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POM as Efficient Tools to Predict and Improve Both Antibacterial and Antifungal Activity of Aryl Aldazines.
Abstract
A general, simple and straight forward approach to symmetric substituted aldazines derivatives via condensation reaction of aromatic aldehydes and ammonia precursors has been demonstrated successfully under mild reaction conditions. Their qualitative antimicrobial activities have been previously evaluated against 10 bacterial and 3 fungal species. We have reported the design and calculated molecular properties of some aldazines derivatives on the basis of hypothetical antibacterial pharmacophore site, structures which were designed to interact with both of Gram positive and Gram negative bacteria. A correlation of structure and activities relationship of these compounds with respect to molecular modeling, Lipinski rule of five, drug likeness, toxicity profiles and other physico-chemical properties of drugs are described and verified experimentally.
... N-carbamidoyl-4-(-4-oxo-3-(3-phenylthioureido)-3,4-dihydroquinazolin-2-ylamino)benzene sulfonamide (29) and N-(2,6-dimethoxypyrimidin-4-yl)-4-[4-oxo-3-(3-phenylthioureido)-3,4-dihydroquinazolin-2-ylamino)benzenesulfonamide (30). -A mixture of compound 6 or 9 (0.01 mol) and phenyl isothiocyanate (1.35 g, 0.01 mol) in ethanol (50 mL) was refluxed for 8 h. ...
... Also, it was hypothesized that the difference in charges between two heteroatoms of the same dipolar phar-macophore site (Xd -…..Yd + ) may facilitate the inhibition of bacteria more than viruses. Hence, the antifungal activity is related to the possible secondary electronic interaction with the positively charged target sites (30). ...
... Elucidation of the binding approaches for the synthesized compounds is based on finding the active structures. Schemes 1-4 show the structure of the training set compounds (4-7, 10, 13, 15-18, 23, 26, 29) and test set compounds (2,9,11,22,30). The test set compounds were selected to represent structural variations in the training set. On the assumption that active compounds bind in a similar fashion at the active site, we employed the LigandScout program (24) to evaluate the common fea- tures essential for activity and the hypothetical geometries adopted by these ligands in their most active forms. ...
In the present work, interaction of the strategic startingmaterial, methyl 2-isothiocyanatobenzoate (1), with sulfadrugs resulted in the formation of methyl 2- [3-(4-(N-sub- stituted sulfamoyl)phenyl)thioureido]benzoates2–5, whichupon reaction with hydrazine hydrate afforded N-aminoderivatives 6–9.Triazoloquinazoline derivatives10–18 were obtained via reaction of compounds6–8with aromaticaldehydes. Also, the reaction of compound 8 with formic acid gave the corresponding triazoloquinazoline derivative19. Triazinoquinazoline derivatives 22,23 were obtained via reaction of N-amino derivatives 6 or 8 with ethylchloroacetate. Interaction of 6 with diethyloxalate yielded triazoloquinazoline 26. The synthesized compounds were screened for theirin vitro antimicrobial activities and someof them exhibited promising antibacterial activity com- pared to ampicillin as positive control. Compounds that revealed significant activity are able to satisfy effectivelythe proposed pharmacophore geometry
... N-carbamidoyl-4-(-4-oxo-3-(3-phenylthioureido)-3,4-dihydroquinazolin-2-ylamino)benzene sulfonamide (29) and N-(2,6-dimethoxypyrimidin-4-yl)-4-[4-oxo-3-(3-phenylthioureido)-3,4-dihydroquinazolin-2-ylamino)benzenesulfonamide (30). -A mixture of compound 6 or 9 (0.01 mol) and phenyl isothiocyanate (1.35 g, 0.01 mol) in ethanol (50 mL) was refluxed for 8 h. ...
... Also, it was hypothesized that the difference in charges between two heteroatoms of the same dipolar phar-macophore site (Xd -…..Yd + ) may facilitate the inhibition of bacteria more than viruses. Hence, the antifungal activity is related to the possible secondary electronic interaction with the positively charged target sites (30). ...
... Elucidation of the binding approaches for the synthesized compounds is based on finding the active structures. Schemes 1-4 show the structure of the training set compounds (4-7, 10, 13, 15-18, 23, 26, 29) and test set compounds (2,9,11,22,30). The test set compounds were selected to represent structural variations in the training set. On the assumption that active compounds bind in a similar fashion at the active site, we employed the LigandScout program (24) to evaluate the common fea- tures essential for activity and the hypothetical geometries adopted by these ligands in their most active forms. ...
In the present work, interaction of the strategic starting material, methyl 2-isothiocyanatobenzoate (1), with sulfa drugs resulted in the formation of methyl 2-[3-(4-(N-substituted sulfamoyl)phenyl)thioureido] benzoates 2-5, which upon reaction with hydrazine hydrate afforded N-amino derivatives 6-9. Triazoloquinazoline derivatives 10-18 were obtained via reaction of compounds 6-8 with aromatic aldehydes. Also, the reaction of compound 8 with formic acid gave the corresponding triazoloquinazoline derivative 19. Triazinoquinazoline derivatives 22, 23 were obtained via reaction of N-amino derivatives 6 or 8 with ethyl chloroacetate. Interaction of 6 with diethyloxalate yielded triazoloquinazoline 26. The synthesized compounds were screened for their in vitro antimicrobial activities and some of them exhibited promising antibacterial activity compared to ampicillin as positive control. Compounds that revealed significant activity are able to satisfy effectively the proposed pharmacophore geometry.
... For a molecule to be a potential drug, besides having a good biological activity, it must have good pharmacokinetic properties in biological systems. To access the pharmacokinetic profile of the synthesized molecules, we have employed well-validated in silico tools: Osiris, Petra and Molinspiration (Alafeefy et al., 2012;Mahajan et al., 2012;Fathi et al., 2011). These tools have been validated with almost 7,000 drug molecules available on the market. ...
... In fact, these compounds are not active presumably due to lack of suitable geometrical conformation of pharmacophores which is another crucial parameter that has to be taken into consideration. The geometrical aspect parameter and the aqueous solubility of each compound significantly affect its absorption, distribution characteristics, and bioactivity (Alafeefy et al., 2012;Mahajan et al., 2012;Fathi et al., 2011). Typically, low solubility goes along with bad absorption, and therefore, the general aim is to avoid poorly soluble compounds. ...
Series of new metronidazole urea and thiourea derivatives have been prepared in good yields through reactions of 2-(2-methyl-5-nitroimidazolyl)ethyl amine hydrochloride with various cyanates and isothiocyanates. Similarly, metronidazole salicylic acid derivatives were synthesized by reacting 2-(2-methyl-5-nitro-1H-imidazol-1-yl) ethyl 4-methyl benzene sulfonate (98) with meta and para hydroxy benzoic acids. Structures of the newly prepared compounds were confirmed through different spectroscopic methods such as 1H-NMR, 13C-NMR, mass spectrometry and also by elemental analyses. The antigiardial and antitrichomonal activities of the prepared compounds were evaluated in vitro. Compounds 3a, 3b, 3c, 6a, and 6b exhibited remarkable antigiardial activitiy and were found to be more active than metronidazole with IC50 of 6.4, 5.25, 5.36, 5.90, and 4.95 µg/mL, respectively, while compounds 3a, 3d, and 3g displayed the most antitrichomonal activity with IC50 of 6.3, 6.3, and 5.2 µg/mL, respectively.
... For a molecule to be a potential drug, besides having a good biological activity, it must have good pharmacokinetic properties in biological systems. To access the pharmacokinetic profile of the synthesized molecules, we have employed well-validated in silico tools: Osiris, Petra and Molinspiration (Alafeefy et al., 2012;Mahajan et al., 2012;Fathi et al., 2011). These tools have been validated with almost 7,000 drug molecules available on the market. ...
... In fact, these compounds are not active presumably due to lack of suitable geometrical conformation of pharmacophores which is another crucial parameter that has to be taken into consideration. The geometrical aspect parameter and the aqueous solubility of each compound significantly affect its absorption, distribution characteristics, and bioactivity (Alafeefy et al., 2012;Mahajan et al., 2012;Fathi et al., 2011). Typically, low solubility goes along with bad absorption, and therefore, the general aim is to avoid poorly soluble compounds. ...
Series of new metronidazole urea and thiourea derivatives have been prepared in good yields through reactions of 2-(2-methyl-5-nitroimidazolyl) ethylamine hydrochloride with various cyanates and isothiocyanates. Similarly, metronidazole hydroxybenzoic acid derivatives were synthesized by reacting 2-(2-methyl-5-nitro-1H-imidazol- 1-yl)ethyl-4-methylbenzene sulfonate (4) with mand p-hydroxybenzoic acids. Structures of the newly prepared compounds were confirmed through different spectroscopic methods such as 1H-NMR, 13C-NMR, mass spectrometry and also by elemental analyses. The antigiardial and antitrichomonal activities of the prepared compounds were evaluated in vitro. Compounds 3a, 3b, 3c, 3d, 3f, 3g, 3j, 3l, 3m, and 6b exhibited remarkable antigiardial activity with IC50 values ranging from 5.2 to 7.5 lg/ mL and were found to be more active than metronidazole which has an IC50 of 8.0 lg/mL. Similarly, several of the tested compounds showed significant antitrichomonal activity with IC50 values ranging from 4.95 to 6.80 lg/mL compared with the standard drug, metronidazole which has an IC50 of 8.0 lg/mL. Compound 6b was the most potent among the prepared compounds and was about 1.6 times more active than metronidazole. In addition, the newly synthesized products were subjected to Petra/Osiris/ Molinspiration (POM) analyses to get insights on the degree of their toxicity.
... Amongst the compounds, acyl/sulfonyl pyrazolines have been studied extensively owing to their effective properties with respect to inhibiting various pathogenic strains, but on the other hand pyrazoline-based isoniazid chemistry is less extensive and has not been analysed rigorously by bioinformatic methods. We have previously published the Petra, Osiris and Molinspiration (POM) methods for antibacterial (Chohan et al., 2010; Fathi et al., 2011; Jarrahpour et al., 2011; Parvez et al., 2011; Sheikh et al., 2011; Ali et al., 2010; Chohan et al., 2010; Parvez et al., 2010), antifungal (Fathi et al., 2011) and antiviral (Bennani et al., 2007 ) pharmacophore sites identification. The control of different physicochemical and pharmacological parameters leads us to seek suitable hits in various areas (Fig. 1). ...
... Amongst the compounds, acyl/sulfonyl pyrazolines have been studied extensively owing to their effective properties with respect to inhibiting various pathogenic strains, but on the other hand pyrazoline-based isoniazid chemistry is less extensive and has not been analysed rigorously by bioinformatic methods. We have previously published the Petra, Osiris and Molinspiration (POM) methods for antibacterial (Chohan et al., 2010; Fathi et al., 2011; Jarrahpour et al., 2011; Parvez et al., 2011; Sheikh et al., 2011; Ali et al., 2010; Chohan et al., 2010; Parvez et al., 2010), antifungal (Fathi et al., 2011) and antiviral (Bennani et al., 2007 ) pharmacophore sites identification. The control of different physicochemical and pharmacological parameters leads us to seek suitable hits in various areas (Fig. 1). ...
In this study, we have amalgamated computational methodologies, viz. Petra, Osiris and Molinspiration (POM) to identify pharmacophores and antipharmacophores for antibacterial/antiviral activities of some 2-pyrazolines derivatives. Lipophilicity and the presence of tautomerism process are the major factors that govern the orientation to antibacterial and/or antiviral activity. On other hand, it was observed that these compounds have two different active sites and can inhibit both antiviral and antibacterial strains. Further, we have carried out receptor-based electrostatic analysis to confirm the electronic, steric and hydrophobic requirements for future modifications. The analyses provide substantial idea about the structural features responsible for their combined antibacterial/antiviral activity and provide guidelines for further modifications, with the aim of improving the activity and selectivity of designed drugs targeting HIV and tuberculosis microorganisms.
Graphical Abstract
The speculative assertions presented in many papers published in many reputed journals are meaningless. Most of the authors discuss of the antiviral activity compared to the antibacterial activity. There authors seem to consider that there is only one tautomeric form taking one mechanism of action for both antiviral and antibacterial activities. This is false; here, we clarify things on the basis of POM analyses.
... Azine compound derivatives (R-C=N-N=C-R) are compound having 2,3-diaza group analogs of 1,3-butadienes. These compounds have been extensively studied for biological activities [1,2], heterocyclic synthesis [3][4][5], ligand synthesis on coordination chemistry [6], dyes, and receptor for chemosensor [7]. Symmetrical azines can be made with easy synthetic procedure, good yield, and easy purification. ...
Symmetrical Amino Azine derivative compound of 6,6'-((1E,1'E)-hydrazine-1,2-diylidenebis (methanyl-ylidene)) bis (3,4-dimethoxyaniline) TM has been synthesized through an unusual reaction route employed benzylidine derivative with some electron withdrawing groups as intermediate compounds. The targeted TM compound was prepared by one pot reaction of the intermediate 2-(4,5-dimethoxy-2-nitrobenzylidene) malononitrile 3 or (E)-1,2-dimethoxy-4-nitro-5-(2-nitrovinyl)-benzene 4 or nitrohydrazone 5 with excess 80% hydrazine hydrate and 10% Pd/C catalyst. However, direct synthesis to produce TM using nitro aryl aldehyde derivatives with 80% hydrazine hydrate and 10% Pd/C catalyst failed to obtain the target compound of TM.
... For a molecule to be a potential drug, besides having a potent biological activity, it must have good pharmacokinetic properties. To access the pharmacokinetic profile of the synthesized molecules, we used well established in silico tools such as Osiris, Petra and Molinspiration (POM), which have been supported with almost 7000 drug molecules available on the market [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29], in rapprochement with Lipinski five rules which is limited to bioavailability prognosis [30][31][32][33]. ...
Background:
Since deficit of acetylcholine has been evidenced in the patients of Alzheimer's disease (AD), cholinesterase inhibitors are currently the most prescribed drug class for the treatment of AD.
Results:
In the present study, 16 compounds (1-16) with dicarbonyl skeletons have been synthesized and tested for their inhibitory potential in vitro against AChE and BChE using ELISA microtiter plate assays at 100 µg/mL. Since metal accumulation is related to AD, the compounds were also tested for their metal-chelation capacity.
Conclusions:
All of the dicarbonyl compounds tested exerted none or lower than 30% inhibition against both cholinesterases, whereas compounds 2, 8 and 11 showed 37, 42, 41% of inhibition toward BChE, being the most active. The highest metal-chelation capacity was observed with compound 8 (53.58 ± 2.06%). POM and DFT analyses are in good agreement with experimental data.
... For a molecule to be a potential drug, besides having a potent biological activity, it must have good pharmacokinetic properties. To access the pharmacokinetic profile of the synthesized molecules, we used well established in silico tools such as Osiris, Petra and Molinspiration (POM), which have been supported with almost 7000 drug molecules available on the market [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29], in rapprochement with Lipinski five rules which is limited to bioavailability prognosis [30][31][32][33]. ...
Background: Since deficit of acetylcholine has been evidenced in the Alzheimer's disease (AD) patients, cholinesterase inhibitors are currently the most specified drug category for the remediation of AD. Method: In the present study, 16 compounds (1-16) with dicarbonyl skeletons have been synthesized and tested for their inhibitory potential in vitro against AChE and BChE using ELISA microtiter plate assays at 100 µg/mL. Since metal accumulation is related to AD, the compounds were also tested for their metal-chelation capacity. Results and Conclusion: All the investigated dicarbonyl compounds exerted none or lower than 30% inhibition against both cholinesterases, whereas compounds 2, 8 and 11 showed 37, 42, 41% of inhibition towards BChE, being the most active. The highest metal-chelation capacity was observed with compound 8 (53.58 ± 2.06%). POM and DFT analyses are in good harmonization with experimental data.
... Also, knowledge on the stability of the drugs in library is necessary. In collaboration with NCI and TAACF of the United States, we have developed a technology platform that enables easy access to structurally diverse libraries based upon anti-bacterial, anti-tumor and anti-HIV pharmacophore sites and employed the technology to discover potent viruses' inhibitors modelling the anti-bacterial/anti-fungal/ anti-viral pharmacophore sites (Chohan et al., 2010a, b; Fathi et al., 2011; Jarrahpour et al., 2011; Parvez et al., 2010a Parvez et al., , b, 2011 Sheikh et al., 2011). There is considerable growing interest in these compounds 4a–4q as anti-viral agents, exhibiting potentially similar pharmacophore pockets to that observed for diketoacids (DKAs). ...
A computation model has been developed for the rational design of bioactive pharmacophore sites as anti-viral candidates based on available X-ray structures of drugs. The compounds have been previously screened for anti-viral activity against HIV-Integrase (HIV IN). Amongst the series, the most potent compounds, 4k and 4d (low lM IC 50) were tested in viral cultures for their ability to present potentials (O 1 d-–O 2 d-–O 3 d-) for anti-viral phar-macophore site but represent a potential risk of toxicity. Furthermore, the compounds 4k and 4d showed potent anti-HIV IN activity. A good correlation was obtained between the theoretical predictions of bioavailability using POM suite (Petra/Osiris/Molinspiration containing Lipin-ski's rule-of-five) and experimental verification. The structure–activity relationships were also analyzed to vin-dicate the POM results.
... The same theoretical approach has been recently used to evaluate the antifungal properties of some drugs ( Jawed et al., 2012). In contrast to first antibacterial pharmacophore site (X d-ÁÁÁY d? ), it was verified that the same negative charge of terminal heteroatoms led to potential antiviral/antifungal pharmacophore site (X d-ÁÁÁY d-) (Tapar et al., 2011;Hadda et al., 2012;Fathi et al., 2011;Masand et al., 2011Masand et al., , 2012Masand et al., , 2013Mahajan et al., 2012;Alafeefy et al., 2012;Chohan et al., 2008). ...
In this work, a new and efficient strategy to identify pharmacophores and anti-pharmacophores sites in thienopyrimidinone derivatives for anti-bacterial/antifungal activity using Petra, Osiris and Molinspiration (POM) analyses is described. We carried out receptor based electrostatic analysis to confirm the electronic, steric and hydrophobic requirements for further modifications. Results showed that, the major factors that govern the orientation to antibacterial/ antiviral activity were of Lipophilicity and presence of tautomerism. In addition, POM analyzed compounds constitute different supplementary attractive active sites that possess significant bioactivity and qualify them as promising candidates that might be responsible to inhibit Kinase enzymes. Furthermore, the POM analyses provide substantial idea about the structural features of thienopyrimidinone derivatives in relation to biological activities against disease causing agents. Our results suggest future work on these POM assessed derivatives to evaluate their toxicity in human cells and selectivity with improve activity against cancer causing kinase enzymes by developing target oriented new drugs to save humanity.
Keywords: Thienopyrimidinones, antibacterial/ antifungal screenings, POM (Petra/ Osiris/ Molinspiration) analyses.
... Also, knowledge on the stability of the drugs in library is necessary. In collaboration with NCI and TAACF of the United States, we have developed a technology platform that enables easy access to structurally diverse libraries based upon anti-bacterial, anti-tumor and anti-HIV pharmacophore sites and employed the technology to discover potent viruses' inhibitors modelling the anti-bacterial/anti-fungal/ anti-viral pharmacophore sites (Chohan et al., 2010a, b; Fathi et al., 2011; Jarrahpour et al., 2011; Parvez et al., 2010a Parvez et al., , b, 2011 Sheikh et al., 2011). There is considerable growing interest in these compounds 4a–4q as anti-viral agents, exhibiting potentially similar pharmacophore pockets to that observed for diketoacids (DKAs). ...
A computation model has been developed for the rational design of bioactive pharmacophore sites as anti-viral candidates based on available X-ray structures of drugs. The compounds have been previously screened for anti-viral activity against HIV-Integrase (HIV IN). Amongst the series, the most potent compounds, 4k and 4d (low μM IC50) were tested in viral cultures for their ability to present potentials (O
1δ−–O
2δ−–O
3δ−) for anti-viral pharmacophore site but represent a potential risk of toxicity. Furthermore, the compounds 4k and 4d showed potent anti-HIV IN activity. A good correlation was obtained between the theoretical predictions of bioavailability using POM suite (Petra/Osiris/Molinspiration containing Lipinski’s rule-of-five) and experimental verification. The structure–activity relationships were also analyzed to vindicate the POM results.
Graphical abstract
A series of known anti-HIV agents; the amide-containing diketoacids were POM and 3D-QSAR analyzed in goal to understand and develop more potent/selective HIV IN inhibitors. Their inhibition of HIV IN was attributed to them containing O1,O2,O4-pharmacophore site. The structure–activity relationships were discussed on the basis of POM analyses.
Inflammation, oxidation, and compromised immunity all increase the dangers of COVID-19, whereas many pharmaceutical protocols may lead to increased immunity such as ingesting from sources containing vitamin E and zinc. A global search for natural remedies to fight COVID-19 has emerged, to assist in the treatment of this infamous coronavirus. Nigella satvia is a world-renowned plant, an esteemed herbal remedy, which can be used as a liquid medicine to increase immunity while decreasing the dangers of acute respiratory distress syndrome. Thymoqinone (TQ), dithemoqunone (DTQ) and thymohydroquinon (THQ), are major compounds of the essential oil contained in N.sativa. A current study aims to discover the antiviral activity of two compounds, Thymohydroquinone and Dithymoquinone, which are synthesized through simple chemical procedures, deriving from thymoquinone, which happens to be a major compound of Nigella sativa. A half maximal cytotoxic concentration, “CC50”, was calculated by MTT assay for each individual drug, The sample showed anti-SARS-CoV-2 activity at non-cytotoxic nanomolar concentrations in vitro with a low selectivity index (CC50/IC50 = 31.74/23.15=1.4), whereby Dimthymoquinone shows high cytotoxicity.
Keywords: Antiviral, SARSCoV-19, thymoquinon, Dithemoquinone , hydrothymoquinone
In present work, 53 synthetic prodiginines were selected to establish thriving CoMSIA (Comparative Molecular Similarity Indices Analysis) model to explore the structural features influencing their anti-malarial activity. POM (Petra/Osiris/Molinspiration) was carried out to get insight into requirements that can lead to the improvement of the activity of these molecules. The CoMSIA model, based on a combination of steric, electrostatic and H-bond acceptor/donor effects, is with R(2)(cv)=0.738 and R(2)=0.911. The analyses reveal that lipophilicity, hydrogen donor/acceptor and steric factors play crucial role. The study with constructive propositions could be useful for the design of new analogues with enhanced activity.
Melatonin (MLT) is a hormone produced in the brain by the pineal gland, from the amino acid tryptophan. It is also an antioxidant hormone with a particular role in the protection of nuclear and mitochondrial DNA. In recent years, many physiological properties of MLT have been described resulting in much attention in the development of synthetic compounds possessing the indole ring. Sixteen MLT analogue indole hydrazide/hydrazone derivatives were synthesized and in vitro antioxidant activity was investigated. Most of the compounds showed significantly higher activity than MLT at 10(-3) M and 10(-4) M concentrations.
Some novel N(1)-arylidene-N(2)-cis-2,6-diphenyltetrahydrothiopyran-4-one azine derivatives were synthesised and their antibacterial activity against Streptococcus faecalis, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus and antifungal activity against Candida-6, Candida-51, Aspergillus niger, and Aspergillus flavus were evaluated.
Some novel N(1)-arylidene-N(2)-t(3)-methyl-r(2),c(6)-diarylpiperidin-4-one azine derivatives were synthesized and their antibacterial activity against Streptococcus faecalis, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus and antifungal activity against Candida-6, Candida-51, Aspergillus niger, and Aspergillus flavus evaluated.
Mono-Mannich bases, 3-amino-1-aryl-1-propanone hydrochlorides (Ig1-Ig4), and their corresponding azine derivatives, N,N'-bis(3- amino-1-aryl-propylidene) hydrazine dihydrochlorides (D1-D4), were synthesized and their anticonvulsant activities were evaluated. Alterations in biological activity depending on modifications in chemical structure were also followed. The aryl part was phenyl in Ig1, D1, Ig2, D2, Ig3, D3, or p-hydroxyphenyl in Ig4, and D4. The amine part was dimethylamine in Ig1, D1, Ig4, and D4, piperidine in Ig2, D2 or morpholine in Ig3, D3. Compounds D2, D3, and D4 are new. The anticonvulsant activity was determined by maximal electroshock (MES) and subcutaneous metrazole (pentetrazol; scMet) tests. The rotorod toxicity test was used for determining neurological deficits. While the compounds were not effective in scMet, they were found to exert protective effect in MES. The results of MES are as follows: Compound [dose level (mg/kg), time (h)]: Ig1 [30 (0.5 h), 100 (0.5 h)]; Ig2 [30 (0.5 h, 4 h)]; Ig3 [30 (0.5 h), 100 (0.5 h), 300 (0.5 h, 4 h)]; Ig4 [300 (0.5 h, 4 h), 100 (4 h)]; D1 [30 (0.5 h)]; D3 [100 (0.5 h,4 h), 300 (0.5 h), 30 (4 h)]]; D4 [300 (0.5 h, 4 h)]. D2 did not show any anticonvulsant activity in both tests. Ig1, Ig2, D1, D2, and D3 exhibited neurotoxicity. Compounds Ig2, D1, and D2 were neurotoxic at 100 mg/kg dose level at 0.5 h. Ig1 was neurotoxic at 300 mg at 0.5 h, D3 was neurotoxic at 300 mg at 4 h. Conversion of mono-Mannich bases to their corresponding azine derivatives generally decreased the anticonvulsant activity. Ig3, Ig4 and D4 seem to be promising candidates to develop new anticonvulsant compounds for grand mal epilepsy for further synthesis and in vivo studies, since they were effective in MES screening and no neurotoxicity was observed with them.
Natural products and their derivatives have historically been invaluable as a source of therapeutic agents. However, in the past decade, research into natural products in the pharmaceutical industry has declined, owing to issues such as the lack of compatibility of traditional natural-product extract libraries with high-throughput screening. However, as discussed in this review, recent technological advances that help to address these issues, coupled with unrealized expectations from current lead-generation strategies, have led to a renewed interest in natural products in drug discovery.
The reaction of 2-hydroxy-1-naphthaldehyde with chloroacetone/phenacyl bromide in presence of weak base gave 2-acylnaphtho [2,1-b] furans 1a-b. The reaction of 1a-b with hydrazine hydrate produced corresponding hydrazones 2a-b, which on treatment with various aromatic aldehydes under different reaction conditions yielded symmetrical azines 3a-d and asymmetrical azines 4a-d & 5a-d. All the synthesized compounds have been characterized by elemental analysis and spectral studies and evaluated for antimicrobial activity by MIC method.
5-((Z)-Arylidene)-2-((2-(E)-benzylidene)hydrazone)-4-imidazolidinones 7a-d and 5-((Z)-arylidene)-2-((2-(E)-polyhydroxyalkylidene)hydrazono)-4-imidazolidinones 11a-d to 15a-d were prepared from the reaction of 5-((Z)-arylidene)-2-methylmercaptohydantoins 3a-d with 2-(E)-benzylidene hydrazone 6 or 2-(E)-monosaccharides hydrazones 9a-e, which in turn were prepared by condensation of benzaldehyde or appropriate monosaccharides 8a-e with hydrazine hydrate. AM1 semi-empirical calculations reveal that the azine system is favoured with a trans geometry and planar conformation for CN-NC. All the new compounds were tested for their potential antiviral and antitumor activities.
Comparative molecular field analysis (CoMFA) is a promising new approach to structure/activity correlation. With the aim to find out the structural features intended for the MAO inhibitory activity, in the present communication we report COMFA Analysis of Coumarin Analogues. The resulting model exhibited good q2 and r2 values up to 0.713 and 0.881 for CoMFA. The contributions from the steric and electrostatic fields were 1.361 and 0.908 respectively. The 3D QSAR analysis provides interesting insights in understanding the Steric and Electronic structural requirements for MAO-B inhibitory activity. Further all molecules were subjected to the toxicity assessment using Molinspiration and Osiris Calculations. Among the various MAO-B inhibitors, compound no-3 is the optimum drug candidate with respect to the activity and toxicity
AbstractThe title compound (3), C17H14BrN3O4S, is a Schiff base compound of 5-bromosalicylaldehyde (1) and sulfamethoxazole (2). The structure of (3) was determined by spectral (IR, 1H and 13C NMR), elemental analyses and X-ray diffraction data. Compound (3) crystallizes in the monoclinic space group C2/c, with a=31.936(3), b=6.2571(5), c=16.903(1)Å, β=94.867(8), V=3365.5(5)Å3, Z=8. In the molecule of compound (3), the molecule is bent at the S atom with a C–SO2–NH–C torsion angle of −86.3(3)°. Pairs of molecules, related by inversion centres, form intermolecular N–H···N hydrogen bonds
to produce a dimer. An intramolecular phenolic O–H···N hydrogen bond is also formed. Intermolecular hydrogen bonding and π–π
stacking hold the molecules together. The average distance between stacked benzene ring planes is 3.625(2)Å.
Graphical Abstract
KeywordsSulfonamide–Bidentate–Antibacterial–Antifungal
A novel dimeric azine derivative designated as limnazine (1) has been isolated from the culture broth of an aquatic Bacillus sp. strain GW90a. The structure has been elucidated, on the basis of spectral data, as N,N'-bis(2,2,6-trimethylchroman-4-ylidene)azine and was additionally confirmed by synthesis. Limnazine (1) is inactive against algae, fungi, and bacteria.
Various classes of cytotoxic compounds which alkylate cellular thiols are described namely alpha,beta-unsaturated ketones, alpha-methylene-gamma-lactones, azines of Mannich bases, imexon, isothiocyanates, a benzoacronycine as well as activation by thiols prior to alkylation. The mechanisms of action of some of the molecules, such as the formation of reactive oxygen species, are presented. The cytotoxicity of a number of drugs can be influenced by modulation of the concentration of thiols including the observation that potencies can be increased by thiol activation. The ability of certain thiol reagents to reverse multidrug resistance as well as some miscellaneous actions of thiol alkylators are described.
A series of novel 3-(indol-1-yl)prop-1-yn-1-yl-substituted phthalazines and related azines was prepared via a concise pathway by palladium-catalyzed cross-coupling of appropriate halo-azines and N-propargylindoles. Some of the compounds exhibited significant antitumor activity in an in-vitro assay.
- F D Popp
F.D. Popp, Journal of Heterocyclic Chemistry, 21 (1984) 617-619.
Synthesis, Biopharmaceutical Characterization
- Ben Hadda
Ben Hadda. Synthesis, Biopharmaceutical Characterization, European Journal of Medicinal
Chemistry. Paper has been accepted for publication at Janv 29-2011.
Paper has been accepted for publication at
- A Parvez
- M Jyotsna
- J Sheikh
- V Tiwari
- R Dongre
- T Ben Hadda
A. Parvez, M. Jyotsna, J. Sheikh, V. Tiwari, R. Dongre, T. Ben Hadda. European Journal of
Medicinal Chemistry. Paper has been accepted for publication at Nov 03-2010.
- H I Gul
- M Gul
- J Vepsälainen
- E Erciyas
- O Hänninen
H.I. Gul, M. Gul, J. Vepsälainen, E. Erciyas and O. Hänninen, Biological andPharmaceutical
Bulletin, 26 (2003) 631-637.
- R N Asolkar
- V P Kamat
- I Wagner-Döbler
- H Laatsch
R.N. Asolkar, V.P. Kamat, I. Wagner-Döbler and H. Laatsch, Limnazine, Journal of
Natural Products, 65 (2002) 1664-1666.
- O T Benjelloun
- M Akkurt
- S Ö Yýldýrým
- M Daoudi
- T Ben Hadda
- A Boukir
- O Büyükgüngör
O.T. Benjelloun, M. Akkurt, S.Ö. Yýldýrým, M. Daoudi, T. Ben Hadda, A. Boukir, O.
Büyükgüngör, and A.F. Jalbout. Arkivoc (ii) (2008) 80-93.
- Z H Chohan
- S H Sumrra
- M H Youssoufi
- T Ben Hadda
Z.H. Chohan, S.H. Sumrra, M.H. Youssoufi, and T. Ben Hadda. European Journal of
Medicinal Chemistry 45 (2010) 2739-2747.
- Z H Chohan
- M H Youssoufi
- A Jarrahpour
- T Ben Hadda
Z.H. Chohan, M.H. Youssoufi, A. Jarrahpour, T. Ben Hadda. European Journal of
Medicinal Chemistry 45 (2010) 1189-1199.
- E Angadi
Angadi, E-Journal of Chemistry, 5 (2008) 395-403.
- Hadda Taibi Ben
Taibi Ben Hadda et al
J. Comput. Method. Mol. Design., 2011, 1 (3):57-68
- A Parvez
- M Jyotsna
- M Hfid Youssoufi
- T Ben Hadda
A. Parvez, M. Jyotsna, M. Hfid Youssoufi, and T. Ben Hadda. Phosphorus, Sulfur, and
Silicon And the related Elements, 7 (2010) 1500-1510.
- J Jayabharathi
- A Thangamani
- M Padmavathy
J. Jayabharathi, A. Thangamani, M. Padmavathy and B. Medicinal Chemistry Research,
15(2007) 431-442.
- G Houari
- A Kerbal
- B Bennani
- M F Baba
- M Daoudi
- T Ben Hadda
G. Al Houari, A. Kerbal, B. Bennani, M.F. Baba, M. Daoudi, and T. Ben Hadda. Arkivoc
(xii), (2008) 42-50.
- G Benazza
- M Demailly
- S Ö Akkurt
- T Ben Yýldýrým
- Hadda
Benazza, G. Demailly, M. Akkurt, S.Ö.Yýldýrým, and T. Ben Hadda. Arkivoc (xvi), (2007) 19-
40.
- P Ertl
- B Rohde
- P Selzer
P. Ertl, B. Rohde, P. Selzer, J. Med.Chem. 43 (2000) 3714-3717.
- I Picón-Ferrer
- F Hueso-Ureña
- N A Illán-Cabeza
- S B Jiménez-Pulido
- J M Martínez Martos
- M J Ramírez-Expósito
I. Picón-Ferrer, F. Hueso-Ureña, N.A. Illán-Cabeza, S.B. Jiménez-Pulido, J.M. Martínez
Martos, M. J. Ramírez-Expósito and M.N. Journal of Inorganic Biochemistry, 103 (2009) 94-100.
- H I Gul
- F Sahin
- M Gul
- S Ozturk
- K O Yerdelen
H.I. Gul, F. Sahin, M. Gul, S. Ozturk and K.O. Yerdelen, Archiv der Pharmazie, 338 (2005)
335-338.
- G Aridoss
- S Amirthaganesan
- M S Kim
- J T Kim
- Y T Jeong
G. Aridoss, S. Amirthaganesan, M.S. Kim, J.T. Kim and Y.T. Jeong, European Journal of
Medicinal Chemistry, 44 (2009) 4199-4210.
- H I Gul
- U Calis
- J Vepsalainen
H. I. Gul, U. Calis and J. Vepsalainen, Arzneimittel-Forschung-Drug Research, 54 (2004)
359-364.
- G Gürkök
- N Altanlar
- S Suzen
G. Gürkök, N. Altanlar and S. Suzen, Chemotherapy, 55 (2009) 15-19.
- T Ben Hadda
- R Badri
- A Kerbal
- B Baba
- M Akkurt
- G Demailly
- M Benazza
T. Ben Hadda, R. Badri, A. Kerbal, B.F Baba, M. Akkurt, G. Demailly and M. Benazza.
Arkivoc (XIV), (2007) 276-288.
- I A Danish
- K R Prasad
I. A. Danish and K.R. Prasad, Acta Pharmaceutica, 54 (2004) 133-142.
- V B Kurteva
- S P Simeonov
- M Stoilova-Disheva
V. B. Kurteva, S. P. Simeonov, M. Stoilova-Disheva, Pharmacology & Pharmacy, 2 (2011),
1-9.
- J L Vennerstrom
- M T Makler
- C K Angerhofer
- J A Williams
J.L. Vennerstrom, M.T. Makler, C. K. Angerhofer and J.A. Williams, Antimicrobial Agents
and Chemotherapy, 39 (1995) 2671-2677.
- H N Pati
- U Das
- R K Sharma
H.N. Pati, U. Das, R.K. Sharma and J.R. Dimmock, Mini Reviews in Medicinal Chemistry,
7(2007) 131-139.
- H J Lindsley
- C Schaffhauser
- D J Sur
- P J Pettibone
- D L Conn
- Williamsjr
Lindsley, H. J. Schaffhauser, C. Sur, D.J. Pettibone, P.J. Conn and D.L. WilliamsJr, Molecular
Pharmacology, 64 (2003) 731-740.
- T Ben Hadda
- B Rahima
- A Kerbal
- B F Baba
- M Akkurt
- G Demailly
- M Benazza
T. Ben Hadda, B. Rahima, A. Kerbal, B.F. Baba, M. Akkurt, G. Demailly, M. Benazza,
Arkivoc, (ii), (2008) 1-13.
- G Y Allen
- S P C Kao
- G Cole
- J Batist
- E Balzarini
- De Clercq
Allen, G. Y. Kao, S. P. C. Cole, G. Batist, J. Balzarini and E. De Clercq, European Journal of
Medicinal Chemistry, 30 (1995)
209-217.
- J R Dimmock
- K K Sidhu
- S D Tumber
- S K Basran
- M Chen
- J W Quail
- J Yang
- I Rozas
- D F Weaver
J.R. Dimmock, K.K. Sidhu, S.D. Tumber, S.K. Basran, M. Chen, J.W. Quail, J. Yang, I.
Rozas and D.F. Weaver, European Journal of Medicinal Chemistry, 30 (1995) 287-301.
The Chemistry of the Carbon-Nitrogen Double Bonds
- S Dayagi
- Y Degani
S. Dayagi and Y. Degani, Formation of the Carbon-Nitrogen Double Bond, In: S. Patai,
Ed., The Chemistry of the Carbon-Nitrogen Double Bonds, Interscience, New York, 1970, 61-147.
- J R Dimmock
- P Kumar
- J W Quail
- U Pugazhenthi
- J Yang
- M Chen
- R S Reid
- T M Allen
- G Y Kao
- S P C Cole
- G Batist
- J Balzarini
- E De Clercq
J. R. Dimmock, P. Kumar, J. W. Quail, U. Pugazhenthi, J. Yang, M. Chen, R. S. Reid, T. M.
Allen, G. Y. Kao, S. P. C. Cole, G. Batist, J. Balzarini and E. De Clercq, European Journal of
Medicinal Chemistry, 30 (1995)
209-217.
- M Revanasiddappa
- T Suresh
- S Khasim
- S C Raghavendray
- C Basavaraja
- S D Angadi
M. Revanasiddappa, T. Suresh, S. Khasim, S.C. Raghavendray, C. Basavaraja and S. D.
Angadi, E-Journal of Chemistry, 5 (2008) 395-403.
- J A O'brien
- W Lemaire
- T.-B Chen
- R S L Chang
- M A Jacobson
- S N Ha
- C W Lindsley
- H J Schaffhauser
- C Sur
- D J Pettibone
- P J Conn
- D L Williamsjr
J.A. O'Brien, W. Lemaire, T.-B. Chen, R. S. L. Chang, M.A. Jacobson, S.N. Ha, C. W.
Lindsley, H. J. Schaffhauser, C. Sur, D.J. Pettibone, P.J. Conn and D.L. WilliamsJr, Molecular
Pharmacology, 64 (2003) 731-740.
- R D Jawarkar
- D T Mahajan
- V H Masand
- T Ben Hadda
- G H Kurhade
R.D. Jawarkar, D.T. Mahajan, V.H. Masand, T. Ben Hadda, G.H. Kurhade. Der Pharmacia
Lettre, 2 (2010) 350-357.