Exploration of 5‐(5‐nitrothiophen‐2‐yl)‐4,5‐dihydro‐1H‐pyrazoles as selective,multitargeted antimycobacterial agents

We report the biological evaluation of 5‐(5‐nitrothiophen‐2‐yl)‐4,5‐dihydro‐1H‐pyrazole derivatives against bacteria, eukaryotic cell lines and the assessment of their mechanisms of action to determine their prospects of being developed into potent antituberculosis agents. The compounds were evaluated for their antibacterial property against Mycobacterium tuberculosis H37Rv, multidrug‐resistant M. tuberculosis, Mycobacterium bovis BCG, Mycobacterium aurum, Escherichia coli, and Staphylococcus aureus using high‐throughput spot‐culture growth inhibition assay. They were found to be selective toward slow‐growing mycobacteria and Gram‐positive bacteria. In M. bovis BCG, they exhibited a bactericidal mode of action. Cytotoxicity was assessed in human THP‐1 and murine RAW 264.7 cell lines, and the compounds showed a lower cytotoxicity potential when compared with their antibacterial activity. They were found to be excellent whole‐cell efflux pump inhibitors of the mycobacterial surrogate M. aurum, performing better than known efflux pump inhibitor verapamil. The 5‐nitrothiophene moiety was identified for the first time as a prospective inhibitor scaffold of mycobacterial arylamine N‐acetyltransferase enzyme, which is the key enzyme in metabolizing isoniazid, a first‐line antituberculosis drug. The two aforementioned findings make the compounds potential hits in the development of adjunctive tuberculosis therapy.     

Synthesis and in‐vitro Antimycobacterial Evaluation of 1‐(Cyclopropyl/2,4‐difluorophenyl/tert‐butyl)‐1,4‐dihydro‐ 8‐methyl‐6‐nitro‐4‐oxo‐7‐(substituted secondary amino)quinoline‐3‐carboxylic acids

Fifty one newer 1‐(cyclopropyl/2,4‐difluorophenyl/tert‐butyl)‐1,4‐dihydro‐8‐methyl‐6‐nitro‐4‐oxo‐7‐(substituted secondary amino)quinoline‐3‐carboxylic acids were synthesized from 1,3‐dichloro‐2‐methylbenzene and evaluated for in‐vitro antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi‐drug resistant Mycobacterium tuberculosis (MDR‐TB), and Mycobacterium smegmatis (MC²). Among the synthesized compounds, 1‐cyclopropyl‐1,4‐dihydro‐7‐(3,4‐dihydro‐6,7‐dimethoxyisoquinolin‐2(1H)‐yl)‐8‐methyl‐6‐nitro‐4‐oxoquinoline‐3‐carboxylic acid 9p was found to be the most active compound in vitro with a MIC value of 0.39 μM against MTB. Against MDR‐TB, compound 7‐(2‐carboxy‐5,6‐dihydroimidazo[1,2‐a]pyrazin‐7(8H)‐yl)‐1‐cyclopropyl‐1,4‐dihydro‐8‐methyl‐6‐nitro‐4‐oxoquinoline‐3‐carboxylic acid 9n was found to be the most active with a MIC value of 0.09 μM.     

Synthesis and Positive Inotropic Evaluation of (E)‐2‐(4‐Cinnamylpiperazin‐1‐yl)‐N‐(1‐substituted‐4,5‐dihydro‐[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)acetamides

A series of (E)‐2‐(4‐cinnamylpiperazin‐1‐yl)‐N‐(1‐substituted‐4,5‐dihydro‐[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)acetamides were synthesized and evaluated for their positive inotropic activity by measuring the left atrium stroke volume on isolated rabbit heart preparations. This class of compounds presented favorable in vitro activity compared with the standard drug, milrinone, among which N‐(1‐(3‐chlorophenyl)‐4,5‐dihydro‐[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)‐2‐(4‐cinnamylpiperazin‐1‐yl)acetamide 5e was found to be the most potent with 16.58 ± 0.11% increased stroke volume (milrinone: 2.46 ± 0.07%) at a concentration of 3 × 10^?5 M. The chronotropic effects of the compounds having inotropic effects were also evaluated.     

Synthesis and structure–activity relationships of pyrazolo‐[3,4‐b]pyridine derivatives as adenosine 5'‐monophosphate‐activated protein kinase activators

A series of pyrazolo[3,4‐b]pyridine derivatives were designed, synthesized, and evaluated for their activation activity toward adenosine 5'‐monophosphate‐activated protein kinase (AMPK). According to the enzyme activity, the pyrazole N?H exposure and para substitution on the diphenyl group were proved to be essential for the activation potency. Compound 17f showed equal activation compared with A‐769662. In the molecular modeling study, compound 17f exhibited important hydrogen bond interaction with Lys29, Asp88, and Arg83. 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assays on the NRK‐49F cell line showed that potent enzyme activators could effectively inhibit cell proliferation, especially for 17f (EC₅₀ [AMPKα1γ1β1] = 0.42 μM, efficacy = 79%; IC₅₀ [NRK‐49F cell line] = 0.78 μM). These results might provide new insights to explore novel AMPK activators.     

Synthesis and Evaluation of Human Monoamine Oxidase Inhibitory Activities of Some 3,5-Diaryl-N-substituted-4,5-dihydro-1H-pyrazole-1-carbothioamide Derivatives

Sixteen 3‐aryl‐5‐(4‐fluorophenyl)‐N‐substituted‐4,5‐dihydro‐1H‐pyrazole‐1‐carbothioamide derivatives were synthesized and their structure were identified by UV, IR, ¹H NMR, mass spectra, and microanalyses. The compounds were evaluated in vitro for their human monoamine oxidase (hMAO) inhibitory activities and their MAO‐A and ‐B selectivity. All the compounds were found to potently inhibit MAO‐A isoforms. 5‐(4‐Fluorophenyl)‐3‐(4‐methoxyphenyl)‐N‐methyl‐4,5‐dihydro‐1H‐pyrazole‐1‐carbothioamide (1.0 × 10^?3 µM) was found to inhibit hMAO‐A most selectively and potently. The binding mode of 5‐(4‐fluorophenyl)‐3‐(4‐methoxyphenyl)‐N‐methyl‐4,5‐dihydro‐1H‐pyrazole‐1‐carbothioamide to hMAO‐A was also predicted using docking studies.     

Synthesis and Positive Inotropic Evaluation of 2‐(4‐(4‐Substituted benzyloxy)‐3‐methoxybenzyl)‐1,4‐diazepan‐1‐yl)‐N‐(4,5‐dihydro‐1‐methyl[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)‐acetamides

In an attempt to search for more potent positive inotropic agents, a series of 2‐(4‐(4‐substituted benzyloxy)‐3‐methoxybenzyl)‐1,4‐diazepan‐1‐yl)‐N‐(4,5‐dihydro‐1‐methyl[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)acetamides was synthesized and their positive inotropic activities were evaluated by measuring left atrium stroke volume on isolated rabbit‐heart preparations. Several compounds showed favorable activity compared with the standard drug Milrinone among which 2‐(4‐(4‐(2‐chlorobenzyloxy)‐3‐methoxybenzyl)‐1,4‐diazepan‐1‐yl)‐N‐(4,5‐dihydro‐1‐methyl‐[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)acetamide 6e was found to have the most desirable potency with the 6.79 ± 0.18% increased stroke volume (Milrinone: 1.67 ± 0.64%) at a concentration of 1×10^–5 M in our in‐vitro study. The chronotropic effects of those compounds having inotropic effects were also evaluated in this work.     

Syntheses,calcium channel modulation effects,and nitric oxide release studies of O2‐alkyl‐1‐(pyrrolidin‐1‐yl) diazen‐1‐ium‐1,2‐diolate 4‐aryl(heteroaryl)‐1,4‐dihydro‐2,6‐dimethyl‐3‐nitropyridine‐5‐carboxylates

A group of racemic 4‐aryl(heteroary)‐1,4‐dihydro‐2,6‐dimethyl‐3‐nitropyridine‐5‐carboxy‐lates possessing a potential nitric oxide donor C‐5 O²‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate ester [alkyl=(CH₂)_n, n=1–4] substituent were synthesized using a modified Hantzsch reaction. Compounds having a C‐4 2‐trifluoromethylphenyl ( 16 ), 2‐pyridyl ( 17 ), or benzofurazan‐4‐yl ( 20 ) substituent generally exhibited more potent smooth‐muscle calcium channel antagonist activity (IC₅₀ values in the 0.55 to 38.6 μM range) than related analogs having a C‐4 3‐pyridyl ( 18 ), or 4‐pyridyl ( 19 ) substituent with IC₅₀ values > 29.91 μM, relative to the reference drug nifedipine (IC₅₀=0.0143 μM). The point of attachment of C‐4 isomeric pyridyl substituents was a determinant of antagonist activity where the relative potency profile was 2‐pyridyl > 3‐pyridyl and 4‐pyridyl. Subgroups of compounds 16a–d , 17a–d , and 20a–d having alkyl spacer groups of variable chain length [–CO₂(CH₂)_nO–, n=1–4] exhibited small differences in calcium channel antagonist potency. Replacement of the ester “methyl” moiety of Bay K 8644 by an O²‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate group provided the Bay K 8644 group of analogs 16a‐d that retained the desired cardiac positive inotropic effect. The most potent compound in this group, O²‐ethyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(2‐trifluoromethylphenyl)pyridine‐5‐carboxylate ( 16b , EC₅₀=0.096 μM) is about eightfold more potent positive inotrope (cardiac calcium channel agonist) than the reference compound Bay K 8644 (EC₅₀=0.77 μM). A similar replacement of the ester “isopropyl” group in the C‐4 benzofurazan‐4‐yl group of compounds by an O²‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate ester substituent provided compounds 20 (n=1 and 4) that were approximately equipotent cardiac positive inotropes with the parent reference compound PN 202‐791 ( 3 , EC₅₀=9.40 μM). The O²‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate ester moiety present in 1,4‐dihydropyridine calcium channel modulating compounds 16–20 is not a suitable ?NO donor moiety because the percent nitric oxide released upon in vitro incubation with either l ‐cysteine, rat serum, or pig liver esterase was less than 1%. Drug Dev. Res. 60:204–216, 2003. © 2003 Wiley‐Liss, Inc.     

Design,Synthesis, and In‐Vivo Pharmacological Screening of N,3‐(Substituted Diphenyl)‐5‐phenyl‐1H‐pyrazoline‐1‐carbothioamide Derivatives

Various 3,5‐(substituted diphenyl)‐4,5‐dihydro‐pyrazole‐1‐carbothioic acid phenylamides were synthesized starting from substituted acetophenones. Structures of the compounds were confirmed on the basis of spectral data. The compounds were evaluated for their anticonvulsant and antidepressant activity. Interestingly, out of 26 compounds, four ( 3f , 3g , 3t , and 3u ) were found to protect 100% of the animals in the MES screen at a dose of 25 mg/kg. They were also found to have appreciable anticonvulsant activity in scPTZ screen. Two compounds, 3j and 3o , significantly reduced the duration of the immobility time at 25 mg/kg dose, when compared to control.     

Antioxidant Potential of New Pyrazoline Derivatives to Prevent Oxidative Damage

Abstract: The antioxidant capacity of a series of six novel synthetic pyrazoline derivatives (i) 5‐hydroxy‐3‐methyl‐5‐trifluoromethyl‐4,5‐dihydro‐1H‐carbaldehyde‐pyrazole, (ii) 5‐hydroxy‐3‐methyl‐5‐trifluoromethyl‐4,5‐dihydro‐1H‐1‐acetyl‐pyrazole, (iii) 5‐hydroxy‐3‐methyl‐5‐trifluoromethyl‐4,5‐dihydro‐1H‐carboxyamide‐pyrazole, (iv) 5‐hydroxy‐3‐methyl‐5‐trifluoromethyl‐4,5‐dihydro‐1H‐1‐benzoyl‐pyrazole, (v) 5‐hydroxy‐3‐methyl‐5‐trifluoromethyl‐4,5‐dihydro‐1H‐1‐(2‐hydroxybenzoyl)‐pyrazole and (vi) 5‐hydroxy‐3‐methyl‐5‐trifluoromethyl‐4,5‐dihydro‐1H‐1‐(4‐methoxybenzoyl)‐pyrazole was evaluated as the capacity of compounds to transfer a hydrogen atom (protection against brain lipid peroxidation and glutathione oxidation) and their capacity to transfer a single electron [ferric‐reducing antioxidant power (FRAP) and 1,1‐diphenyl‐2‐picrylhydrazyl radical scavenging (DPPH) assays]. Compound 5 had the highest free radical scavenging capacity in the DPPH assay, while compound 2 had the highest FRAP value (P < 0.05). Only compounds 1, 4 and 5 protected against lipid peroxidation in rat brain homogenate. However, compound 5 was the most effective to prevent basal and iron‐, sodium nitroprusside‐ and H₂O₂‐stimulated lipid peroxidation (IC₅₀ < 15 µM) and the only one effective to block glutathione oxidation‐mediated by H₂O₂ (at 150 µM). Our results indicate that compound 5 has the greatest potential to prevent oxidative damage in brain homogenates.     

Effectiveness of Novel 5‐(5‐amino‐1‐aryl‐1H‐pyrazol‐4‐yl)‐1H‐tetrazole Derivatives Against Promastigotes and Amastigotes of Leishmania amazonensis

In this research, a series of substituted 5‐(5‐amino‐1‐aryl‐1H‐pyrazol‐4‐yl)‐1H‐tetrazoles were synthesized and evaluated for in vitro antileishmanial activity. Among the derivatives, examined compounds 3b and 3l exhibited promising activity against promastigotes and amastigotes forms of Leishmania amazonensis. The cytotoxicity of these compounds was evaluated on murine cells, giving access to the corresponding selectivity index (SI).     

Synthesis and anti‐Candida activity of novel benzothiepino[3,2‐c]pyridine derivatives

A novel series of thiepine derivatives were synthesized and evaluated as potential antimicrobials. All the synthesized compounds were evaluated for their antimicrobial activities in vitro against the fungi Candida albicans (ATCC 10231), C. parapsilosis (clinical isolate), Gram‐negative bacterium Pseudomonas aeruginosa (ATCC 44752), and Gram‐positive bacterium Staphylococcus aureus (ATCC 25923). Synthesized compounds showed higher antifungal activity than antibacterial activity, indicating that they could be used as selective antimicrobials. Selected thiepines efficiently inhibited Candida hyphae formation, a trait necessary for their pathogenicity. Thiepine 8‐phenyl[1]benzothiepino[3,2‐c]pyridine ( 16 ) efficiently killed Candida albicans at 15.6 μg/mL and showed no embryotoxicity at 75 μg/mL. Derivative 8‐[4‐(4,5‐dihydro‐1H‐imidazol‐2‐yl)phenyl][1]benzothiepino[3,2‐c]pyridine ( 23 ) caused significant hemolysis and in vitro DNA interaction. The position of the phenyl ring was essential for the antifungal activity, while the electronic effects of the substituents did not significantly influence activity. Results obtained from in vivo embryotoxicity on zebrafish (Danio rerio) encourage further structure optimizations.     

Amino Acid Derivatives,Part 4: Synthesis and Anti‐HIV Activity of New Naphthalene Derivatives

A new series of 2‐(naphthalen‐2‐yloxy)‐N‐[(aryl‐5‐thioxo‐4,5‐dihydro‐1H‐1,2,4‐triazol‐3‐yl)methyl] acetamides 5a–f was synthesized from naphthalene‐derived glycine derivative 2 via the hydrazinoacetamide analogs 4a–f . Alternatively, treatment of 4a with H₂SO₄ afforded 2‐(naphthalen‐2‐yloxy)‐N‐((5‐(phenylamino)‐1,3,4‐thiadiazol‐2‐yl)methyl) acetamide 6a . Alkylation or sulphonylation of 5a afforded the S‐alkylated derivatives 7 and 8 , respectively. Interestingly, treatment of 3 with methoxide ion gave the triazine derivative 9 . The synthesized compounds have been screened for their inhibitory activity against HIV‐1 and HIV‐2 in MT‐4 cells. However, 7 was found to be the potent inhibitor in vitro for the replication of HIV‐1 (EC₅₀ = 0.20 μg/mL), suggesting a new lead in the development of an antiviral agent.     

Novel pyridine‐2,4,6‐tricarbohydrazide thiourea compounds as small key organic molecules for the potential treatment of type‐2 diabetes mellitus: In vitro studies against yeast α‐ and β‐glucosidase and in silico molecular modeling

A range of novel pyridine‐2,4,6‐tricarbohydrazide thiourea compounds ( 4a–i ) were synthesized in good to excellent yields (63–92%). The enzyme inhibitory potentials of these compounds were investigated against α‐ and β‐glucosidases because these enzymes play a crucial role in treating type‐2 diabetes mellitus (T2DM). As compared to the reference compound acarbose (IC₅₀ 38.22 ± 0.12 μM), compounds 4i (IC₅₀ 25.49 ± 0.67 μM), 4f (IC₅₀ 28.91 ± 0.43 μM), 4h (IC₅₀ 30.66 ± 0.52 μM), and 4e (IC₅₀ 35.01 ± 0.45 μM) delivered better inhibition against α‐glucosidase and were quite inactive/completely inactive against β‐glucosidase. The structure–activity relationship of these compounds was developed and elaborated with the help of molecular docking studies.     

4‐Substituted‐1‐phenyl‐1H‐pyrazolo[3,4‐d]pyrimidine Derivatives: Design,Synthesis, Antitumor and EGFR Tyrosine Kinase Inhibitory Activity

Four series of some 4‐substituted‐1‐phenyl‐1H‐pyrazolo[3,4‐d]pyrimidine derivatives 5a – f , 6a – f , 8a – f , and 9a – f were designed to be screened for their antitumor activity. All compounds were evaluated against breast (MCF‐7) and lung (A‐549) cell lines. Six compounds 5a , 5b , 6b , 6e , 9e , and 9f displaying activity against both cell lines were further estimated for their EGFR‐TK inhibitory activity where they revealed 41–91% inhibition and compound 6b elicited the highest activity (91%). A docking study of these compounds into the ATP‐binding site of EGFR‐TK demonstrated their binding mode where H‐bonding interaction with Met793 through N¹ of pyrimidine or N² of pyrazole was observed.     

Synthesis and Biological Evaluation of Novel 6‐Hydrazinyl‐2,4‐bismorpholino pyrimidine and 1,3,5‐Triazine Derivatives as Potential Antitumor Agents

A series of 6‐hydrazinyl‐2,4‐bismorpholino pyrimidine and 1,3,5‐triazine derivatives ( 5a – 5l and 8a – 8o ) were synthesized and their chemical structures as well as the relative stereochemistry were confirmed. All the synthesized compounds were evaluated for antiproliferative activity against three cancer cell lines (H460, HT‐29, and MDA‐MB‐231). Several potent compounds were further evaluated against two other cell lines (U87MG, H1975). Most of the prepared compounds, particularly compounds 5c and 5j with IC₅₀ values (0.07 and 0.05 µM, respectively) in the nM range, exhibited moderate to excellent antiproliferative activity and high selectivity against the H460 cancer cell line as compared with compound 1 . The most promising compound 5j , possessing a cyano group at the 3‐position of the benzene ring, showed strong antiproliferative activity against H460, HT‐29, and MDA‐MB‐231 cell lines with IC₅₀ values of 0.05, 6.31, and 6.50 µM, which were 4.6‐ to 190.4‐fold more active than compound 1 (9.52, 29.24, and 36.21 µM), respectively.     

Solid‐Supported Synthesis and 5‐HT7/5‐HT1A Receptor Affinity of Arylpiperazinylbutyl Derivatives of 4,5‐dihydro‐1,2,4‐triazine‐6‐(1H)‐one

A series of arylpiperazinylbutyl derivatives of 4,5‐dihydro‐1,2,4‐triazine‐6(1H)‐ones was designed and synthesized according to the new solid‐supported methodology. In this approach, triazinone scaffold was constructed from the Fmoc‐protected glycine. The library representatives showed different levels of affinity for 5‐HT₇ and 5‐HT_1A receptors; compounds 13 , 14 and 18 – 20 were classified as dual 5‐HT₇/5‐HT_1A receptors ligands. The structure–affinity relationship analysis revealed that the receptor affinity and selectivity of the tested compounds depended on the kind of substituent in position 3 of triazinone fragment as well as substitution pattern of the phenylpiperazine moiety.     

Design,Synthesis, and Anticonvulsant Activity Evaluation of 4‐(3‐Alkoxy‐phenyl)‐2,4‐dihydro‐[1,2,4]triazol‐3‐ones

A series of 4‐(3‐alkoxy‐phenyl)‐2,4‐dihydro‐[1,2,4]triazol‐3‐ones were synthesized using the appropriate synthetic route and evaluated experimentally in the maximal electroshock test; their neurotoxicities were evaluated by the rotarod neurotoxicity test. The structures of these compounds were confirmed by IR, MS, ¹H‐NMR, and elementary analysis. All target compounds exhibited anticonvulsant activity to varying degrees in the maximal electroshock test. 4‐(3‐Benzyloxy‐phenyl)‐2,4‐dihydro‐[1,2,4]triazol‐3‐one ( 4i ) was the most promising compound with an ED₅₀ value of 30.5 mg/kg and a protective index (PI) of 18.63, showing a higher safety than the standard carbamazepine (PI = 6.45). In addition, the potency of compound 4i against seizures induced by pentylenetetrazole and 3‐mercaptopropionic acid suggested its broad‐spectrum activity, and the mechanisms of action including inhibition of voltage‐gated ion channels and modulation of GABAergic activity might be involved in its anticonvulsant activity.     

Synthesis of valproate,valerate, and 1‐methyl‐1, 4‐dihydropyridyl‐3‐carbonyloxy ester derivatives of Hantzsch 1,4‐dihydropyridines as potential prodrugs and their evaluation as calcium channel antagonist and anticonvulsant agents

A group of 3‐(hydroxyalkyl) 5‐alkyl 1,4‐dihydro‐2,6‐dimethyl‐4‐aryl‐3,5‐pyridinedicarboxylates ( 11–15 ) were prepared using a modified Hantzsch reaction, which were then elaborated to valproate ( 16–18 ), valerate ( 19, 20 ), and 1‐methyl‐1,4‐dihydropyridyl‐3‐carbonyloxy ( 25, 26 ) derivatives. Alternatively, the valproate derivative 3‐(2‐n‐propylpentanoyloxymethyl) 5‐isopropyl 1,4‐dihydro‐2,6‐dimethyl‐4‐(2,3‐dichlorophenyl)‐3,5‐pyridinedicarboxylate ( 34 ) was prepared by the reaction of isopropyl 1,4‐dihydro‐2,6‐dimethyl‐4‐(2,3‐dichlorophenyl)‐3,5‐pyridinedicarboxylate ( 30 ) with chloromethyl valproate ( 33 ). This class of lipophilic compounds possess partition coefficients (Kp) in the 149–452 range, relative to the reference drug nimodipine (Kp = 187). All compounds exhibited potent calcium channel antagonist (CCA) activity (IC₅₀ = 10^–7 to 10^–10 M range), relative to the reference drug nimodipine (IC₅₀ = 1.49 × 10^–8 M). CCA structure–activity relationships showed the parent C‐3 2‐hydroxyethyl compounds were more potent than their valproate derivatives, but less active than their valerate derivatives. Compounds having a 1‐methyl‐1,4‐dihydropyridyl‐3‐carbonyloxy chemical delivery system (CDS) were approximately equiactive to the parent C‐3 2‐hydroxyethyl compounds. Anticonvulsant activity was determined in the maximal electroshock (MES) and subcutaneous metrazol (scMet) screens. 3‐(2‐Hydroxyethyl) 5‐isopropyl 1,4‐dihydro‐2,6‐dimethyl‐4‐(2,3‐dichlorophenyl)‐3,5‐pyridinedicarboxylate ( 12 ) provided modest protection in the MES and scMet screens. In the C‐3 valproate [CO₂(CH₂)nO₂CCH(n‐Pr)₂] group of compounds, those possessing an ethylene spacer (n = 2) provided protection in the MES screen, whereas those having a propylene spacer (n = 3) or methylene spacer (n = 1) were inactive. Related C‐3 valerate esters [CO₂(CH₂)₂O₂C‐n‐Bu] also provided protection in the MES screen, whereas those having a 1‐methyl‐1,4‐dihydropyridyl‐3‐carbonyloxy CDS moiety were inactive. Drug Dev. Res. 48:26–37, 1999. © 1999 Wiley‐Liss, Inc.     

Synthesis and Biological Activity of Some 1,3‐Dihydro‐2H‐3‐benzazepin‐2‐ones with a Piperazine Moiety as Bradycardic Agents

A series of 1,3‐dihydro‐2H‐3‐benzazepin‐2‐ones with a piperazine moiety were designed and synthesized by treating the common intermediate of 1,3‐dihydro‐7,8‐dimethoxy‐3‐[3‐(1‐piperazinyl)propyl]‐2H‐3‐benzazepin‐2‐ones with a variety of N‐aryl‐2‐chloroacetamides and acyl chlorides. Their structures have been characterized by ¹H‐NMR, MS, and elemental analysis. The title compounds were evaluated for their bradycardic activity in vitro. Most of the synthesized compounds exhibited some vasorelaxant activity and heart‐rate‐reducing activity with bradycardic potency.     

Synthesis and Antimicrobial Evaluation of 6‐Alkylamino‐N‐phenylpyrazine‐2‐carboxamides

This work presents synthesis and antimicrobial evaluation of nineteen 6‐alkylamino‐N–phenylpyrazine‐2‐carboxamides. Antimycobacterial activity was determined against Mycobacterium tuberculosis H37Rv, M. kansasii and two strains of M. avium. Generally, the antimycobacterial activity increased with prolongation of simple alkyl chain and culminated in compounds with heptylamino substitution ( 3e , 4e ) with MIC = 5–10 μm against M. tuberculosis H37Rv. On the contrary, derivatives with modified alkyl chain (containing e.g. terminal methoxy or hydroxy group) as well as phenylalkylamino derivatives were mainly inactive. The most active compounds (with hexyl to octylamino substitution) were evaluated for their in vitro activity against drug‐resistant strains of M. tuberculosis and possessed activity comparable to that of the reference drug isoniazid. None of the tested compounds were active against M. avium. Some derivatives exhibited activity against Gram‐positive bacteria including methicillin‐resistant Staphylococcus aureus (best MIC = 7.8 μm ), while Gram‐negative strains as well as tested fungal strains were completely unsusceptible. Active compounds were tested for in vitro toxicity on various cell lines and in most cases were non‐toxic up to 100 μm .