Synthesis,biological evaluation,and molecular docking studies of novel 3‐aryl‐5‐(alkyl‐thio)‐1H‐1,2,4‐triazoles derivatives targeting Mycobacterium tuberculosis

A small library of new 3‐aryl‐5‐(alkyl‐thio)‐1H‐1,2,4‐triazoles was synthesized and screened for the antimycobacterial potency against Mycobacterium tuberculosis H₃₇Ra strain and Mycobacterium bovis BCG both in active and dormant stage. Among the synthesized library, 25 compounds exhibited promising anti‐TB activity in the range of IC₅₀0.03–5.88 μg/ml for dormant stage and 20 compounds in the range of 0.03–6.96 μg/ml for active stage. Their lower toxicity (>100 μg/ml) and higher selectivity (SI = >10) against all cancer cell lines screened make them interesting compounds with potential antimycobacterial effects. Furthermore, to rationalize the observed biological activity data and to establish a structural basis for inhibition of M. tuberculosis, the molecular docking study was carried out against a potential target MTB CYP121 which revealed a significant correlation between the binding score and biological activity for these compounds. Cytotoxicity and in vivo pharmacokinetic studies suggested that 1,2,4‐triazole analogues have an acceptable safety index, in vivo stability and bio‐availability.     

Synthesis and Antibacterial Activity of a New Series of 3‐[3‐(Substituted Phenyl)‐1‐Isonicotinoyl‐1H‐Pyrazol‐5‐yl]‐2H‐Chromen‐2‐one Derivatives

A novel series of 3‐[3‐(substituted phenyl)‐1‐isonicotinoyl‐1H‐pyrazol‐5‐yl]‐2H‐chromen‐2‐one derivatives 4a – k have been synthesized by the reaction of 3‐[2,3‐dibromo‐3‐(substituted phenyl) propanoyl]‐2H‐chromen‐2‐one 3a – k and isonicotinic acid hydrazide in the presence of triethylamine in absolute ethanol, characterized by spectral data and screened for their in‐vitro antibacterial activity against Gram‐positive and Gram‐negative bacteria. Among the series, compounds 4e , 4i , and 4k displayed an encouraging antibacterial activity profile as compared to the reference drug ampicillin against tested bacterial strains.     

Design,Synthesis, and Biological Evaluation of 1‐(thiophen‐2‐yl)‐9H‐pyrido[3,4‐b]indole Derivatives as Anti‐HIV‐1 Agents

A novel series of 1‐(thiophen‐2‐yl)‐9H‐pyrido [3,4‐b]indole derivatives were synthesized using DL‐tryptophan as starting material. All the compounds were characterized by spectral analysis such as ¹H NMR, Mass, IR, elemental analysis and evaluated for inhibitory potency against HIV‐1 replication. Among the reported analogues, compound 7g exhibited significant anti‐HIV activity with EC₅₀ 0.53 μm and selectivity index 483; compounds 7e , 7i , and 7o displayed moderate activity with EC₅₀ 3.8, 3.8, and 2.8 μm and selectivity index >105, >105, and 3.85, respectively. Interestingly, compound 7g inhibited p24 antigen expression in acute HIV‐1_IIIB infected cell line C8166 with EC₅₀ 1.1 μm . In this study, we also reported the Lipinski rule of 5 parameters, predicted toxicity profile, drug‐likeness, and drug score of the synthesized analogues.     

New pyrazole derivative 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole: synthesis and assessment of some biological activities

The molecular modification and synthesis of compounds is vital to discovering drugs with desirable pharmacological and toxicity profiles. In response to pyrazole compounds' antipyretic, analgesic, and anti‐inflammatory effects, this study sought to evaluate the analgesic, anti‐inflammatory, and vasorelaxant effects, as well as the mechanisms of action, of a new pyrazole derivative, 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole. During the acetic acid‐induced abdominal writhing test, treatments with 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole reduced abdominal writhing, while during the formalin test, 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole reduced licking times in response to both neurogenic pain and inflammatory pain, all without demonstrating any antinociceptive effects, as revealed during the tail flick test. 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole also reduced carrageenan‐induced paw edema and cell migration during the carrageenan‐induced pleurisy test. As demonstrated by the model of the isolated organ, 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole exhibits a vasorelaxant effect attenuated by Nω‐nitro‐l ‐arginine methyl ester, 1H‐[1,2,4]oxadiazolo[4,3‐alpha]quinoxalin‐1‐one, tetraethylammonium or glibenclamide. 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole also blocked CaCl₂‐induced contraction in a dose‐dependent manner. Suggesting a safe toxicity profile, 5‐[1‐(4‐fluorophenyl)‐1H‐pyrazol‐4‐yl]‐2H‐tetrazole reduced the viability of 3T3 cells at higher concentrations and was orally tolerated, despite signs of toxicity in doses of 2000 mg/kg. Lastly, the compounds' analgesic activity might be attributed to the involvement of the NO/cGMP pathway and K⁺ channels observed in the vasorelaxant effect.     

Synthesis and Biological Evaluation of a Series of 2‐((1‐substituted‐1H‐1,2,3‐triazol‐4‐yl)methylthio)‐6‐(naphthalen‐1‐ylmethyl)pyrimidin‐4(3H)‐one As Potential HIV‐1 Inhibitors

A series of novel S‐DABO derivatives with the substituted 1,2,3‐triazole moiety on the C‐2 side chain were synthesized using the simple and efficient CuAAC reaction, and biologically evaluated as inhibitors of HIV‐1. Among them, the most active HIV‐1 inhibitor was compound 4‐((4‐((4‐(2,6‐dichlorobenzyl)‐5‐methyl‐6‐oxo‐1,6‐dihydropyrimidin‐2‐ylthio)methyl)‐1H‐1,2,3‐triazol‐1‐yl)methyl)benzenesulfonamide ( B5b7) , which exhibited similar HIV‐1 inhibitory potency (EC₅₀ = 3.22 μm ) compared with 3TC (EC₅₀ = 2.24 μm ). None of these compounds demonstrated inhibition against HIV‐2 replication. The preliminary structure–activity relationship (SAR) of these new derivatives was discussed briefly.     

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.     

New Compounds Hybrids 1H‐1,2,3‐Triazole‐Quinoline Against Plasmodium falciparum

Malaria is one of the most prevalent parasitic diseases in the world. The global importance of this disease, current vector control limitations, and the absence of an effective vaccine make the use of therapeutic antimalarial drugs the main strategy to control malaria. Chloroquine is a cost‐effective antimalarial drug with a relatively robust safety profile, or therapeutic index. However, chloroquine is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of chloroquine‐resistant strains, which have also been reported for Plasmodium vivax. However, the activity of 1,2,3‐triazole derivatives against chloroquine‐sensitive and chloroquine‐resistant strains of P. falciparum has been reported in the literature. To enhance the anti‐P. falciparum activity of quinoline derivatives, we synthesized 11 new quinoline‐1H‐1,2,3‐triazole hybrids with different substituents in the 4‐positions of the 1H‐1,2,3‐triazole ring, which were assayed against the W2‐chloroquine‐resistant P. falciparum clone. Six compounds exhibited activity against the P. falciparum W2 clone, chloroquine‐resistant, with IC₅₀ values ranging from 1.4 to 46 μm . None of these compounds was toxic to a normal monkey kidney cell line, thus exhibiting good selectivity indexes, as high 351 for one compound ( 11 ).     

A Novel Antifungal Agent with Broad Spectrum: 1‐(4‐Biphenylyl)‐3‐(1H‐imidazol‐1‐yl)‐1‐propanone

A series of (1‐substituted aryl)‐3‐(1H‐imidazol‐1‐yl)‐1‐propanones was synthesized through the N‐alkylation of imidazole with 3‐dimethylamino‐1‐(substituted aryl)‐1‐propanone hydrochlorides (ketonic Mannich bases). A second series of N¹‐substituted imidazoles was obtained by the reduction of the carbonyl function of the imidazole–ketones in the previous series by means of NaBH₄. All of the compounds were evaluated for antifungal activity against 16 strains of Candida, and 3‐(1H‐imidazol‐1‐yl)‐1‐(4‐biphenylyl)‐1‐propanone emerged as a broad‐spectrum antifungal agent. Several 3‐(1H‐imidazol‐1‐yl)‐1‐(2′‐(substituted benzyl)oxyphenyl)‐1‐propanones were also active towards Candida kefyr.     

Synthesis and Antistaphylococcal Activity of N‐Substituted‐1H‐benzimidazole‐sulphonamides

A series of N‐substituted‐1H‐benzimidazole‐5(6)‐sulfonamides and 3‐(5,6‐dichloro‐1H‐benzimidazol‐2‐yl)‐N‐substituted benzensulfonamides were synthesized and evaluated for antibacterial activity against Staphylococcus aureus and methicillin‐resistant S. aureus (MRSA). Certain compounds inhibit bacterial growth with low MIC (μg/mL) values. The most active compounds 30 , 31 , and 32 have the lowest MIC values with 0.39 to 0.19 μg/mL. Among the compounds having sulfonamido moities, 16 , 23 , and 24 exhibited the strongest antibacterial activity with 1.56 μg/mL MIC values.     

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.     

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 5,8‐Disubstituted‐2‐methyl‐2,3,4,5‐tetrahydro‐1H‐pyrido[4,3‐b] indoles as 5‐HT6 and H1 Receptors Antagonists

Synthesis, biological evaluation, and structure‐activity relationships (SAR) for a series of novel γ‐carboline analogues of Dimebon are described. Among the studied compounds, tetrahydro‐γ‐carboline 5b (2,8‐dimethyl‐5‐[cis‐2‐pyridin‐3‐ylvinyl]‐2,3,4,5‐tetrahydro‐carboline) has been identified as the most potent small molecule antagonist, in particular against histamine H₁ and serotonin 5‐HT₆ receptors (IC₅₀ < 0.45 μM and IC₅₀ = 0.73 μM, respectively). A thorough comparative SAR study performed for the tested compounds has revealed significant correlations between the nature of side substituents and the related antagonistic activity.     

Synthesis and Pharmacological Evaluation of Some Novel Thebaine Derivatives: N‐(Tetrazol‐1H‐5‐yl)‐6,14‐endoethenotetrahydrothebaine Incorporating the 1,3,4‐Oxadiazole or the 1,3,4‐Thiadiazole Moiety

In this study, we synthesized some novel N‐(tetrazol‐1H‐5‐yl)‐6,14‐endoethenotetrahydrothebaine 7α‐substituted 1,3,4‐oxadiazole and 1,3,4‐thiadiazole derivatives as potential analgesic agents. The structures of the compounds were established on the basis of their IR, ¹H NMR, ¹³C NMR, 2D NMR, and high‐resolution mass spectral data. The analgesic activity was evaluated by a rat‐hot plate test model and a rat tail‐flick model. Compound 12 showed analgesic activity higher than that of morphine. In addition to a histopathological and biochemical evaluation, the LD₅₀ dose for the most active compound 12 was determined.     

Regioselective synthesis of 3‐(1H‐indol‐3‐yl)‐5‐(1H‐indole‐3‐carbonyl)‐4‐hydroxyfuroic acids: route to hydroxyfuroic acid‐based insulin receptor activators

A new class of insulin receptor activator with a hydroxyfuroic acid in place of a hydroxyquinone moiety is reported. The synthesis of 3‐(1H‐indol‐3‐yl)‐5‐(1H‐indole‐3‐carbonyl)‐4‐hydroxyfuroic acids ( 26 – 30 ) requires seven major steps. Key elements in the syntheses include (1) sequential preparation of two 4‐(N‐protected indole)‐3‐methoxy‐furoic 2,5‐dicarboxylic esters ( 4 and 6 ); (2) regioselective conversion of the furoic diacid 8 into its C‐5 methyl ester 10 with methyl chloroformate; and (3) acylation of 10 by a 7‐substituted indole under a mild condition. This study demonstrates a feasible route of synthesizing insulin receptor activators with a hydroxyfuroic acid scaffold. Among those hydroxyfuroic acid compounds, compound 28 demonstrates insulin receptor activation potential comparable to Merck's compound 2 with a dihydroxybenzoquinone scaffold. Drug Dev Res 72: 247–258, 2011. © 2010 Wiley‐Liss, Inc.     

The synthesis and structures of deuterium‐labeled 5‐substituted 1H‐tetrazoles

The synthesis and crystal structures of deuterium‐labeled 5‐substituted 1H‐tetrazoles, 5‐[²H₅]phenyl‐1H‐tetrazole (I), 5‐[²H₇]tolyl‐1H‐tetrazole (II), and 5‐[²H₇]benzyl‐1H‐tetrazole (III) are reported. All syntheses were carried out using simple, facile steps and the products were obtained in high yields. Copyright © 2008 John Wiley & Sons, Ltd.     

Design and synthesis of 9H‐fluorenone based 1,2,3‐triazole analogues as Mycobacterium tuberculosis InhA inhibitors

We prepared fifty various 9H‐fluorenone based 1,2,3‐triazole analogues varied with NH, –S–, and –SO₂– groups using click chemistry. The target compounds were characterized by routine analytical techniques, ¹H, ¹³CNMR, mass, elemental, single‐crystal XRD ( 8a ) and screened for in vitro antitubercular activity against Mycobacterium tuberculosis (MTB) H37Rv strain and two “wild” strains Spec. 210 and Spec. 192 and MIC₅₀ was determined. Further, the compounds were evaluated for MTB InhA inhibition study as well. The final analogues exhibited minimum inhibitory concentration (MIC) ranging from 52.35 to >295 μm . Among the –NH– analogues, one compound 5p (MIC 58.34 μm ), among –S– containing analogues four compounds 8e (MIC 66.94 μm ), 8f (MIC 74.20 μm ), 8g (MIC 57.55 μm ), and 8q (MIC 56.11 μm ), among –SO₂– containing compounds one compound 10p (MIC 52.35 μm ) showed less than MTB MIC 74.20 μm : Compound 4‐(((9H‐fluoren‐9‐yl)sulfonyl)methyl)‐1‐(3,4,5‐trimethoxyphenyl)‐1H‐1,2,3‐triazole ( 10p ) was found to be the most active compound with 73% InhA inhibition at 50 μm ; it inhibited MTB with MIC 52.35 μm . Further, 10f and 10p were docked to crystal structure of InhA to know binding interaction pattern. Most active compounds were found to be non‐cytotoxic against HEK 293 cell lines at 50 μm .     

2‐Aryl‐3‐(1H‐Azol‐1‐yl)‐1H‐Indole Derivatives: A New Class of Antimycobacterial Compounds – Conventional Heating in Comparison with MW‐Assisted Synthesis

2‐Aryl‐3‐(1H‐imidazol‐1‐yl and 1H‐1,2,4‐triazol‐1‐yl)‐1H‐indole derivatives were synthesized and tested for their in‐vitro antifungal and antimycobacterial activities. These indole derivatives were devoid of antifungal activity against the tested strains of Candida spp. Yet, they exhibited an interesting antitubercular activity against Mycobacterium tuberculosis reference strain H₃₇Rv.     

Highly Active Potential Antituberculotics: 3‐(4‐Alkylphenyl)‐4‐thioxo‐2H‐1,3‐benzoxazine‐2(3H)‐ones and 3‐(4‐Alkylphenyl)‐2H‐1,3‐benzoxazine‐2,4(3H)‐dihiones Substituted in Ring‐B by Halogen

A series of 6‐chloro‐3‐(4‐alkylphenyl)‐4‐thioxo‐2H‐1,3‐benzoxazine‐2(3H)‐ones, 7‐chloro‐3‐(4‐alkylphenyl)‐4‐thioxo‐2H‐1,3‐benzoxazine‐2(3H)‐ones, 6‐bromo‐3‐(4‐alkylphenyl)‐4‐thioxo‐2H‐1,3‐benzoxazine‐2(3H)‐ones, 6,8‐dibromo‐3‐(4‐alkylphenyl)‐4‐thioxo‐2H‐1,3‐benzoxazine‐2(3H)‐ones, 6‐chloro‐3‐(4‐alkylphenyl)‐2H‐1,3‐benzoxazine‐2,4(3H)‐dithiones, 7‐chloro‐3‐(4‐alkylphenyl)‐2H‐1,3‐benzoxazine‐2,4(3H)‐dithiones, 6‐bromo‐3‐(4‐alkylphenyl)‐2H‐1,3‐benzoxazine‐2,4(3H)‐dithiones and 6,8‐dibromo‐3‐(4‐alkylphenyl)‐2H‐1,3‐benzoxazine‐2,4(3H)‐dithiones was synthesized. The compounds exhibited in‐vitro activity against Mycobacterium tuberculosis, M. kansasii (two strains), and M. avium. 6‐bromo‐3‐(4‐propylphenyl)‐4‐thioxo‐2H‐1,3‐benzoxazin‐2(3H)‐one and 6‐bromo‐3‐(4‐propylphenyl)‐2H‐1,3‐benzoxazin‐2,4(3H)‐dithione are the most active compounds against M. tuberculosis. The activity is similar to isoniazid (INH). The compounds under study have a broad spectrum of activity against potential pathogenic strains. The replacement of the oxo group by thioxo group of 3‐(4‐alkylphenyl)‐2H‐1,3‐benzoxazine‐2,4(3H)‐diones often led to an improvement in the antimycobacterial activity against M. tuberculosis.     

Synthesis,In Vitro Antimicrobial and Antioxidant Activities of Some New 4,5‐Dihydro‐1H‐1,2,4‐triazol‐5‐one Derivatives

A series of compounds derived from 4,5‐dihydro‐1H‐1,2,4‐triazol‐5‐one were synthesized and characterized by spectral data. The 12 new compounds were analyzed for their potential in vitro antioxidant activities by three different methods. Compound 4f showed the best activity for the iron binding. In addition, the compounds 4 were titrated potentiometrically with tetrabutylammonium hydroxide in non‐aqueous solvents. The RP‐HPLC capacity factors (k′) of the series were also determined on a C18 column, with methanol/water as the mobile phase. The correlation between log k′ with the percentage of methanol in the mobile phase was used for the determination of the log k_w values for these compounds. The antimicrobial activities of these compounds were also screened against bacteria and yeast.     

Synthesis and pharmacological evaluation of 3‐(4‐chloro phenyl)‐2‐substituted‐3H‐quinazolin‐4‐ones as analgesic and anti‐inflammatory agents

A new series of 3‐(4‐chloro phenyl)‐2‐substituted‐3H‐quinazolin‐4‐ones were synthesized by reacting the amino group of 2‐hydrazino‐3‐(4‐chloro phenyl)‐3H‐quinazolin‐4‐one with different aldehydes and ketones. The compounds were investigated for their analgesic activity in albino mice, and for their anti‐inflammatory and ulcerogenic activities in Wistar rats. All test compounds exhibited analgesic and anti‐inflammatory activities. Compound VA2 (2‐(1‐ethylpropylidene‐hydrazino)‐3‐(4‐chloro phenyl)‐3H‐quinazolin‐4‐one) showed moderately more potent analgesic activity and compound VA3 (2‐(1‐methylbutylidene‐hydrazino)‐3‐(4‐chlorophenyl)‐3H‐quinazolin‐4‐one) showed moderately more potent anti‐inflammatory activity when compared with the reference standard, diclofenac sodium. The test compounds showed only mild ulcerogenic side effects when compared with aspirin. Drug Dev Res 69: 226–233, 2008 ©2008 Wiley‐Liss, Inc.