Synthesis, antimicrobial evaluation and molecular modelling of novel sulfonamides carrying a biologically active quinazoline nucleus

A novel series of quinazolines 5–10, triazoloquinazolines 11–17 and triazinoquinazoline 19 bearing a biologically active sulfonamide moiety were synthesized, utilizing methyl 2-isothiocyanato benzoate 2. Some of the newly synthesized compounds revealed promising bacterial growth inhibition, compared with the ampicillin, as the reference drug. A LigandScout approach-generated pharmacophore model for the Staph aureus bacteria growth inhibition was done. The degree of fitting of the test set compounds (3, 4, 6, 8, 11, 17) to the generated hypothetical model revealed a qualitative measure of the more or less microbial inhibition of Staphylococcus aureus. Compounds (7, 8, 10, 12, 15, 17 and 22), which revealed significant activity, are able to effectively satisfy the proposed pharmacophore geometry, using the energy accessible conformers (E _conf < 20 kcal/mol).     

Discovery of novel DPP IV inhibitors: application of pharmacophore-based virtual screening

Dipeptidyl peptidase IV (DPP-IV) is a potential drug target for type-2 diabetes and DPP-IV inhibitors are known to efficiently improve glucose tolerance. In the present study, pharmacophore model for a set of 29 DPP-IV inhibitors was generated by ligand-based pharmacophore generation process. The best hypothesis, hypo 1, consisting of four chemical features, namely, one hydrogen bond donor, one hydrogen bond acceptor, one hydrophobe and one ring aromatic was validated by cost function analysis, test set prediction and Fischer test. The validated pharmacophore model was then used for searching new lead compounds from Maybridge and NCI database. Four compounds (CD01797, CD06202, CD02493, and AW01077) from Maybridge database and three compounds (NSC997, NSC2450, and NSC5815) from NCI database were identified as structurally diverse druggable novel leads with nM activity against DPP-IV.     

(Naphthalen-1-yloxy)-acetic acid benzylidene/(1-phenyl-ethylidene)-hydrazide derivatives: synthesis, antimicrobial evaluation, and QSAR studies

A series of (naphthalen-1-yloxy)-acetic acid hydrazides (1–36) was synthesized and screened, in vitro, for antibacterial, antifungal, and antiviral activities. The results of antiviral activity showed that none of the tested compounds was active against viruses at subtoxic concentrations. Further, the antimicrobial screening results demonstrated that compounds having 3,4,5-trimethoxy benzaldehyde (18), o-Br, p-CN (31), and m-NO₂ acetophenone (32) substituents were the most active ones against tested strains. QSAR investigations revealed that multi-target QSAR models were effective in describing the antimicrobial activity.     

Docking, synthesis, and pharmacological evaluation of isoindoline derivatives as anticonvulsant agents

Eleven analogs of N-arylisoindoline pharmacophore were synthesized and evaluated for their anticonvulsant activities. The in vivo screening data acquired indicate that all the analogs have the ability to protect against pentylenetetrazole-induced seizure. Compounds 2, 6, and 11 elevated clonic seizure thresholds at 30 min which were more active than reference drug phenytoin, and compounds 2, 7, and 11 showed marked anticonvulsant activity on tonic seizure. The most potent compounds were 2 and 11 which had comparative activity to the phenytoin. Using a model of the open pore of the Na channel, we have docked all compounds. Docking studies have revealed that these compounds interacted mainly with residues II-S6 of NaV1.2 by making hydrogen bonds and have additional hydrophobic interactions with other domains in the channel’s inner pore.     

Evaluation of insecticidal activity of camptothecin analogs against Brontispa longissima

Continuing our search for natural product-based compounds for the control of Brontispa longissima Larvae, 31 camptothecin analogs were first tested for their insecticidal activity against the fifth-instar larvae of B. longissima in vivo. Among them, compounds 6–8, 11, 26, 28, and 29 showed more promising and pronounced insecticidal activity than toosendanin, a commercial insecticide derived from Melia azedarach. The different insecticidal activity ranges of compounds 1–31 indicated that variation of chemical structures in the camptothecin skeleton markedly affected the activity profiles of this compound class, and some important SAR information has been revealed from it. The quantitative structure–activity relationship (QSAR) model was applied to provide insight into the camptothecin analogs’ structural properties that are responsible for their activities. The results obtained from SAR analysis showed good correlation with the QSAR studies, which allowed for the rational design of more potent camptothecin analogs in the development of potential new insecticides.     

Synthesis of benzothiazole derivatives having acetamido and carbothioamido pharmacophore as anticonvulsant agents

A new series of N-(6-chlorobenzothiazol-2-yl)-2-substituted-acetamides (3a–h) and N-(6-chlorobenzothiazol-2-yl)-2-(substituted-benzylidene)hydrazinecarbothioamides (5a–h) were synthesized and characterized by IR, ¹H NMR, mass and elemental analysis. In vivo anticonvulsant and acute toxicity screening of all the synthesized compounds showed morpholino (3f) and imidazolyl (3g) derivatives as promising anticonvulsant lead. Furthermore, In silico drug-likeness parameters have also been investigated for filtering out the likelihood of poor drug absorption or brain penetration. 3D four-point pharmacophore measurements of compounds were also carried out to match these with established anticonvulsants agents.     

Design, synthesis and pharmacophoric model building of novel substituted nicotinic acid hydrazones with potential antiproliferative activity

Novel 6-aryl-2-methylnicotinic acid hydrazides 4a-c and their corresponding hydrazones 5a-c and 6a-i were synthesized. X-ray single crystal diffraction of 6h confirmed the chemical structure of hydrazones 6a-i. Antiproliferative activity of the synthetic compounds was investigated against K562 leukemia cell lines. Variable cell growth inhibitory activities were obtained with IC₅₀ range from 24.99 to 66.78 ??M where the compound 6c exhibited the maximum activity. Structure activity relationship analysis has been performed and a common pharmacophore model for the synthesized derivatives has been obtained by using the pharmacophore elucidation module of the software MOE. The best model obtained is characterized by two projected locations of potential H-bond donors (F 3 and F4) and two Aromatic annotations (F1 and F2).     

Computational POM evaluation of experimental in vitro Trypanosoma cruzi and Mycobacterium tuberculosis inhibition of heterocyclic-2-carboxylic acid (3-cyano-1,4-di-noxidequinoxalin-2-yl)amide derivatives

A computation model has been developed for the rational design of bioactive pharmacophore sites as anti-Mycobacterium tuberculosis and anti-Trypanosoma cruzi (TC) candidates. The 40 compounds 1–40 analyzed have been previously screened for their antitubercular and antitrypanosomal activity. The highest anti-TC activity is obtained for compounds 8 and 18 which exhibited low IC₅₀ values (9.2 and 10.8 μM), almost equal to clinical drug, nifurtimox (7.7 μM; 100 % Inhib.). This could be attributed to the existence of two synergic (O ^δ?–N ^δ?) and (O ^δ?–O ^δ?) antitrypanosomal pharmacophore sites. In contrast to compounds 8 and 18 which contain electro-attractor groups (R¹, R² = F), analog compounds 1 and 13 with electro-donor or only hydrogen (R¹, R² = CH₃, H) show best antibacterial activity (MIC = 0.977 and 1.190 μg/mL) very close to antitubercular activity of Rifampicin (MIC = 0.125 μg/mL). This could be attributed to the existence of (O ^δ?–NH ^δ+) antibacterial pharmacophore site.     

Elaborate ligand-based modeling reveals new human neutrophil elastase inhibitors

Human neutrophil elastase inhibitors (HNE-Is) have been recently implicated in inflammatory diseases. Accordingly, we applied a drug discovery workflow to unveil novel inhibitory HNE leads via combining pharmacophore modeling, quantitative structure–activity relationship (QSAR) analysis, and in silico screening. We employed the pharmacophoric models and associated QSAR equation to screen the National Cancer Institute (NCI) list of compounds. Virtual screening identified 14 novel leads from NCI compounds. The most potent hit 126 exhibited 93 % inhibition at 10 μM.     

Synthesis,antimicrobial, and antioxidant activity of benzofuran barbitone and benzofuran thiobarbitone derivatives

The synthesis of novel series of benzofuran derivatives, containing barbitone moiety, 5-[(2/4-substitutedphenyl)(5-substituted-1-benzofuran-2-yl) methylidene]pyrimidin-2,4,6(1H,3H,5H)-trione (4a–i) and thiobarbitone moiety, 5-[(2/4-substitutedphenyl)(5-substituted-1-benzofuran-2-yl)methylidene]-2-thioxodihydropyrimidin-4,6(1H, 5H)-dione (5a–i) have been reported. The target compounds (4a–i) and (5a–i) were synthesized by the Knoevenagel condensation of (5-substituted-1-benzofuran-2-yl)(2/4-substitutedphenyl) methanone (3a–i) with barbituric acid and thiobarbituric acid, respectively, in acid medium. These compounds were screened for the antimicrobial and antioxidant activities. From antimicrobial activity results it was found that compounds 4a, 5a, 4c, and 5c displayed good antibacterial and antifungal activity against all tested strains. Further, the synthesized compounds were studied for docking on the enzyme, Glucosamine-6-phosphate synthase and the compounds 4c and 5c have emerged has an active antimicrobial agent with least binding energy (?5.27 and ?4.85 kJ mol^?1). Compounds 4e, 4f, 5e, and 5f showed promising free radical scavenging activity and compounds 5a and 5b showed good chelating ability with Fe²⁺ ions.     

Synthesis, antimycobacterial, antiviral, antimicrobial activities, and QSAR studies of isonicotinic acid-1-(substituted phenyl)-ethylidene/cycloheptylidene hydrazides

A series of isonicotinic acid-1-(substituted phenyl)-ethylidene/cycloheptylidene hydrazide derivatives (1–12) was tested for their, in vitro antimycobacterial activity against Mycobacterium tuberculosis, and compound 2 was found to be more active than isoniazid. The antiviral screening results indicated that none of the tested compounds was active against a broad variety of DNA and RNA viruses at subtoxic concentrations, except compounds 8 and 10 that proved to be active against DNA viruses at concentrations close to their cytostatic potential. The synthesized compounds were also screened for their antimicrobial potential against S. aureus, B. subtilis, E. coli, C. albicans and A. niger, and the results indicated that compounds having Br, OCH₃ and Cl groups were highly active. The multi-target QSAR models indicated the importance of lipophilic (log P) and topological parameters (³χ^v) in describing the antimicrobial activity.     

Phytochemical constituents of Mongolian traditional medicinal plants, Chamaerhodos erecta and C. altaica, and its constituents prevents the extracellular matrix degradation factors

Activity-guided isolation of the n-butanol fraction of Chamaerhodos erecta and water soluble fraction of C. altaica resulted in the isolation of 39 compounds, including new compounds identified as 4,5-dihydroxybenzaldehyde-3-O-β-d-glucopyranoside (1) from C. erecta and quercetin-3-O-β-d-glucuronopyranosyl-4′-O-β-d-glucopyranoside (2) from C. altaica. A total of 37 other compounds were identified based on physico-chemical properties and spectroscopic data. Antioxidative activity was evaluated using a DPPH radical-scavenging method, hyaluronidase inhibitory activity, and advanced glycation end products production inhibitory activity of isolated compounds. Some flavonols (4, 6, 9–11, 14, 15), catechins (18, 19), an amino acid (20), a lignan glucoside (23), and tannins (29–39) exhibited potential a free radical scavenging activity while the new compound (1) showed weak activity. A catechin (18) and some of the tannins (32, 33, 35, 36, 38) had moderate hyaluronidase inhibitory activity. Some of flavonoids and tannins prevented advanced glycation end products production, and the IC₅₀ of compounds 3, 9, 14–16, 33, 34, 36, 38, and 39 were determined.     

Synthesis, characterization, and biological evaluation of some N-aryl hydrazones and their 2,3-disubstituted-4-thiazolidinone derivatives

A series of 2,3-disubstituted 4-thiazolidinones 6 and 8a-p have been prepared by the cyclo condensation reaction of various substituted N-aryl hydrazones 5 and 7a–p with mercapto acetic acid. The intermediate N-aryl hydrazones 5 and 7a–p were synthesized by the condensation of 2-bromo-5-methoxy benzohydrazide 4 with 2 or various substituted aromatic aldehydes. The new Naphthalene-2-carboxaldehyde 2 has been synthesized by Vilsmeier-Haack reaction of naphthalen-1(2H)-one 1. The key starting compound 2-bromo-5-methoxy benzohydrazide 4 was prepared from methyl 2-bromo-5-methoxybenzoate 3 by the reaction with hydrazine hydrate in alcoholic medium. The formulae of the compounds were confirmed by elemental analyses and their structures were determined based on IR, ¹H-NMR, ¹³C-NMR, ¹³C-NMR-DEPT, and mass spectral data. The newly synthesized compounds were evaluated for their antioxidant, anti-inflammatory, and analgesic activities. The antibacterial activities of the newly synthesized compounds against E. coli ATCC 8739, S. aureus ATCC 6538, P. aeruginosa ATCC 1539, and Bacillus cereus, while the antifungal activities of the compounds against Candida albicans were tested. The acute cytotoxicity data of compounds 7h and 8a are tested and are found to be nontoxic up to 2,500 mg/kg.     

Anticandidiasis agents from a Tanzanian plant, Combretum zeyheri

Combretum zeyheri Sond (Combretaceae) has been reported to exhibit anticandida activity against Candida kruzei, C. albicans, and C. parapsilosis; however, the active constituents have not been isolated so far. A bioactivity-guided fractionation of MeOH extract of C. zeyheri resulted in the isolation of triterpenoids, ursolic acid (1.1), oleanolic acid (1.2), maslinic acid (2.1), 2α,3β-dihydroxyurs-12-en-28-oic acid (2.2), 6β-hydroxymaslinic acid (3), and terminolic acid (4). These compounds were characterized on the basis of their 1D, 2D NMR, ESI-MS and FT-IR spectroscopic data. All the isolated compounds, 1.2, 2.1, 2.2, 3, and 4 except ursolic acid (1.1) are being reported for the first time from C. zeyheri. Later, the isolated triterpenoids (1–4) were evaluated for their anticandida activity against the three strains of C. albicans and all compounds showed anticandida activity of which terminolic acid (4) was most active. Furthermore, structure–activity relationship of isolated triterpenoids (1–4) was studied, which showed that triterpenoids of oleanane and ursane having 2α,3β,23-trihydroxyl group are more active.     

Synthesis, antimicrobial, and antioxidant activities of some new indole analogues containing pyrimidine and fused pyrimidine systems

To examine new leads with potential antimicrobial and antioxidant activities, a new series of tetrahydropyrimidines (2a–c, 3a–c and 4a–c), pyrazolo[3,4-d]pyrimidines (5a–c), and ditetrazolo[1,5-a;1′,5′-c]pyrimidines (6a–c) were synthesized in this study using appropriate synthetic routes. The newly synthesized compounds have been tested for their antimicrobial and antioxidant activities against DPPH stable free radical. In the case of antibacterial activity, compounds 2a, 6a, and 6c exhibited the maximum zone of inhibition against Staphylococcus aureus; compound 6c exhibited maximum zone of inhibition against Pseudomonas aeruginosa; and compound 2a showed maximum inhibitory growth against Klebsiella pneumonia. While in the case of antifungal activities, compound 5a showed good zone of inhibition against Aspergillus oryzae, compounds 2b and 6a exhibited maximum zone of inhibition against Aspergillus niger. In case of antioxidant activities, compound 2a showed the highest DPPH radical scavenging activity.     

Antimicrobial and antiquorum-sensing studies. Part 2: synthesis, antimicrobial, antiquorum-sensing and cytotoxic activities of new series of fused [1,3,4]thiadiazole and [1,3]benzothiazole derivatives

New series of [1,3,4]thiadiazolo[3,2-a]pyrimidines, [1,3,4]thiadiazolo[2,3-b]quinazolines, and pyrimido[2,1-b][1,3]benzothiazoles have been synthesized and characterized by analytical and spectrometrical methods (IR, MS, ¹H, and ¹³C NMR). Sixteen of the synthesized compounds; namely, 3a, b, 5a–f, 8a, b, 10, 11a–c, and 13a, b were screened for antibacterial activity against Escherichia coli, Staphylococcus aureus, and Bacillus cereus. They were found to be either moderately active, slightly active or inactive against the selected microorganisms. The antifungal activity of these compounds were also tested against Candida albicans, Aspergillus fumigatus 293, and Aspergillus flavus 3375. Compound 11a showed potent antifungal activity against the three selected fungi; the rest of the tested compounds displayed either weaker activity or were completely inactive. The same compounds were examined for antiquorum-sensing activity against Chromobacterium violaceum ATCC 12472, where compounds 3a, 10, 11a, and 13a, b exhibited promising activity. The in vitro cytotoxic activity of these compounds was also studied by brine shrimp lethality bioassay, and results indicated that compounds 3a, 11a, and 13a have the highest cytotoxic activity.     

Synthesis, characterization and antimicrobial studies of a few novel thiazole derivatives

A series of novel N-[4-(substituted)-1,3-thiazol-2-yl]-2-(substituted)acetamide (9a–m) and methyl 2-(2-(2-(substituted)acetamido)thiazol-4-yl)acetate (9n–o) derivatives have been synthesized and compounds were characterised by spectral and analytical studies. All compounds were screened for their in vitro antibacterial activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumonia by disc diffusion method and for antifungal activity against Penicillium marneffei, Trichophyton mentagrophytes, Aspergillus flavus and Aspergillus fumigatus by serial plate dilution method. Compounds 9b, 9e, 9m and 9o exhibited growth inhibition against all the tested bacterial strains, with MIC values varying from 12.5 to 6.25 μg/ml. Among the compounds tested for antifungal activity, 9a, 9b, 9d, 9j, 9k, 9p and 9n showed wide range of activity against all the tested strains. Most of the newly synthesized compounds were effective against fungal strains rather than bacterial strains. However, some of the compounds like 9a, 9e, 9j, 9k and 9i showed selective sensitivity against some of the bacterial strains whereas they were unable to sustain the growth of other strains.     

Synthesis of some new indolo[2,3-c]isoquinolinyl pyrazoles, -1,3,4-oxadiazoles and their biological activities

A new series of novel compounds [10-substituted 6H, 7H-indolo[2,3-c]isoquinolin-5-one-6-yl]carbohydrazides (3a–c), 1-[10-substituted 6H, 7H-indolo[2,3-c]isoquinolin-5-one-6-yl]fomyl-, -3′,5′-dimethylpyrazoles (4a–c), -3′,5′-diphenylpyrazoles (5a–c), -3′-methylpyrazol-5′-ones (6a–c) and -1′,3′,4′-oxidiazole-2′-thiones (7a–c) linked to indoloisoquinoline at position-6 through formyl bridge was prepared. The structures of these newly synthesized compounds were confirmed by their spectral studies and elemental analysis. These compounds have been screened for their antimicrobial and antioxidant activities. Compounds 4a, 4b, 5a, 5b, 5c, 6b, 7a, and 7c exhibited the maximum zone of inhibition against A. niger, A. flavus, and A. fumigatus. Compounds 4a, 5a, 5c, 6b, 6c, 7a, and 7b showed good antibacterial activity. Compounds 4b, 4c, 5b, 5c, 6a, 6b, 7a, 7b, and 7c showed good radical scavenging activity compared with standards.