5-Nitroimidazole-based 1,3,4-thiadiazoles: heterocyclic analogs of metronidazole as anti-Helicobacter pylori agents

A series of 5‐nitroimidazole‐based 1,3,4‐thiadiazoles were prepared and tested for antibacterial activity against Helicobacter pylori. The anti‐H. pylori activity of target compounds along with the commercially available antimicrobial metronidazole was evaluated by comparing the inhibition‐zone diameters determined by the paper disc diffusion bioassay. From our bioassay results against 20 clinical isolates it is evident that piperazinyl, 4‐methylpiperazinyl, 3‐methylpiperazinyl, and 3,5‐dimethylpiperazinyl analogs ( 6a , 6b , 6e , and 6f , respectively) and pyrrolidine derivative 7 had strong activity at 0.5 µg/disc (average of inhibition zone >20 mm) while metronidazole had no activity at this dose. Compound 6f containing the 3,5‐dimethylpiperazinyl moiety at the 2‐position of the 5‐(1‐methyl‐5‐nitro‐1H‐imidazol‐2‐yl)‐1,3,4‐thiadiazole skeleton was the most potent compound tested at low concentrations.     

Efficient Synthesis and Biological Evaluation of a Novel Series of 1,5‐Benzodiazepine Derivatives as Potential Antimicrobial Agents

A series of novel 1,5‐benzodiazepine derivatives were rationally designed and synthesized following the principle of the superposition of bioactive substructures by the combination of 1,5‐benzodiazepine, pyridine (phenyl), and an ester group. The structures of the target compounds were determined by ¹H NMR, ¹³C NMR, MS, IR, and elemental analysis. All the synthesized compounds were evaluated for their antimicrobial activities in vitro against the fungi C. neoformans, C. neoformans clinical isolates (ATCC 32264), C. albicans (ATCC 10231), Gram‐negative bacterium E. coli (ATCC 44752), and Gram‐positive bacterium S. aureus (ATCC 25923). The results of the bioactive assay demonstrated that most of the tested compounds exhibited variable inhibitory effects on the growth of the tested microorganisms. All the active compounds showed better antifungal activity than antibacterial activity. Notably, compound 2b displayed the highest activity (MIC = 30 μg/mL) against C. neoformans and (MIC = 31 μg/mL) against C. neoformans clinical isolates. In addition, compound 2a also showed excellent activity against C. neoformans and C. neoformans clinical isolates with minimum inhibitory concentration of 35 and 36 μg/mL, respectively. Compounds 2a and 2b were further studied by evaluating their cytotoxicities, and the results showed that they have relatively low level cytotoxicity for BV2 and 293T cell. Preliminary structure‐activity relationship study on three diverse sets (C‐2, C‐3, and C‐8 positions) of 1,5‐benzodiazepines was performed. The results revealed that the presence of a ‐CH₃ group at the C‐8 position had a positive effect on the inhibitory activity of these compounds. Additionally, the 2‐pyridyl group at the C‐2 position may be a pharmacophore and ‐COOC₂H₅ at C‐3 position is the best substituent for the maintenance of antimicrobial activities.     

Synthesis,biological evaluation,and docking studies of some 5‐chloro‐2(3H)‐benzoxazolone Mannich bases derivatives as cholinesterase inhibitors

A series of N‐substituted‐5‐chloro‐2(3H)‐benzoxazolone derivatives were synthesized and evaluated for their acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) inhibitory, and antioxidant activities. The structures of the title compounds were confirmed by spectral and elemental analyses. The cholinesterase (ChE) inhibitory activity studies were carried out using Ellman's colorimetric method. The free radical scavenging activity was also determined by in vitro ABTS (2,2‐azinobis(3‐ethylbenzothiazoline‐6‐sulfonic acid)) assay. The biological activity results revealed that all of the title compounds displayed higher AChE inhibitory activity than the reference compound, rivastigmine, and were selective for AChE. Among the tested compounds, compound 7 exhibited the highest inhibition against AChE (IC₅₀ = 7.53 ± 0.17 μM), while compound 11 was found to be the most active compound against BuChE (IC₅₀ = 17.50 ± 0.29 μM). The molecular docking study of compound 7 showed that this compound can interact with the catalytic active site (CAS) of AChE and also has potential metal chelating ability and a proper log P value. On the other hand, compound 2 bearing a methyl substituent at the ortho position on the phenyl ring showed better radical scavenging activity (IC₅₀ = 1.04 ± 0.04 mM) than Trolox (IC₅₀ = 1.50 ± 0.05 mM).

     

Novel 3,6‐Disubstituted 7H‐1,2,4‐Triazolo[3,4‐b][1,3,4]thiadiazines: Synthesis,Characterization, and Evaluation of Analgesic / Anti‐inflammatory,Antioxidant Activities

In this study, the synthesis of a new series of 3,6‐disubstituted‐7H‐1,2,4‐triazolo[3,4‐b][1,3,4]thiadiazine 1a – 4c compounds derived from 4‐amino‐3‐substituted‐1,2,4‐triazole‐5‐thiones 1 – 4 is described. All of the synthesized compounds were screened for their possible analgesic / anti‐inflammatory, antioxidant activities and gastric toxicity. The compound 2c was found to have both significant analgesic and consistent anti‐inflammatory activity without inducing any gastric lesions along with minimal lipid peroxidation. A deep insight into the structures of the active compounds revealed that the compounds carrying an electron withdrawing group (a chloride or fluoride) on the phenyl ring at 6‐position of the condensed heterocyclic derivatives exhibited noticeable higher activity.     

Dopamine receptor ligands. Part VII [1]: novel 3-substituted 5-phenyl-1, 2, 3, 4, 5, 6-hexahydro-azepino-[4, 5-b]indoles as ligands for the dopamine receptors

A number of 5‐phenyl‐1, 2, 3, 4, 5, 6‐hexahydro‐azepino‐[4, 5‐b]indoles 3 were synthesized with different substituents at the azepine‐N position (methyl‐, allyl‐, 2‐phenyl‐ethyl‐, cyclopropylmethyl‐ and unsubstituted). Furthermore, the indole‐N‐methylated compound was generated and by using norephedrines and norpseudoephedrines as a chiral pool, 4‐methyl‐5‐phenyl‐1, 2, 3, 4, 5, 6‐hexahydro‐azepino‐[4, 5‐b]indoles were prepared which contained racemisation at the reacting C‐atom. These compounds, as well as the ring‐open amino‐alcohols, were screened for their affinity to the hD₁‐, hD₅‐, hD_2L‐, and hD₄‐receptors (ç please check sentence). They had micromolar affinities for the receptors and showed the highest affinity to the D₁‐subtype family. The cyclic compounds possessed the highest affinity, with the cyclopropylmethyl‐( 3c ) and methyl‐substituents ( 3e ) being the most active of the tested compounds. Based on an intracellular cAMP‐assay, the unsubstituted compound (at the azepine‐N position) turned out to be an agonist for the D₁‐and D₅‐subtype family, whereas the substituted compounds showed (partial) agonistic, or even inverse agonistic activity.     

5′-Substituted Thalidomide Analogs as Modulators of TNF-α

The synthesis of 5′-substituted thalidomide analogs is described. The amino acids 2 necessary to synthesize the target compounds were prepared by Michael reaction. Condensation of 2 with phthalic anhydrides followed by reaction with urea yielded 4 as diastereomeric mixtures. Furthermore glutethimide ( 5 ) was brominated by an improved method and the resulting compound 6 was reacted in several steps with sodium azide, hydrogen, and phthalic anhydride to give 8 . In a similar manner, 6 was reacted with sodium azide and various phthalic anhydrides to give 9 , 10 , and 11 . All final compounds were tested in vitro for their inhibitory activity on the release of TNF-α, using stimulated peripheral mononuclear blood cells (PBMCs). Compounds with an additional aromatic substituent in position 5’ of the thalidomide molecule were more active than thalidomide. Compound 11 was able to reduce increased levels of IL-2 in vitro.     

根治间日疟化合物:2,5-双取代苯氧基伯喹衍生物的合成

作者等按Mislow等法先合成6-甲氧基-8-硝基-N-甲基-1 H-喹啉-2-酮后,在喹啉环2位及5位分别引入氯和溴,然后在2、5两位代入相同的取代苯氧基,再经还原、缩合、氯解等反应,最后合成了一类新的2,5-双取代苯氧基伯喹衍生物。化合物1,13和19对子孢子感染的鼠疟P.yoelii有效。     

Synthesis and Comparative Study of Anti‐Mycobacterium Activity of a Novel Series of Fluoronitrobenzothiazolopyrazoline Regioisomers

In an attempt to find a new and a safer drug for tuberculosis, we have synthesized a series of fluoronitrobenzothiazolopyrazolines for antitubercular activity. The series comprises three subclasses: fluorobenzothiazolopyrazolines ( 11a–f ), fluoronitrobenzothiazolopyrazoline, nitro group at 5^th position ( 12a–f ) and 4^th position ( 13a–f ). All compounds were screened for their in‐vitro antitubercular activity against Mycobacterium tuberculosis H37Rv strain by using Middlebrook 7H‐9 broth. An introduction of ? NO₂ group at 5^th position of benzothiazole ring ( 12a–f ) increased the antitubercular activity whereas introduction of ? NO₂ group at 4^th position ( 13a–f ) was found to decrease the activity remarkably. Two compounds from each series showing good antitubercular activity were tested for cytotoxicity on THP‐1 cell lines and they showed low cytotoxicity.     

抗疟药咯萘啶有关化合物的合成及抗疟活性比较

合成了咯萘啶(Ⅰ)的有关化合物Ⅱ～Ⅴ,以探讨抗疟药咯萘啶化学结构中母环1位上氮杂原子及吡咯烷基Mannich碱侧链的存在,对该化合物抗疟作用的关系。经对有抗药性的疟原虫体内试验,合成的有关化合物Ⅱ～Ⅴ以及抗疟药氯喹和阿的平等的抗疟作用,均不如咯萘啶。提示上述氮杂原子及Mannich碱铡链的存在,对咯萘啶的抗疟作用,起着重要的和不可缺少的作用。     

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 and structure-activity relationships of a novel class of dithiocarbamic acid esters as anticancer agent

Based on a novel lead compound 4‐methylpiperazine‐1‐carbodithioic acid 3‐cyano‐3,3‐diphenylpropyl ester 1 , the systematic structural modification was carried out. All the synthesized compounds were evaluated for their in‐vitro anticancer activities on four to six different cell lines at three different concentrations. Most of the tested compounds could selectively inhibit the growth of HL‐60 and Bel‐7402 cell lines at a medium concentration. Four compounds ( 3f , 3g , 3n , and 5 ) were selected for the IC₅₀ test, and the results revealed that three compounds ( 3g , 3n , and 5 ) showed almost the same or a slightly weaker activity than compound 1 against HL‐60, and three compounds ( 3f , 3g , and 3n ) showed >2‐fold higher potency than compound 1 against Bel‐7402. The in‐vivo efficacy of 3n · HCl was evaluated with transplanted hepatocyte carcinoma 22 as an in‐vivo test model. It was found that 3n · HCl could inhibit significantly the growth of tumor, and that this effect was dose‐dependent. Meanwhile, the compound 3n · HCl showed low toxicity compared with compound 1 · HCl as evidenced by the little body‐weight loss. These results confirmed that compound 3n · HCl is more potent than the lead compound 1 · HCl . Preliminary structure–activity relationships indicated that: a) Both nitrile group and the cyclic amine containing at least two nitrogens were indispensable moieties to keep the activity; b) substitution of the piperazine ring is unfavorable for the improvement of activity; c) the suitable linker joining the piperazinyl dithiocarboxyl and diphenylacetonitril group should be ethylene; d) a non‐coplanar arrangement of the two benzene rings appears to be essential for activity.     

Design,synthesis, and evaluation of novel (E)-N'-(3-allyl-2-hydroxy)benzylidene-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides as antitumor agents

In our continuing search for novel small-molecule anticancer agents, we designed and synthesized a series of novel (E)-N'-(3-allyl-2-hydroxy)benzylidene-2-(4-oxoquinazolin-3(4H)-yl)acetohydrazides ( 5 ), focusing on the modification of substitution in the quinazolin-4(3H)-one moiety. The biological evaluation showed that all 13 designed and synthesized compounds displayed significant cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). The most potent compound 5l displayed cytotoxicity up to 213-fold more potent than 5-fluorouracil and 87-fold more potent than PAC-1, the first procaspase-activating compound. Structure–activity relationship analysis revealed that substitution of either electron-withdrawing or electron-releasing groups at positions 6 or 7 on the quinazolin-4(3H)-4-one moiety increased the cytotoxicity of the compounds, but substitution at position 6 seemed to be more favorable. In the caspase activation assay, compound 5l was found to activate the caspase activity by 291% in comparison to PAC-1, which was used as a control. Further docking simulation also revealed that this compound may be a potent allosteric inhibitor of procaspase-3 through chelation of the inhibitory zinc ion. Physicochemical and ADMET calculations for 5l provided useful information of its suitable absorption profile and some toxicological effects that need further optimization to be developed as a promising anticancer agent.     

Synthesis and in vitro anti-Helicobacter pylori activity of 2-[(chlorobenzyl)thio]-5-(5-nitro-2-furyl)-1,3,4-thiadiazoles

A new series of 2-[(chlorobenzyl)thio]-5-(5-nitro-2-furyl)-1,3,4-thiadiazoles (6a–h) were synthesized and evaluated by the disc diffusion method against Helicobacter pylori. Four compounds which exhibited strong anti-H. pylori activity at concentration of 8–32 μg/disc (average of inhibition zone >20 mm) were further tested against 20 clinical isolates of H. pylori at lower concentrations. The averages of inhibition zone diameters indicated that all selected compounds exhibit better anti-H. pylori activity profile against clinical isolates of H. pylori with respect to standard drug metronidazole. Compound 6c, containing the 3-chlorobenzylthio moiety, was the most potent compound tested.     

Synthesis, antimalarial and antibacterial activities of 3-amino acid- and aryl amine-substituted 2-methyl-3H-quinalzolin-4-ones

A new series of 2-methyl-3H-quinazolinones substituted at the third position with amino acids (2–5) and aryl amine (6, 7) was designed, synthesized, and analyzed by infrared, NMR, and mass spectral analysis. Further, the compounds were screened for their in vivo antimalarial activity using the rodent malaria parasite Plasmodium yoelii (N-67) with the Swiss mice model. The compounds were also tested for their antibacterial activity.     

A novel carbapenem antibiotic, SM-7338 structure-activity relationships

A series of new carbapenem compounds, which have a pyrrolidin-3'-ylthio group substituted with various aminocarbonyl group at C-5' position as C-2 side chain, have been prepared. The antibacterial activity and the stability to renal dehydropeptidase-I of these compounds were investigated, and the structure-activity relationships were discussed. In this series, SM-7338; (1R,5S,6S)-2-[(3S,5S)-5-dimethylaminocarbonylpyrrolidin-3-ylthi o]-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid (5a) was the most interesting compound.     

The Novel Ketoprofen Amides – Synthesis and Biological Evaluation as Antioxidants,Lipoxygenase Inhibitors and Cytostatic Agents

The novel amides of ketoprofen and its reduced derivatives (5a–f, 4a–n, 6a–g) with aromatic and cycloalkyl amines or hydroxylamines were prepared and screened for their reducing and cytostatic activity as well as for their ability to inhibit soybean lipoxygenase and lipid peroxidation. 1,1-Diphenyl-picrylhydrazyl test for reducing ability revealed that ketoprofen amides were more potent antioxidants than the amides of the reduced ketoprofen derivatives. The most active compound was benzhydryl ketoprofen amide 5f. Lipoxygenase inhibition of the tested compounds varied from strong to very weak. The most potent compound was benzhydryl derivative 6f (IC₅₀ = 20.5 μm ). Aromatic and cycloalkyl amides 4 and 5 were more potent lipoxygenase inhibitors than derivatives with carboxylic group. Aromatic amides of series 4 and 5 showed excellent lipid peroxidation inhibition (92.2–99.9%). On the other hand, the most pronounced cytostatic activity was exerted by O-benzyl derivative 4i, although in general all tested reduced and non-reduced lipophilic derivatives showed similar activity.     

Synthesis and biologic activity of conformationally constrained analogs of L‐363,301

Abstract: We report the synthesis, biological activity and conformational analysis of analogs of the cyclic hexapeptide L‐363,301, c[Pro⁶‐Phe⁷‐d ‐Trp⁸‐Lys⁹‐Thr¹⁰‐Phe¹¹] (numbering as in the native hormone somatostatin‐14). The d ‐Trp in position 8 was replaced with (2R,3S)‐ and (2R,3R)‐β‐MeTrp respectively, with an added methyl group in the beta position of Trp. The objective of our study was to determine the potency and selectivity generated by the added constraint in the beta position of the d ‐Trp upon binding to human somatostatin receptors hsst1‐5. We synthesized the building blocks enantioselectively and incorporated them into the peptides by SPPS. Competition binding assays revealed that both compounds 2 and 3 were selective for hsst2 over hsst5. The (2R,3S) analog 2 was approximately 30 times more potent at hsst2 than the (2R,3R) analog 3 . Interestingly, the (2R,3R) compound showed no binding affinity at hsst5.     

Recognition of pharmacophore of ar-turmerone for its anticancer activity

For the analysis of structure activity relationship of ar-turmerone analogues, the compounds containing the various substituents on the phenyl ring and 1(or 2)-naphthyl group in the place of phenyl of ar-turmerone were prepared and tested their cytotoxicity against HL-60, K-562, and L1210 leukemia cellsin vitro. The substituents at para position are methoxy, phenoxy, methyl, trifluoromethyl, fluoro, and chloro. Atmeta position methoxy, methyl, trifluoromethyl, or chloro groups and atortho position methoxy or chloro group were introduced. Against HL-60 and K-562 cells, ED₅₀ values of the analogues are ranged from 0.8 to 30.0 μg/ml. Against L1210 cell, these are located more than 20.0 μg/ml. However, 5-carboethoxy-2-methyl-6-(1-naphthyl)-2-octen-4-one (5n) possesses ED50 valuses 0.8, 2.1, 6.5 μg/ml against HL-60, K-562, L1210 cells, respectively. The electronic nature of the subsituents on phenyl ring of ar-turmerone dose not affect the biological activity. Therefore the flat structure of aromatic portion of ar-turmerone analogues is the more important factor for their activity rather than its electronic nature. The potentiation of the cytotoxicity with the enlargement of aromatic ring region also supports the importance of the plane structure of this area. The restriction of the single bond rotation between C-6 and aromatic ring through the introduction of substituents at theortho position of phenyl ring and the increment of size of alkyl group at C-6 position enhances the activity. Therefore the effective conformation should be the one having the orthogonal arrangement between the aromatic ring and the side chain.     

New Phorbol and Deoxyphorbol Esters: Isolation and Relative Potencies in Inducing Platelet Aggregation and Erythema of Skin

Abstract: Diester diterpenes based upon phorbol, 4-deoxyphorbol, 4α-deoxyphorbol, 4-deoxy-5-hydroxy-phorbol and 4,20-dideoxy-5-hydroxyphorbol were isolated from the fruit oil of Sapium indicum. Corresponding tri- and tetra-esters were produced by acetylation and mono-esters by selective hydrolysis. Twenty-six compounds were tested for production of erythema in vivo and induction of human and rabbit platelet aggregation in vitro. The flatter shape of the AB-ring trans compounds is necessary for interaction of phorbolesters at their receptor in that the cis analogues were inactive. The tertiary C-4 hydroxy group of phorbol was not necessary for activity although the 4-deoxy derivatives were less potent than the 4-hydroxy diterpenes. A primary hydroxy group at C-20 was essential for biological activity because the methyl and aldehyde derivtives of this position were inactive. The C-20 acetates were also inactive on platelets, but they did produce erythema, possibly because of the removal of the ester due to lipase activity in the skin. 5-hydroxy-analogues which undergo intramolecular hydrogen bonding had greatly reduced activities in both systems. Membrane stabilisers, phospholipase A₂ and calmodulin inhibitors were antagonists for phorbol esters in platelet aggregation tests, whilst cyclo-oxygenase inhibitors and free radical scavengers had no inhibitory effects. Consequently, one electron withdrawal and free radical formation plays no part in the biological activity of these compounds.     

抗结核桿菌化合物的合成Ⅱ. 2-烷氧基-氨基喹啉及其衍生物和2-烷氧基-6-氨基辛可宁酸酰肼

1.本文叙述了2-烷氧基-6-(或5-,或7-或8-)氨基喹啉,以及2-正丁氧基-6-乙酰(或二氯乙酰,或二甲)氨基喹啉的合成.2.合成了2-烷氧(甲氧,或乙氧,或正丙氧,或正丁氧)基-6-氨基辛可宁酸酰肼.3.将上述各产物及其中间体均进行了对结核分枝杆菌607及恥垢杆菌的体外抑制作用.结果表示Ⅲ类型化合物在体外的抗结核杆菌作用仅与联在芳香环上的烷氧基及伯氨基有关,而氨基在喹啉环的苯环部分上的位置则无关.4.加入一个羰肼基于Ⅲa 及其烷氧基同系物的4-位上对体外抗结核杆菌作用不利.