Letters in Drug Design & Discovery - Volume 15, Issue 8, 2018

Background: 2-Indolinone is a bicycle, heterocyclic compound analogous of indole skeleton containing a carbonyl group at 2-position of the 5-membered ring. Recently, different biological evaluations of oxindole derivatives have been reported. A variety of compounds with oxindoles moiety exhibit useful pharmaceutical properties like anti-inflammatory, anti-bacterial, anticancer, anti-proliferative, anti-hypertensive, anti-HIV and anti-convulsant activities. Methods: In the present study, fifteen 6-chloro-3-oxindole derivatives (1-15) were screened for urease inhibitory activity. The binding mode of the synthesized compounds was studied by molecular docking and found good results. 6-Chloro-3-oxindole derivatives 1-15 were synthesized from 6-chlorooxindole by refluxing with different aromatic aldehydes in ethanol in the presence of piperidine in high yields. Docking was carry out of the ligands into HCV NS3/4A protein. The software package MOE (Molecular Operating Environment) was used for docking. Results: Our present study has shown that compound 6 (IC50 = 13.34 ± 1.75 μM), 2 (IC50 = 16.67 ± 1.73 μM), and 5 (IC50 = 17.85 ± 2.21 μM) were found to be the most potent urease inhibitors as compared to the standard thiourea (IC50 = 21.1 ± 0.11 μM). Conclusion: Our present study has shown that Compounds 6 (IC50 = 13.34 ± 1.75 μM), 2 (IC50 = 16.67 ± 1.73 μM), and 5 (IC50 = 17.85 ± 2.21 μM) were found to be the most potent urease inhibitors as compared to the standard thiourea (IC50 = 21.1 ± 0.11 μM). These may serve as lead compounds for better urease inhibitors after fine tuning in the structure and further studies in future.

Background: Novel, more lipophilic analogs of pralidoxime - 2-PAM (K347, K087) and 4-PAM (K349, K120) have been tested in this study due to the recently discovered fact that monoquaternary AChE reactivators penetrate BBB in higher amount. In vitro tests were run against the several organophosphorus agents including tabun, sarin, cyclosarin, soman, VX-agent, Russian VX-agent, diisopropylfluorophosphate and chlorpyrifos. Methods: Standard potentiometric method was used for the evaluation of reactivation efficacy. Rat brain homogenate was used as the source of acetylcholinesterase. Results: The efficacy of novel reactivators was compared against standard AChE reactivators (2- PAM and 4-PAM). K349 and K120 (10-3 M) were 1.1 and 4.8-fold more effective in the reactivation of sarin-inhibited AChE compared with 4-PAM, respectively. Moreover, K120 in 10- 5 M concentration, which is attainable in the plasma within antidotal treatment of intoxication, was 2.1-fold more effective than standard. Generally, the best results were observed for oxime K120. Conclusion: None of the newly prepared benzylated 2-PAM and 4-PAM analogs showed such a broad spectrum of action as standard pralidoxime.

Background: The cationic surfactants are a huge group of compounds with thousands of applications. Quaternary Ammonium Salts (QAS) make up the majority of this group. Their countless applications in chemistry, the food industry and textile industry are indubitable. The antibacterial and antifungal effect of the various novel QAS is usually referred to in comparison with commercially used benzalkonium and pyridinium salts, since such compounds have found widespread use as common disinfectants e.g. in hospitals as prevention against nosocomial infections. Methods: Three series of N-alkylpyridinium salts with a hydroxymethyl group in positions 2, 3 and 4 were synthesized as novel potential antimicrobial agents. The nucleophilic substitution-type reaction has been used. The novel compounds have been tested as a disinfection agents against bacteria and fungi. The microdilution broth method was utilized for antimicrobial evaluation. Conductivity measurement method has been used for the determination of Critical Micelle Concentration (CMC). Standard MTT test was used for cytotoxic evaluation. Results: We have prepared 15 new compounds based on hydroxymethylpyridine in different positions (2, 3, 4) and the different length of lipophilic alkyl chain on the quaternary nitrogen (C10-18). The compounds were characterized with analytical data (NMR, HRMS) and tested for in vitro antimicrobial activity. The highest, and submicromolar antimicrobial activity was achieved for the 3- hydroxymethylpyridinium salts substituted with longer alkyl chains (C14, C16 and C18). Nhexadecyl- 3-hydroxymethylpyridinium bromide (10b) showed even better performance than standard benzalkonium salts. Conductometric analysis confirmed the trend of decreasing CMC with elongation of the alkyl side chain. Generally, the location of the hydroxymethyl function on the pyridinium scaffold induced only negligible changes in antimicrobial efficacy. Finally, potential use of the N-alkylhydroxymethylpyridinium salts in practice was supported by MMT tests which proved relatively low cytotoxicity of the compounds. Conclusion: We have designed, synthesized and characterized three series of cationic surfactants based on 2-, 3- and 4-hydroxymethylpyridine. The cationic surfactants differ in the length of alkyl side-chain (C10, C12, C14, C16, C18). The antimicrobial effect was evaluated against four groups of microorganisms (gram- positive and gram-negative bacteria, yeasts, and filamentous fungi). The Critical Micelle Concentrations (CMC) were measured by conductivity method, and finally cytotoxicity tests were performed.

Background: Bacterial biofilms are a cause of a number of infections and are associated with specific drug resistance. In particular, dental biofilm can consist of up to 100 bacterial species and may result in the diseases in the teeth and the surrounding tissues, including dental caries and periodontal diseases. Moreover, pathogens from the dental biofilm can migrate to other organs and lead to systemic diseases. Thus, it is important to search for inhibitors of dental biofilm formation. The series of 1,4-disubstitued thiosemicarbazide derivatives were evaluated for their ability to inhibit mono-species Streptococcus mutans or Streptococcus sanguinis biofilm formation. Methods: The Minimum Biofilm Inhibitory Concentration (MBIC) is defined as the lowest concentration of an antimicrobial agent required to inhibit the formation of biofilm. MBIC was determined spectrophotometrically. Molecular docking was performed using Glide from the Schrödinger suite of software. The grid file was generated indicating acarbose as a reference ligand. The compounds were modeled using LigPrep protocol from the Schrödinger suite of software. Molecular docking was performed using the SP (standard precision) protocol of Glide. Molecular dynamics studies of ligand-receptor complexes was performed using Desmond v. 3.0.3.1.4. Results: The series of 1,4-disubstituted thiosemicarbazide derivatives were synthesized and investigated for their ability to inhibit S. mutans or S. sanguinis biofilm. The most active compounds caused inhibition of S. sanguinis and S. mutans biofilm formation in the concentration of 7.81 μg/ml- 62.5 μg/ml. We showed, that growth of S. mutans and S. sanguinis biofilm was faster and higher in presence of sucrose. Additionally it was harder to inhibit the growth of biofilm in BHIbroth with the presence of sucrose, than the biofilm growing in BHI without sucrose. It seems that colonization by tested caries bacteria depends on sucrose content in medium. Based on above in vitro anti-biofilm data, we postulated that the mechanism of antibacterial activity of the investigated compounds might be connected with the inhibition of mono-species bacteria biofilm formation. In order to demonstrate that the investigated compounds may inhibit the enzyme glucansucrase and thus, biofilm formation, we performed molecular docking and molecular dynamics of the studied compounds to glucansucrase crystal structure. The obtained results reveal that the thiosemicarbazide derivatives can be used as potential inhibitors of dental biofilm formation, acting possibly through inhibition of glucansucrase. Conclusion: In this study we showed that some of tested thiosemicarbazide derivatives can be used as potential inhibitors for mono-species cultures of S. mutans or S. sanguinis biofilm. The possible blocking mechanism of mono-species biofilm formation was proposed via molecular modelling technique. The data suggested that this mechanism may involve the glucansucrase inhibition as it was demonstrated that tested derivatives occupy the same binding pocket in this enzyme as acarbose, commonly known inhibitor of glucosylotransferases. Therefore, it is possible that tested derivatives could be used in prevention of dental caries.

Background: Plectrantus barbatus Andr. (Lamiaceae) has been used in Hindu and Ayurvedic Indian traditional as well as Brazilian folk medicine for the treatment of several diseases. Chemical investigation of different parts of this plant has led to isolation of essential oil, diterpenes (abietane and labdane), flavonoids, phenolic compounds with interesting biological properties. The objective of study was to isolate pure new chemical entities from aerial parts of P.barbatus. Methods: Different chromatographic methods were used to isolate pure compounds from the ethyl acetate soluble fraction of ethanol extract of P. barbatus. Their chemical structures were verified utilizing various spectroscopic experiments such as NMR (1H, 13C, COSY, HMBC, HSQC), Mass spectrometry (EI-MS experiments) as well as by chemical degradation. Results: The chemical investigation of ethyl acetate soluble fraction of the ethanol extract of P. barbatus resulted in six compounds, barbaterpene (2) (2`R-hydroxydocosanoylursa-12-en-3β-ol) and barbatusterol (3) new to the literature along with four known compounds, stigmasterol (1), sugiol (4), 11,14-dihydroxy-8,11,13-abietatrien-7-one (5), and caffeic acid (6). Conclusion: Two new metabolites: barbaterpene (2) (2`R-hydroxydocosanoylursa-12-en-3β-ol) and barbatusterol (3) (3β,5α-dihydroxy-stigma-7(8),22-diene), in addition to stigmasterol (1), sugiol (4), 11,14-dihydroxy-8,11,13-abietatrien-7-one (5), and caffeic acid (6) were separated from the aerial parts of P.barbatus.

Background: Chromene, benzochromene and their derivatives have been considered as an important class of oxygen-containing heterocycles. There has been increasing interest in the study of chromenes and benzochromenes due to their biological and pharmacological activities. Methods: 3-Amino-1-(4-chlorophenyl)-9-hydroxy-1H-benzo[f]chromene-2-carbonitrile (3) was used as precursor for the synthesis of novel 1H-benzo[f]chromene (4,8-11) and 12Hbenzo[ f]chromeno[2,3-d]pyrimidine (5-7,12-14) derivatives via reaction of compounds 3 with appropriate chemical reagents. The structures of the synthesized compounds were confirmed on the basis of spectral data, IR, 1H NMR, 13C NMR and MS data. The targeted compounds were tested in-vitro for their antimicrobial activity and showed congruent results against the most tested microorganisms compared to the standard drugs Gentamycin and Ketoconazol. The Structure Activity Relationship (SAR) study for the target compounds agreed with the in-vitro essays and confirmed higher potent antimicrobial activity against some of the tested microorganisms. Results: In this study, the antimicrobial activity of the synthesized compounds 3–14 was examined and showed congruent results against the most tested microorganisms compared to the standard drugs Gentamycin and Ketoconazol. Conclusion: Several 1H-benzo[f]chromene (4,8-11) and 12H-benzo[f]chromeno[2,3-d]- pyrimidine (5-7,12-14) derivatives were synthesized in good yields, starting from β-enaminonitrile 3 and elucidated on the basis of spectral data. An antimicrobial study has been performed and some compounds showed congruent results against the most tested microorganisms compared to the standard drugs Gentamycin and Ketoconazol.

Background: Novel 4-(3-(4-ethylpiperazin-1-yl)propoxy)-N-phenylbenzamide derivatives (C-1 to C-10) and (4-(3-(4-ethylpiperazin-1-yl)propoxy)phenyl)(4-(2-methoxyphenyl)piperazin-1- yl)ethanone derivatives (C-11 to C-16) were designed and synthesized by pharmacophore approach. Methods: All compounds were evaluated for their in-vitro cytotoxicity against a panel of three cancer cell lines (A-549 human lung carcinoma, HCT-116 colon cancer and pancreatic cancer MIAPaCa-2). Results: The results indicated that in A-549 human lung carcinoma cell line, compounds C-4 and C-5 showed IC50 values of 33.20μM and 21.22μM, respectively, which is comparable to standard (gefitinib, IC50 value: 16.56 μM). These compounds, in HCT-116 colon cancer line, showed IC50 values of 11.33μM and 45.89μM which was again comparable to gefitinib that showed IC50 value of 10.51μM. Also, in MIAPaCa-2 cell line, compound C-14 showed IC50 value of <1μM. To give mechanistic basis, in silico docking studies were done and it shows good in silico – in vitro correlation. Conclusion: These results provide an encouraging lead that could be used for the development of new potent anticancer agents.

Background: Nowadays inflammation recognized as the underlying basis of number of diseases but still NSAIDS are the first drugs of choice having several side effects. In addition to that, oxidative stress also triggers the inflammation. This creates an initiation to introduce new molecules which act as efficient COX-2 inhibitors with diminished side effects. Objective: As a part of our search for newer agents, we designed a series of N-acylhydrazones by combining the pharmacophoric features of hydrazones with feruloyl derivatives in hope of enhancing the activity profile of title compounds. Methods: The title compounds (3a-l) were synthesized by the condensation of α-benzamido-(4- hydroxy-3-methoxy)-cinnamhydrazide (2) with different aromatic aldehydes in acidic conditions and characterized by elemental, spectral (IR, 1H NMR, 13C NMR, MASS) data and also evaluated for antiinflammatory (in-vivo, in-vitro and docking), analgesic and antioxidant activities. Results: The in-vivo anti-inflammatory data revealed that compounds 3j and 3i reduced the edema by 74% and 72% respectively at 100 mg /kg which is comparable to the standard, supported by in-vitro studies (3j: 10μM and 3i: 16μM as IC50) and also showed good docking scores (3j:-10.28 and 3i:- 10.13). The analgesic activity profile suggested that compounds 3j (65%) and 3e (60%) exhibited good activity by writhing test. Besides having good anti-inflammatory activity, title compounds also exhibited appreciable antioxidant potential evaluated by four in-vitro methods. Compounds 3j and 3f displayed good antioxidant potential than the standard by lipid peroxidation and DPPH scavenging methods respectively. Conclusion: Results suggested that the compound 3j emerged as a lead compound having multi target affinities.

Background: One of the successful approaches for rational design of bioactive compounds is the bioisosterism strategy. Thus, the bioisosteric relation of thieno[2,3-d]pyrimidin-4- ones with quinazolines, cytosine and uracil resulted in the generation of compounds with variety of biological properties including antiparasitic activity. In contrast to mammals, all parasites are unable to synthesize purines de novo and rely instead on the Purine Salvage Pathway (PSP) to obtain purines, which are essential for their survival. Having in view the above mentioned facts we designed and synthesized some thieno[2,3-d]pyrimidines as bioisosters in order to evaluate their antitrichinellosis efficacy. Methods: The target compounds were synthesized by one-pot cyclocondensation reaction passing dry hydrogen chloride gas through a solution of 2-aminothiophene-carboxylate and a series of alkyl respectively aryl nitriles as precursors. The parasitological screening in vitro was carried out by using encapsulated infective larvae of Trichinella spiralis, 100 speciments per 1 mL physiological solution, released in advance from the muscle capsules by digestion with acid pepsin solution. Results: Fourteen 2-substituted-thieno[2,3-d]pyrimidin-4-ones were synthesized and their structure was identified. The data obtained by the antitrichinellosis screening showed that compounds 2, 8 and 15 exhibit higher activity than the reference drugs albendazole and ivermectin at concentrations of 0.37, 0.35 and 0.48 μM resp. 0.92, 0.88 and 1.2 μM after 24-hour incubation of the samples. The highest efficacy at both incubations was revealed by 2-benzyl-5,6,7,8- tetrahydrothieno[2,3-d]pyrimidin-4(3H)-one 2 - 97.94% and 100%, respectively. Compound 15 demonstrated 97.5% antiparasitic activity after 48h at concentration of 250 μg/ml. The theoretically calculated intestinal absorption (%ABS) of the tested thieno[2,3-d]pyrimidines displayed higher values than that of albendazole. The structure-activity relationship (SAR) data of the tested compounds 2, 4-8 and 15 complies with the Lipinski's rule. It was assumed that the low molecular volume (Vol.) and logP of compound 15 led to enhancement of the compound activity by increasing the penetration through the ion channels of the parasitic cells as it was observed in some albendazole derivatives. Conclusion: The tested thienopyrimidin-4-ones possess higher anthelminthic effect than albendazole against Trichinella spiralis. Compounds 2, 4-8 and 15 demonstrated higher absorption %ABS than albendazole. According to the SAR analysis, the partition coefficient (logP) is essential for parasite drug penetration due to diffusion through the cell membrane.

Introduction: Bacterial infections account for maximum deaths worldwide than for any other single cause. Methods: Here in, we report a convenient synthesis of new fluoroquinolone molecules substituted with endo- nortropine and its derivatives at C-7position. All the synthesized molecules, when screened for their antibacterial activity by agar diffusion method against Vibrio cholerae, Bacillus subtilis, Staphylococcus aureus and Escherichia coli were found to be active against the first three strains. The shortlisted compounds in the series, RG and RO, were further evaluated to determine their MIC values by micro-dilution broth assay. Result & Conclusion: Compound RG was ten times more effective in case of S. aureus (15.0 nM), two times in case of V. cholerae (3.7 nM) and the same as that of standard drug Levofloxacin in case of Bacillus subtilis (7.8 nM). Compound RO also displayed an impressive MIC value (62.5 nM) in case of S. aureus as compared to control (125 nM). The results have been supported by in-silico docking studies, where increased hydrogen bonding interactions in case of RG as compared to standard drug levofloxacin with DNA gyrase (2XCT) of S. aureus resulted in decreased energy of the former.

Background: Natural products have been an exemplary source of new drugs as they have served as direct or indirect precursors for many currently available medicines. The natural product β -elemene has been used clinically in the treatment of various cancers; however, its efficacy is hampered by its poor solubility and bioavailability. Methods: An aldehyde metabolite of β-elemene, 13-β-elemenal, was further identified and proved to exhibit significantly better anti-proliferative activity than β -elemene. A series of prodrug-like 13- and 14-substituted ester derivatives, as well as their alcohol and aldehyde intermediates, were rational designed, synthesized and biologically evaluated. Results: The intermediates and ester derivatives of β-elemene displayed comparable to better antiproliferative activity on human cancer cell lines (A549, HepG-2 and U87). Notably, ester compounds 10d, 10m-o, 10s, 10t, 13d, 13h and 13m-o were superior over β-elemene in their antiproliferation effects, while the predicted in vivo metabolites of the designed ester compounds, 13- β-elemental (8) and 14-β-elemental (11), demonstrated the most potent anti-proliferative effect. Conclusion: Most of the esters displayed better antitumor effects than β -elemene, which were predicted to play more significant roles in the in vivo treatment by being metabolized continuously to β -elemental. More importantly, these compounds showed better drug-like properties, such as decreased LogP values and improved solubility.