethane gave ¹¹C‐labelled versions of 5a and 5b , namely 5g and 5h , in 44 ± 5% radiochemical yield (decay‐corrected) and 97.4 ± 1.3% radiochemical purity with specific radioactivities of 26.4 ± 9.4 GBq/µmol within 41.2 ± 3.4 min from the end of bombardment (n = 14). 5g and 5h are now being evaluated as candidate radioligands for myocardial β₁‐ARs. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis,In Vitro Cytotoxicity and Radiosensitizing Activity of Novel 3‐[(2,4‐Dinitrophenylamino)Alkyl] Derivatives of 5‐Fluorouracil

Previously, it was reported that 3[3‐(2,4‐dinitrophenylamino)‐propyl]‐5‐fluorouracil 8c unlike its components 5‐fluorouracil (5‐FU) 6 and 2,4‐dinitroaniline 2 in HT‐29 cells under aerobic conditions had no cytotoxicity but showed radiosensitizing activity. In this study several analogues of 8c differing in the number of linking methylene groups were prepared and tested for in vitro cytotoxicity and radiosensitizing activity under both aerobic and hypoxic conditions. Tethered compound 8a was prepared in one pot by the reaction of 5‐FU 6 with paraformaldehyde and 2,4‐dinitroaniline 2 in the presence of the concentrated hydrochloric acid, and compounds 8b–f were prepared by the reaction of N‐(bromoalkyl) ‐ 2,4‐dinitrobenzeneamines 5b–f with 1‐(t‐butoxycarbonyl)‐5‐fluorouracil 7 followed by hydrolysis of the protecting group. The cytotoxicity of the tested compounds were measured by 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT), and propidium iodide (PI)‐digitonin assays and values of sensitization enhancement ratio (SER) as a measure of the radiosensitizing activity were measured from radiation survival curves in the absence and presence of each sensitizer for 37% survival respectively. Results showed that tethered compounds 8a–f induced time‐ and concentration‐dependent cytotoxicity under hypoxia but had no significant effect under aerobic conditions. These compounds also showed selective and concentration‐dependent radiocytotoxicity under hypoxic conditions.     

Synthesis of [2‐13C, 4‐13C]‐(2R,3S)‐catechin and [2‐13C, 4‐13C]‐(2R,3R)‐epicatechin

The first synthesis of doubly labeled, [2‐¹³C, 4‐¹³C]‐(2R,3S)‐catechin 15 and [2‐¹³C, 4‐¹³C]‐(2R,3R)‐epicatechin 18 starting from labeled 2‐hydroxy‐4, 6‐bis(benzyloxy)acetophenone 3 and labeled 3, 4‐bis(benzyloxy)‐benzaldehyde 7 are described. Copyright © 2010 John Wiley & Sons, Ltd.     

Synthesis of 2H‐ and 3H‐labeled N‐cyclopropylmethyl‐7α‐[(R)‐1‐hydroxy‐1‐methyl‐3‐(2thienyl)‐propyl]‐6,14‐endoethano‐6,7,8,14‐tetrahydro nororipavine

A procedure for deuterium and tritium labeling of the titled compound, an analgesic agent, was developed. A secondary amine intermediate was acylated to an acylamide, then the carbonyl function was reduced by LiAlD₄ to yield the tertiary amine. In the tritium‐labeled synthesis, the process utilized a bromo‐substituted precursor, which was subsequently reduced with ³H₂ in the presence of a Pd/C catalyst. The labeled compounds were successfully applied in pharmacokinetic and pharmacological studies. Copyright © 2005 John Wiley & Sons, Ltd.     

1‐[(2,3‐Dihydro‐1‐benzofuran‐2‐yl) methyl]piperazines as novel anti‐inflammatory compounds: Synthesis and evaluation on H3R/H4R

The histamine receptors (HRs) are members of G‐protein‐coupled receptor superfamily and traditional targets of huge therapeutic interests. Recently, H₃R and H₄R have been explored as targets for drug discovery, including in the search for dual‐acting H₃R/H₄R ligands. The H₄R, the most recent histamine receptor, is a promising target for novel anti‐inflammatory agents in several conditions such as asthma and other chronic inflammatory diseases. Due to similarity with previously reported ligands of HRs, a set of 1‐[(2,3‐dihydro‐1‐benzofuran‐2‐yl)methyl]piperazines were synthesized and evaluated in competitive binding assays as H₃R/H₄R ligands herein. The results showed the compounds presented affinity (K_i) for H₃R/H₄R in micromolar range, and they are more selective to H₃R. All the compounds showed no important cytotoxicity to mammalian cells. The phenyl‐substituted compound LINS01005 has shown the higher affinity of the set for H₄R, but no considerable selectivity toward this receptor over H₃R. LINS01005 showed interesting anti‐inflammatory activity in murine asthma model, reducing the eosinophil counts in bronchoalveolar lavage fluid, as well as the COX‐2 expression. The presented compounds are valuable prototypes for further improvements to achieve better anti‐inflammatory agents.     

Virtual screening,SAR, and discovery of 5‐(indole‐3‐yl)‐2‐[(2‐nitrophenyl)amino] [1,3,4]‐oxadiazole as a novel Bcl‐2 inhibitor

A new series of oxadiazoles were designed to act as inhibitors of the anti‐apoptotic Bcl‐2 protein. Virtual screening led to the discovery of new hits that interact with Bcl‐2 at the BH3 binding pocket. Further study of the structure–activity relationship of the most active compound of the first series, compound 1 , led to the discovery of a novel oxadiazole analogue, compound 16j , that was a more potent small‐molecule inhibitor of Bcl‐2. 16j had good in vitro inhibitory activity with submicromolar IC₅₀ values in a metastatic human breast cancer cell line (MDA‐MB‐231) and a human cervical cancer cell line (HeLa). The antitumour effect of 16j is concomitant with its ability to bind to Bcl‐2 protein as shown by an enzyme‐linked immunosorbent assay (IC₅₀ = 4.27 μm ). Compound 16j has a great potential to develop into highly active anticancer agent.     

Synthesis of N‐(2‐diethylamino‐ethyl)‐4‐(4‐fluoro‐benzamido)‐2‐methoxybenzamide (desiodo‐MIP‐1145) by coupling technique and its radioiodination: a potential melanoma imaging agent

Radioiodinated MIP‐1145, which specifically targets melanin, is an ideal candidate for targeted therapy of melanoma. An analogue of MIP‐1145 lacking the iodo‐substituent (desiodo‐MIP‐1145) was synthesized as a labeling precursor in three simple steps. The radioiodination of desiodo‐MIP‐1145 by iodine‐125 was carried out via an electrophilic substitution reaction. An optimization study for the iodination reaction was carried out. The labeled compound was isolated and purified by means of electrophoresis and HPLC. The maximum radiochemical yield, 76%, was obtained with radiochemical purity greater than 99%. The log P value for [¹²⁵I]MIP‐1145 was measured as 4.5.     

Design,Synthesis, Structure–Activity Relationships,and Docking Studies of 1‐(γ‐1,2,3‐Triazol Substituted Prolyl)‐(S)‐3,3‐Difluoropyrrolidines as a Novel Series of Potent and Selective Dipeptidyl Peptidase‐4 Inhibitors

Dipeptidyl peptidase‐4 inhibitors hold great potential for the treatment of type 2 diabetes. A series of 1‐(γ‐1,2,3‐triazol substituted prolyl)‐(S)‐3,3‐difluoropyrrolidines were designed, synthesized, and evaluated as novel dipeptidyl peptidase‐4 inhibitors. Most of the compounds exhibited good in vitro potency against dipeptidyl peptidase‐4. Among these, compounds 7j , 7q, and 7s displayed good dipeptidyl peptidase‐4 activity and excellent selectivity versus other proteases including dipeptidyl peptidase‐8, dipeptidyl peptidase‐9, and FAP. The possible binding modes of compounds 7j , 7q, and 7s with dipeptidyl peptidase‐4 were also explored by molecular docking simulation.     

Evaluation of Novel N‐(piperidine‐4‐yl)benzamide Derivatives as Potential Cell Cycle Inhibitors in HepG2 Cells

In this study, a series of novel N‐(piperidine‐4‐yl)benzamide derivatives was designed, synthesized, and evaluated for antitumor activity. Some compounds were found to have potent antitumor activity. In particular, compound 47 showed the most potent biological activity against HepG2 cells, with an IC₅₀ value of 0.25 μm . Western blot analysis demonstrated that compound 47 inhibited the expression of cyclin B1 and p‐Rb and enhanced the expression of p21, p53, Rb, and phospho‐adenosine monophosphate‐activated protein kinase (p‐AMPK). Further, cell cycle arrest was observed by flow cytometry (FCM). In summary, compound 47 was screened to have potential activity for the treatment of hepatocarcinoma via the induction of cell cycle arrest by a p53/p21‐dependent pathway.     

Synthesis and In‐Vitro Activity of New 1β‐Methylcarbapenem Derivatives as Antibacterial Agents

The synthesis of a new series of 1β‐methylcarbapenems having pyrrolidine and piperidine moieties is described. Their in‐vitro antibacterial activities against both Gram‐positive and Gram‐negative bacteria were tested and the effect of substituents on the pyrrolidine ring was investigated. A particular compound III b having an oxime‐pyrrolidine moiety showed the most potent antibacterial activity.     

Synthesis of N‐(2‐chloro‐3,4‐dimethoxybenzylideneamino)guanidinium acetate [α‐14C]

¹⁴C‐Labelled N‐(2‐chloro‐3,4‐dimethoxybenzylideneamino)guanidinium acetate has been synthesized as a part of a four‐step procedure which involved decarboxylation of 2‐chloro‐3,4‐dimethoxybenzoic acid by Pb(OAc)₄ to give 2‐chloro‐3,4‐dimethoxy‐1‐iodobenzene, followed by a selective lithiation at the iodine position and electrophilic substitution with N,N‐dimethylformamide [α‐¹⁴C] and final reaction with aminoguanidine bicarbonate. The specific activity was 59 mCi/mmol and the overall yield 49%. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis,In Vitro Protoporphyrinogen Oxidase Inhibition,and Herbicidal Activity of N‐(Benzothiazol‐5‐yl)hexahydro‐1H‐isoindole‐1,3‐diones and N‐(Benzothiazol‐5‐yl)hexahydro‐1H‐isoindol‐1‐ones

Protoporphyrinogen oxidase ( EC 1.3.3.4 ) is one of the most significant targets for a large family of herbicides. As part of our continuous efforts to search for novel protoporphyrinogen oxidase‐inhibiting herbicides, N‐(benzothiazol‐5‐yl)tetrahydroisoindole‐1,3‐dione was selected as a lead compound for structural optimization, leading to the syntheses of a series of novel N‐(benzothiazol‐5‐yl)hexahydro‐1H‐isoindole‐1,3‐diones ( 1a – o ) and N‐(benzothiazol‐5‐yl)hexahydro‐1H‐isoindol‐1‐ones ( 2a – i ). These newly prepared compounds were characterized by elemental analyses, ¹H NMR, and ESI‐MS, and the structures of 1h and 2h were further confirmed by X‐ray diffraction analyses. The bioassays indicated that some compounds displayed comparable or higher protoporphyrinogen oxidase inhibition activities in comparison with the commercial control. Very promising, compound 2a , ethyl 2‐((6‐fluoro‐5‐(4,5,6,7‐tetrahydro‐1‐oxo‐1H‐isoindol‐2(3H)‐yl)benzo[d]thiazol‐2‐yl)‐sulfanyl)acetate, was recognized as the most potent candidate with K_i value of 0.0091 μm . Further greenhouse screening results demonstrated that some compounds exhibited good herbicidal activity against Chenopodium album at the dosage of 150 g/ha.     

Syntheses of [14C]‐labeled 2‐(3‐chlorophenyloxy)‐3‐[3‐(3‐hydroxy) pyridin‐4‐yl propoxy]pyridine,a phosphodiesterase 4 inhibitor and its metabolites

We describe here the synthesis of [¹⁴C]‐2‐(3‐chlorophenyloxy)‐3‐[3‐(3‐hydroxy)pyridin‐4‐yl propoxy]pyridine (1), a phosphodiesterase 4 inhibitor. [¹⁴C]‐Labeled 1 was prepared in three steps from [¹⁴C]‐2‐bromopyridin‐3‐ol in an overall yield of 32%. Preparation of [¹⁴C]‐labeled 2 and 3, two metabolites of 1, is also described. Copyright © 2014 John Wiley & Sons, Ltd.