Current Bioactive Compounds - Volume 14, Issue 3, 2018

Background: A large number of scientific researches have been reported for isatin and its Schiff base metal complexes, but there is no detailed compilation of these isatin Schiff base metal complexes with their biological properties. This review may help scientist to develop new drugs with more potent activity and specificity in their action. Method: This review is designed according to the different metal complexes of different metal ions complexed with isatin Schiff base ligand. It includes introduction about isatin, its biological activity, details about schiiff base and then details about metal complexes. All the metals involved in the formation of isatin Schiff base metal complexes were discussed in this review with their biological activities. Results: Sixty papers were included in the review, among which thirty seven papers included complete introduction about isatin, its Schiff base and metal complexes. Eleven papers basically described different metal complexes synthesized by different scientists, their biological study and structures. Twelve papers included all the data related to the structure of different metal ion complexes, their reactivity at different positions, etc. Conclusion: The findings of this review confirm the importance of complexation with metal ions; it confirms that on complexation, biological activity of metal complexes increases in comparison to isatin Schiff base. This review may contribute in future research as structure activity of the complexes was also discussed in detail.

In 1863, Diphenylamine (DPA) was prepared by Hoffmann by the destructive distillation of different triphenylmethane dyes. DPA are naturally occurring compounds, present in onions, leaves of black and green tea and peel of citrus fruits. DPA derivatives belong to the category of Non Steroidal Anti-inflammatory Drugs (NSAIDs). Diclofenac, chemically called 2-(2,6-dichloranilino) phenylacetic acid, is a well-known NSAID. Other important compounds are tolfenamic acid, flufenamic acid and mefenamic acid, etc. DPA derivatives are claimed for several important biological activities which include anti-microbial, analgesic, anti-inflammatory, anti-convulsant and anti-cancer activities. Many more compounds have been discovered and many are still being focused. The key goal of this article is to show up the different derivatives and the pharmacological activities of DPA. Hence, it can be concluded that DPA and its derivatives possess significant therapeutic functions and many potent derivatives are still to be discovered.

Background: Considering the fact that many nitrogenated aromatic derivatives such as pyrazoles, hydrazones, pyrazolo[1,5-a]-pyrimidines and pyrazolo [3,4-b]-pyridine have shown antiparasitic properties, the current study was carried out to analyze the in vitro antileishmanial and antitrypanosomal potential of some derivatives, synthesize from 6-substituted-3-formylcromone. Method: The pyrazoles (4a-c), hydrazones (5a-c), pyrazolo[1,5-a]-pyrimidines (6a, 6b) and pyrazolo [3,4-b]-pyridine (7) were prepared by condensation reaction between 6-substituted 3-formylchromones (1a-c) with N-substituted hydrazines (2a-c) and aminopyrazole 3. The synthesized compounds were tested for their in vitro antiparasitic activity against promastigotes of Leishmania mexicana (Bel 21) and epimastigotes of Trypanosoma cruzi (DM28) using a modified MTT assay to determine the compounds IC50 on each parasite strain. The selectivity index (SI) of each compound was also determined by testing the compounds on fibroblasts. Results: IC50 values of all compounds were between 6 – 89 μM for L. mexicana and 4 – 174 μM for T. cruzi. Hydrazones 5a and 5b exhibited the highest antiparasitic activity against both L. mexicana, with IC50 values of 6.3 μM and 15 μM respectively, and T. cruzi, with IC50 4.1 μM and 10 μM and were 2 to 5 times more active on these parasites than on fibroblasts. Conclusion: These results suggest that compound 5a is a suitable candidate for further development of molecules with antileishmanial and antitrypanosomal activity.

Background: Novel oximinoethers of indanones / aryloxy indanones were designed, synthesized and evaluated in vitro as antileishmanials against Leishmania donovani. Most of the synthesized compounds (5-12) exhibited 100% inhibition at 10 μg/mL against promastigotes and six compounds (5, 6, 7, 9, 11 and 12) exhibited 100% inhibition at 10 μg/mL with an IC50 in the range of 1.65-4.98 μg/mL against amastigotes. Among all, compounds (5-8 and 11) with monochloro, dichloro and fluoro group on aryloxy moiety exhibited excellent in vitro inhibition, thus providing new structural scaffold that can be further optimized to new antileishmanials agents. Methods: In this we were prepared stereo selective oximes. We explored green synthetic method that is replacing DMF as water. Results: The compounds used in the present study were prepared utilizing previously developed methodology for Mannich-aldol reaction. The synthetic route for the preparation of (E)-2-Imidazol-1- ylmethyl-indan-1-one O-benzyl-oximes 5-8 and aryloxy oximes alkyl azoles of indanone 13 and 14 and 9-12 is outlined in (Scheme 2-4). Earlier, the Mannich-aldol-type reaction is described between ketone, paraformaldehyde and azoles using L-proline as an organic catalyst to yield the 2-hydroxymethyl-2- imidazol-1-ylmethyl-indan-1-one (2). However, we modified the reaction conditions in a green manner by replacing organic toxic solvent DMF to water, reducing temperature and source of Imidazole to yield the same intermediate in excellent yields. We have utilized this intermediate (2) for the synthesis of designed molecules (Prototype I-II) for antileishmanial study. Conclusion: We have designed and synthesized the novel azoles with aryloxy and oximino functions making use of our developed methodology of the water mediated Mannich-aldol-type adducts. The preliminary investigations of biological results revealed that, these compounds have potential as antileishmanial agents and has opened a new avenue for further exploration.

Background: 4-substituted pyroglutamates have found use in the synthesis of ACE inhibitors e.g. Fosinopril, conformationally constrained peptides as well as bioactive natural products. Such versatile applications associated with 4-substituted Pyroglutamates encouraged researchers to study the Lienolate derived alkylation of pyroglutamate with electrophiles. Though several reports are available on Li-enolate derived reactions of pyroglutamates with electrophiles, but sodium-enolate derived reactions of pyroglutamate with electrophiles have not been investigated, and that prompted us to study the behaviour of sodium enolate derived reactions of N-protected pyroglutamates with electrophiles. Results and Discussion: Herein we have reported our studies on the sodium enolate derived reactions of N-protected pyroglutamate with electrophiles, where N-Boc-(2S)-menthyl pyroglutamate on reaction with various electrophiles in the presence of Sodium hydride afforded 4-substituted pyroglutamates while under similar conditions N-benzyl-(2S)-menthyl pyroglutamate afforded exclusively 2-substituted pyroglutamates. Conclusion:We have successfully accomplished sodium enolate derived alkylation/aldol reaction on NBoc- (2S)-menthyl and N-Benzyl-(2S)-menthyl pyroglutamate with an objective to synthesize 4– substituted pyroglutamates as well as 2-substituted pyroglutamates. These 4-substituted pyroglutamates and 2-substituted pyroglutamates have potential to serve as intermediate for the synthesis of bioactive natural products, ACE inhibitors and conformationally restricted peptide analogs.

Background: Prevalence of lung cancer and breast cancer is increasing worldwide. Current therapies have certain limitations for the treatment of lung cancer and breast cancer. We herewith report a series of novel 2-((1H-1,2,3-triazol-1-yl)methyl)-3-phenylquinazolin-4(3H)-ones as anticancer agents for the treatment of lung cancer and breast cancer. Method: Synthesis of 2-((1H-1,2,3-triazol-1-yl)methyl)-3-phenylquinazolin-4(3H)-ones involves four steps. Step 1 is the formation of 2-(2-chloroacetamido)benzoic acid from 2-aminobenzoic acid by coupling with 2-chloroacetyl chloride, followed by step 2 which involves the formation of quinazolinone ring scaffold 2-(chloromethyl)-3-phenylquinazolin-4(3H)-ones on cyclisation with substituted anilines. Step 3 and 4 follow click chemistry approach of Huisgen's 1,3-dipolar cycloaddition which include conversion to 2-(azidomethyl)-3-phenylquinazolin-4(3H)-ones by sodium azide and further reaction with substituted alkynes to obtain 2-((1H-1,2,3-triazol-1-yl)methyl)-3-phenylquinazolin- 4(3H)-ones. All the molecules are characterized by spectral analysis and tested for anti-cancer activity against A-549 lung cancer and MDAMB-231 breast cancer cell lines using colorimetric MTT assay. Results: Amongst the synthesized compounds, 3-(4-nitrophenyl)-2-((4-phenyl-1H-1,2,3-triazol-1- yl)methyl)quinazoline-4-(3H)-one 5i and 3-(2,4-Dimethoxyphenyl)-2-((4-phenyl-1H-1,2,3-triazol-1- yl)methyl)quinazoline-4(3H)-one 5o were found to be active based on cell viability assays using A- 549 lung and MDAMB-231 breast cancer cell lines. Conclusion: Novel route for the synthesis of hitherto unknown 2-((1H-1,2,3-triazol-1-yl)methyl)-3- phenylquinazolin-4(3H)-ones was developed. All the molecules were tested for their anti-cancer activities and two molecules were shown to exhibit anti-cancer activity in micromolar range.

Objective: In the present work, we aim to investigate the acute toxicity and to evaluate the antioxidant, anti-inflammatory, analgesic, and antipyretic activities of the methanol extract (UDME) of Urospermum dalechampii (L.) Scop. ex F.W.Schmidt. Methods: Total phenolics, total flavonoids, and condensed tannins content were estimated by colorimetric methods. The antioxidant activity was evaluated by various antioxidant assays including DPPH free radical scavenging, β-carotene bleaching test, and metal chelating ability. The acute oral toxicity study was conducted where the limit test dose of 2000 mg/kg body weight was used. The analgesic activity was estimated peripherally using the writhing test and the anti-inflammatory activity was established with the carrageenan-induced pleurisy model. Moreover, the antipyretic activity was estimated using brewer's yeast-induced hyperthermia assay in rats. Results: Total phenolic content determination showed that UDME is rich in phenolic compounds and it exhibited a good antioxidant activity. A single dose of the extract did not cause any signs of acute toxicity in rats. Significant antinociceptive effect (68.4 and 80.6%) was found in the writhing test at the doses of 200 and 400 mg/kg, p.o. respectively. Also, both doses significantly decreased the neutrophil migration to the pleural cavity. Furthermore, no antipyretic activity was observed. Conclusion: This study demonstrates that the aerial parts of Urospermum dalechampii exhibited potent antioxidant, anti-inflammatory, and analgesic activities which proved the use of this species in folk medicine.

Background: Thiabendazole (TBZ; 4-(1H-benzimidazol-2-yl)-1,3-thiazole) is a well known anti-fungal and anti-helminthic agent. It has been observed that substitution pattern by different alkyl, aryl or heterocyclic functionalities at the various positions of benzimidazole as well as thiazole nucleus markedly influence the biological efficacy. In this study, we synthesized a novel series of TBZ derivatives with structure modifications involving incorporation of amino aryl moiety at 2nd position of thiazole nucleus as a trial to obtain safer and potent antimicrobial agents. Method: 2-Acetylbenzimidazole was prepared by oxidation of 2-(α-hydroxyethyl)benzimidazole with potassium dichromate in acidic condition. The latter was prepared from o-phenylenediamine on condensation with lactic acid using 4N HCl. The treatment of 2-acetylbenzimidazole with substituted phenylthioureas and iodine in isopropanol under reflux for 3.5 h afforded 4-(1H-benzo[d]imidazol-2- yl)-N-substituted phenylthiazol-2-amines. The structures of these compounds have been characterized from the rigorous analysis of their IR, 1H NMR, 13C NMR, MS and elemental analysis. These compounds were evaluated for their antibacterial and antifungal activities. Results: TBZ derivatives compounds 7a, 7b, 7c and 7e exhibited total inhibition of Candida albicans as evident by minimum inhibitory concentration (MIC) of 125 μg/ml. These derivatives were moderately active against Bacillus cereus, Escherichia coli, Yersinia enterocolitica and Staphylococcus aureus. Conclusion: By structural modification of TBZ by incorporation of amino aryl moiety at 2nd position of thiazole nucleus, we synthesized 4-(1H-benzo[d]imidazol-2-yl)-N-substituted phenylthiazol-2- amines and found antimicrobial action. Our findings suggest that there is a need for further substitutions to obtain potent antibacterial and antifungal derivatives of TBZ.

Background: We developed Multicomponent synthesis for novel Mannich products with biologically active quinoline nucleolus under solvent free condition. This methodology provided us good amount of yield with the exception of chromatographic separation. The structure of novel compounds (4d1-d13) was characterized by elemental, mass, 1H-NMR, 13C-NMR and IR spectroscopic analysis. In vitro antimicrobial studies also indicate that most of the compounds are active against gram positive and gram negative bacteria. M. Tuberculosis activity of five compounds shows excellent properties. Methods: The present methodology deals with Multicomponent reaction, in which, the mixture of 2,4- dihydroxybenzophenone 1.07 gm (0.005 M), 2-chloro-6-methoxyquinoline-3-carboxaldehyde 1.105 gm (0.005 M), with various amines 0.30 gm (0.005M) and EAN 30 ml (1 M) was stirred at 80°C temperature. The completion of reaction was monitored by TLC by using (chloroform/methanol, 70:30). On completion of the reaction, the reaction mixture was extracted thrice with 20 ml ethyl acetate. The extract was dried over anhydrous sodium sulfate, evaporated under vacuum and the residue was purified via recrystallisation from methanol or ethyl acetate to obtain pure new Mannich products 4(d1-d13). All synthesized compounds were screened for their in vitro antibacterial activity by using the agar dilution technique. Results: The promising results obtained using 1M EAN as catalyst at the 80°C temperature encouraged us to investigate the feasibility of solvent-free MCRs protocol for the synthesis of new Mannich products 4(d1-d13). The recovery and recyclability of EAN were investigated for the synthesis of new Mannich products 4(d1-d13). It was found that, recycled ionic liquid was used up to four to five times without the loss of catalytic activity. The high yield (90-95%) of this products was observed at milder reaction condition compared to the other ionic liquid which rationalized due to high acidity associated with it (pH=5) along with its capacity to absorb water formed during the course of the reaction. All the compounds showed very good activity accept 4d13, especially against P. aeruginosa MTCC 1688 (MIC=25- 75 μg/mL), E. coli MTCC 443 (MIC = 25-100 μg/mL) and S. aureus MTCC 96 (MIC=25–75 μg/mL) whereas, 4d3 and 4d12, were found to be more potent rather than standard drugs Chloramphenicol and Ciprofloxacin. All the compounds showed excellent antifungal activity against C. albicans MTCC 227 (MIC=75-100 μg/mL) and A. niger MTCC 282 (MIC=75-100 μg/mL) whereas, 4d2 to 4d7 were found more potent rather Nystatin and Griseofulvin. Antituberculosis activity of all the compounds showed excellent activity 0.10 μg/mL rather than standard drug isoniazide (0.20 μg/mL) accept 4d2 and 4d3 using L. J. medium conventional method. Conclusion: We developed an environmental friendly, high yield and mild condition protocol for the three-component Mannich-type reactions using EAN as ionic liquid. This method provided us several advantages by comparison with reported literature; which are as follows: (a) highly efficient catalyst activity, (b) ease of workable with green catalyst, (c) reaction proceeds without preparation of enol derivatives and pre-formed imines, (d) effective reusability of catalyst, making it a useful and attractive strategy. EAN was recovered and recycled four to five times without decreasing catalytic activity. Most of the compounds showed potential activities against Gram-positive bacteria rather than Chloramphenicol and Ciprofloxacin, accept 4d13. Compounds 4d3 to 4d12 were found to be more potent against C. Albicans and A. Niger rather than Nystatin and Griseofulvin. Antituberculosis activity of 4d8 to 4d12 compounds showed excellent activity rather than isoniazide against H37RV bacteria using L. J. medium conventional method.

Background: Several synthesized chromones derivatives have been found to promote intense vasodilation and antihypertensive activity. 2 hydroxymethylchromone (2HMC) is a benzopyrane derivative that vasodilator effect on small arteries has not yet been investigated. This study describes its synthesis, examines any vasodilator effect observed, and clarifies its mechanism of action in rat mesenteric arterial bed (MAB). Material and Method: Intact and denuded rat mesenteric arterial bed pre-contracted with PHE (2-4 ng/mL) was exposed to bolus injections of 2HMC (3-1000 μg). The effect of the latter was also studied in the presence of specific inhibitors such as L-NAME, indomethacine, atropine, glybenclamide, tetraethylammonium, BaCl2 and apamin. The effect of 2HMC on restricted calcium influx and calcium release from sarcoplasmic reticulum was investigated. Results: The data show that bolus injections of 2HMC induced in a dose dependent manner, a reversible vasorelaxant effect on pre-contracted preparations. This effect remained unaltered by endothelium removal and was not significantly affected by L-NAME, indomethacine, atropine, glybenclamide, BaCl2 tetraethylammonium or apamin. On the contrary, 2HMC significantly shifted to the right the concentration-response curve to high K+-induced MAB contraction during Ca2+ supplementation. Also, 2HMC strongly reduced the response to PHE when the MAB(s) were maintained under calcium-free conditions. Conclusion: Our results suggest that 2HMC-induced vasorelaxation is not mediated via the endothelium pathways, but rather might be due at least to both antagonistic action on extracellular calcium influx (blockade of voltage operated calcium channels) and restriction of calcium mobilization from intracellular stores.

Background: Breast cancer is the most common invasive cancer in female worldwide. Indole scaffold represents an important class of therapeutic agents in medicinal chemistry. Many indole derivatives are reported as potent anticancer agents. This study aims to design, and synthesize anti-breast cancer potential of new bisindole derivatives. Method: The target molecules were prepared by reacting cyano acetyl indoles with substituted indole-3- carboxyaldehydes in the presence of piperidine. All the newly synthesized compounds were in vitro screened for their anticancer activities against breast carcinoma (MCF-7) by employing the sulforhodamine B (SRB) assay method. Results: Preliminary in vitro evaluation indicated that most of the compounds possess distinct cytotoxicity profile against MCF-7 cell line compared to standard drug adriamycin. Among them, compounds 5g, 5b, and 5q demonstrated excellent activities against breast carcinoma (GI50 < 0.1μM) as good as adriamycin (GI50 < 0.1μM). Active compounds were further subjected for molecular docking and bioavailability studies. These studies supported activities of the present series compounds. Conclusion: New anti-breast cancer agents are the need of time, we believe that the new α-cyano substituted 1,3-bisindolyl-2-propen-1-one derivative 5g reported in this work may provide an interesting insight for further optimization.

Objective: The objective of this study was to synthesize a series of 1,3,4-thiadiazole derivative and evaluate their possible in vitro and in vivo anticancer activity. Method: Compounds 7a-f have been synthesized by chlorination of 2-[bis(2-hydroxyethyl)amino]-N-[5- substituted phenyl)-1,3,4-thiadiazol-2-yl]acetohydrazide with phosphorous oxychloride and phosphorous pentachloride. Synthesis of the targeted compounds was (7a-f) confirmed through their MP, IR, 1HNMR and mass spectrum studies. Results: Compounds 7a and 7d showed considerable anticancer activity against Hep-2 cell lines and, therefore, selected for the in vitro studies and DLA cell line for the in vivo studies. Conclusion: It may be concluded that the presence of nitro and chloro phenyl substituted 1,3,4- thiadiazoles showed significant anticancer activity.