Antimycobacterial activity of nitrogen heterocycles derivatives: 7-(pyridine-4-yl)-indolizine derivatives. Part VII8–12

A series of 13 compounds having a monoindolizine mono-salt skeleton was designed and synthesised in order to evaluate their antimycobacterial activity. The synthesis is efficient, involving only three steps: two alkylations and one 3?+?2 dipolar cycloaddition. The antimicrobial activity against Mycobacterium tuberculosis H37Rv grown under aerobic conditions was evaluated, eight compounds showing a very good antimycobacterial activity. SAR correlation reveals a certain influence of the R substituent from the para position of benzoyl moiety at position 3 of indolizine. The most active five compounds passed the second stage of anti-TB testing, the assay demonstrating that they are potent against both replicating and non-replicating Mtb, have a bactericidal mechanism of action, are active against drug-resistant Mtb strains, present a moderate to good activity against nontuberculous mycobacteria, a good intracellular activity, and a moderate to high cytotoxicity. For one compound showing a promising anti-TB profile, a complete ADMET study has been performed.     

Total synthesis and biological evaluation of spirotryprostatin A analogs

Based on the spirotryprostatin A structure, a series of compounds belonging to spiro‐indolyl diketopiperazine structural class were designed and synthesized, which embody an oxindole with an all‐carbon quaternary stereocenter. The total synthesis can efficiently be accessed in a seven‐step reaction sequence with 18–28% overall yield from commercially available materials, and a highly enantioselective 1,3‐dipolar cycloaddition, N ‐acylation of the resulting stereochemically complex spiro[pyrrolidin‐3,3′‐oxindole]s core with Fmoc‐L ‐pro‐Cl and spontaneous ring closure upon N ‐deprotection were obtained. The synthesized compounds 13a–e and 15a–e were evaluated for their antibacterial activities. The result showed that compounds 13b and 15b were active only against Gram‐positive bacteria, and selective antibacterial activity was exhibited by compounds 13d and 13e against Streptococcus lactis . Further, all the remaining compounds showed a certain degree of antibacterial activity. In addition, the structure–activity relationship is also discussed.     

New pyridazine derivatives: Synthesis,chemistry and biological activity

In this paper we report a feasible study concerning synthesis, structure and biological activity of some new pyridazine derivatives. Syntheses have been done both under classical conditions and microwave [in liquid phase and interphasic transfer catalysis (PTC)]. The MW induced a remarkable acceleration for the [3+2] dipolar cycloaddition reaction of pyridazinium ylides to activated alkenes and alkynes, the yields were increased in some cases, and the amount of used solvents decrees in liquid phase (while PTC do not use solvents). Consequently, these types of reactions could be considered environmentally friendly. The in vitro antibacterial and antifungal activities of the newly obtained diazine compounds were tested, some of the compounds have proved to have a remarkable activity against Gram positive germs, the results on Sarcinia luteea being spectacular.     

Langaside,a novel secoiridolactone glycoside derivative from Tachiadenus longiflorus Griseb. (Gentianaceae) formed by a [2+2] cycloaddition reaction

Langaside (1), a secoiridoid lactone glucoside possessing a novel skeleton formed by a [2 + 2] cycloaddition reaction between the secoiridolactone glucoside, 1,9-trans-9,5-cis-sweroside, and p-coumaric acid was isolated from the fruits and flowers of the Malagasy Tachiadenus longiflorus Griseb. (Gentianaceae), alongside another seven known compounds. The structure of langaside was established using HRESIMS, IR and NMR spectroscopy and comparison of experimental and calculated electronic circular dichroism (ECD) spectra. Langaside was screened for its neuritogenic activity against SHSY-5Y cells and anticancer activity against the NCI59 human tumour cell panel but not found to be active.     

Pyrazolo[4,3-e][1,2,4]triazine sulfonamides as carbonic anhydrase inhibitors with antitumor activity

A series of sildenafil analogues and aniline substituted pyrazolo[4,3-e][1,2,4]triazine sulfonamides were prepared and evaluated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors and for their anticancer activity against two human breast cancer cell lines (MCF-7, MDA-MB-231). The new compounds were ineffective as CA I inhibitors, poorly inhibited CA II, but were more effective against the tumor-associated isoforms CA IX and XII, with some compounds acting as low nanomolar inhibitors. Evaluation of the cytotoxicity by using an MTT assay, the inhibition of [³H]thymidine incorporation into DNA as well as collagen synthesis inhibition, demonstrated that these sulfonamides exhibit cytotoxic effects on breast cancer cell lines ex vivo.     

Synthesis, structure, and antimycobacterial activity of 6-[1(3H)-isobenzofuranylidenemethyl]purines and analogs

6-Benzofuryl-, styryl, benzyl, and furfurylpurines as well as 6-[1(3H)-isobenzofuranylidenemethyl]purines have been synthesized and their activities against Mycobacterium tuberculosis (Mtb) determined. Several compounds displayed profound antimycobacterial activity in combination with low toxicity towards mammalian cells. NMR and X-ray crystallography were employed to determine the detailed structures and the results were supported by quantum chemical calculations.     

Spirooxindole-pyrrolidine heterocyclic hybrids promotes apoptosis through activation of caspase-3

A small library of spirooxindole-pyrrolidine hybrids have been synthesized for the first time in an ionic liquid, [bmim]Br in good to excellent yields employing a new class of non-stabilized azomethine ylides derived from isatin and tyrosine, a combination that has been rarely employed for the in situ generation of azomethine ylides using [3+2] cycloaddition strategy. Following the synthesis and characterization of the spirooxindole-pyrrolidine heterocyclic hybrids, they were tested for their anticancer activity as against the changes in the concentrations and time periods with different in vitro cell cultures containing cancer and non-cancer cells, where the results revealed for a potential therapeutic activity. Further analysis for the mechanism of cell death by the cancer cells indicated for the caspase-dependent apoptotic pathway, specifically mediated by caspase-3. Based on these results, it can be demonstrated that the synthesized spirooxindole-pyrrolidine hybrids may serve as one of the better therapeutic agents used for the treatment of malignant tumors.     

Synthesis,biological evaluation and docking studies of new pyrrolo[2,3-d] pyrimidine derivatives as Src family-selective tyrosine kinase inhibitors

In this study, the synthesis and potential enzyme interactions of new Pyrrolo[2,3-d]pyrimidine derivatives along with their inhibitory activity against SFK enzymes such as Fyn, Lyn, Hck, and c-Src were reported. The results indicated that compounds were slightly active of tested SFK enzymes in comparison with PP2 for Fyn, A-419259 for Lyn and CGP77675 for c-Src. Compound N-((2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl)-4-(3,4-dimethoxyphenyl)butanamide (5) was identified as a non-selective slight inhibitor against Fyn, Lyn and c-Src. However, compounds did not show any inhibitory effects on Hck. Docking studies were performed to analyze the binding mode of compounds against SFKs. The best interaction was obtained between compound 5 and the active site of Fyn and c-Src enzymes in comparison with reference compounds PP2 and CGP77675, respectively.     

The crystal structure of AbsH3: A putative flavin adenine dinucleotide‐dependent reductase in the abyssomicin biosynthesis pathway

Natural products and natural product‐derived compounds have been widely used for pharmaceuticals for many years, and the search for new natural products that may have interesting activity is ongoing. Abyssomicins are natural product molecules that have antibiotic activity via inhibition of the folate synthesis pathway in microbiota. These compounds also appear to undergo a required [4 + 2] cycloaddition in their biosynthetic pathway. Here we report the structure of an flavin adenine dinucleotide‐dependent reductase, AbsH3, from the biosynthetic gene cluster of novel abyssomicins found in Streptomyces sp. LC‐6‐2.     

Design,synthesis, cytotoxic evaluation,and QSAR study of some 6H-indolo[2,3-b]quinoxaline derivatives

In the pathway of anticancer drug development, we designed and synthesized some 6H-indolo[2,3-b]quinoxaline derivatives (which act as DNA intercalators) by structural modification. The structure of the 6H-indolo[2,3-b]quinoxaline derivatives was confirmed by IR, NMR, Mass and elemental analysis. The compounds (IDQ-5, IDQ-10, IDQ-11, IDQ-13, and IDQ-14) exhibited significant in vitro activity against a human leukemia (HL-60) cell line. The QSAR derived for modeling the cytotoxic activity of 6H-indolo[2,3-b]quinoxaline derivatives suggests that candidate structures for increased cytotoxic potency should incorporate cyclic substituents or substituents with primary carbon atoms.     

Synthesis,Characterization, and Biological Study of 3-Trifluoromethylpyrazole Tethered Chalcone-Pyrrole and Pyrazoline-Pyrrole Derivatives

The present study illustrates the design and synthesis of new series of 3-trifluoromethylpyrazole tethered chalcone-pyrrole and pyrazoline-pyrrole derivatives. All compounds were further screened for in vitro cytostatic activities on full NCI 60 cancer cell lines at National Cancer Institute, USA. Compounds (2E)-3-(1H-pyrrol-2-yl)-1-{4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}prop-2-en-1-one ( 5a ) and (2E)-1-{3-methyl-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-3-(1H-pyrrol-2-yl)prop-2-en-1-one ( 5c ) displayed significant antiproliferative activity (Growth Percentage: −77.10 and −92.13, respectively at 10 μM concentration) against the UO-31 cell lines from renal cancer and were further selected for assay at 10-fold dilutions of five different concentrations (10⁻⁴ to 10⁻⁸ M). Both compounds 5a and 5c exhibited promising antiproliferative activity (GI₅₀: 1.36 to 0.27 μM) against leukemia cancer cell lines HL-60 and RPMI-8226, colon cancer cell lines KM-12; breast cancer cell lines BT-549. Moreover, both compounds 5a and 5c were found to be non-cytotoxic (LC₅₀>100) against HL-60, RPMI-8226, and KM-12 cell lines. Remarkably, GI₅₀ values of compounds 5a and 5c were identified as more promising than sunitinib against most cancer cell lines. In silico study of compounds 5a and 5c exemplified the desired ADME properties for drug-likeness as well as tighter interactions with VEGFR-2. Hence, compounds 5a and 5c would be good cytotoxic agents after further clinical study.     

Trypanoside,anti-tuberculosis,leishmanicidal, and cytotoxic activities of tetrahydrobenzothienopyrimidines

The synthesis of 2-(5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl)hydrazone-derivatives (BTPs) and their in vitro evaluation against Trypanosoma cruzi trypomastigotes, Mycobacterium tuberculosis, Leishmania amazonensis axenic amastigotes, and six human cancer cell lines is described. The in vivo activity of the most active and least toxic compounds against T. cruzi and L. amazonensis was also studied. BTPs constitute a new family of drug leads with potential activity against infectious diseases. Due to their drug-like properties, this series of compounds can potentially serve as templates for future drug-optimization and drug-development efforts for use as therapeutic agents in developing countries.     

A facile stereoselective synthesis of dispiro-indeno pyrrolidine/pyrrolothiazole–thiochroman hybrids and evaluation of their antimycobacterial,anticancer and AchE inhibitory activities

A facile stereoselective synthesis of novel dispiro indeno pyrrolidine/pyrrolothiazole–thiochroman hybrids has been achieved by 1,3-dipolar cycloaddition of azomethine ylides, generated in situ from ninhydrin and sarcosine/thiaproline, on a series of 3-benzylidenethiochroman-4-ones. The synthesised compounds were screened for their antimycobacterial, anticancer and AchE inhibition activities. Compound 4l (IC₅₀ 1.07 μM) has been found to exhibit the most potent antimycobacterial activity compared to cycloserine (12 times), pyrimethamine (37 times) and ethambutol (IC₅₀ <1.56 μM) and 6l (IC₅₀ = 2.87 μM) is more active than both cycloserine (4 times) and pyrimethamine (12 times). Three compounds, 4a, 6b and 6i, display good anticancer activity against CCRF-CEM cell lines. Compounds 6g and 4g display maximum AchE inhibitory activity with IC₅₀ values of 1.10 and 1.16 μmol/L respectively.     

Synthesis and evaluation of 4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran] analogues against both active and dormant Mycobacterium tuberculosis

Need for new drugs to fight against tuberculosis (TB) is increasing day by day. In the present work we have taken a spiro compound (GSK 2200150A) reported by GSK as a lead and we modified the structure of the lead to study the antitubercular activity. For structure activity profiling twenty-one molecules have been synthesized, characterized and evaluated for their antimycobacterial potency against both active and dormant TB. Compound 06, 1-((4-methoxyphenyl)sulfonyl)-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran] was found to be the most potent compound (MIC: 8.23?µM) in active TB and was less effective than the lead but more potent than standard first line drug ethambutol. It was also found to be more efficacious than Isoniazid and Rifampicin and equipotent as Moxifloxacin against dormant Mycobacterium tuberculosis (MTB). Compound 06 also showed good inhibitory potential against over expressed latent MTB enzyme lysine ε-amino transferase with an IC₅₀ of 1.04?±?0.32?µM. This compound is a good candidate for drug development owing to potential against both active and dormant stages of MTB.     

Synthesis and antifungal activity of benzo[d]oxazole-4,7-diones

Benzo[d]oxazole-4,7-diones were synthesized and tested for in vitro antifungal activity against fungi. Among them tested, many compounds showed good antifungal activity. The results suggest that benzo[d]oxazole-4,7-diones would be potent antifungal agents.     

Introducing novel potent anticancer agents of 1H-benzo[f]chromene scaffolds,targeting c-Src kinase enzyme with MDA-MB-231 cell line anti-invasion effect

In our effort to develop novel and powerful agents with anti-proliferative activity, two new series of 1H-benzo[f]chromene derivatives, 4a–h and 6a–h, were synthesised using heterocyclocondensation methodologies under microwave irradiation condition. The structures of the target compounds were established on the basis of their spectral data, IR, ¹H NMR, ¹³?C NMR, ¹³?C NMR-DEPT/APT, and MS data. The new compounds have been examined for their anti-proliferative activity against three cancer cell lines, MCF-7, HCT-116, and HepG-2. Vinblastine and Doxorubicin have been used as positive controls in the viability assay. The obtained results confirmed that most of the tested molecules revealed strong and selective cytotoxic activity against the three cancer cell lines. Moreover, these molecules exhibited weak cytotoxicity on the HFL-1?line, which suggested that they might be ideal anticancer candidates. The SAR study of the new benzochromene compounds verified that the substituents on the phenyl ring of 1H-benzo[f]chromene nucleus, accompanied with the presence of bromine atom or methoxy group at the 8-position, increases the ability of these molecules against the different cell lines. Due to their high anti-proliferative activity, compounds 4c and 6e were selected to be examined their proficiency to inhibit the invasiveness of the highly sensitive and invasive breast cancer cell line, MDA-MB-231. The anti-invasion behaviour of these molecules against the highly sensitive, non-oestrogen, and progesterone MDA-MB-231 cell line gave rise to their decreasing metastatic effect compared to the reference drug. Furthermore, this report explores the apoptotic mechanistic pathway of the cytotoxicity of the target compounds and reveals that most of these compounds enhance the Caspase 3/7 activity that could be considered as potential anticancer agents.     

5-Chloro-2-thiophenyl-1,2,3-triazolylmethyldihydroquinolines as dual inhibitors of Mycobacterium tuberculosis and influenza virus: Synthesis and evaluation

This study describes synthesis and evaluation of novel 5-Chloro-2-thiophenyl-1,2,3-triazolylmethyldihydroquinolines 7a-o as dual inhibitors of Mycobacterium tuberculosis and influenza virus. Huisgen’s [3+2] dipolar cycloaddition of 6-(azidomethyl)-5-chloro-2-(thiophen-2-yl)-7,8-dihydroquinoline 5 with various alkynes 6a-o using sodium ascorbate and copper sulphate gave new dihydroquinoline-1,2,3-triazoles 7a-o in good to excellent yields. The new compounds were evaluated for in vitro antimycobacterial against M. tuberculosis H37Rv (Mtb) and antiviral activity against influenza virus A/Puerto Rico/8/34 (H1N1). Among the fifteen new analogs, compounds 7a (MIC: 3.12 µg/mL), 7j and 7k (MIC: 6.25 µg/mL) were identified as potent antitubercular agents. The virus-inhibiting activity of all the fifteen compounds was found to be moderate, and among them the compound 7l, bearing thiophene moiety appeared the most active with good selectivity index (IC₅₀ = 19.5 µg/mL; SI = 15). The results presented here will help developing newer dual inhibitors of tuberculosis and influenza virus.     

SYNTHESIS OF UNNATURAL 7-SUBSTITUTED-1-(2-DEOXY-β-D-RIBOFURANOSYL)ISOCARBOSTYRILS†: “THYMINE REPLACEMENT” ANALOGS OF DEOXYTHYMIDINE FOR EVALUATION AS ANTIVIRAL AND ANTICANCER AGENTS

A group of unnatural 1-(2-deoxy-β-D-ribofuranosyl)isocarbostyrils having a variety of C-7 substituents [H, 4,7-(NO₂)₂, I, CF₃, CN, (E)-CH=CH-I, -C═CH, -C═C-I, -C═C-Br, -C═C-Me], designed as nucleoside mimics, were synthesized for evaluation as anticancer and antiviral agents. This class of compounds exhibited weak cytotoxicity in a MTT assay (CC₅₀=10^?3 to 10^?5 M range) with the 4,7-dinitro derivative being the most cytotoxic, relative to thymidine (CC₅₀=10^?3 to 10^?5 M range), against a variety of cancer cell lines. The 4,7-dinitro, 7-I and 7-C═CH compounds exhibited similar cytotoxicity against non-transfected (KBALB, 143B), and HSV-1 TK⁺ gene transfected (KBALB-STK, 143B-LTK) cancer cell lines possessing the herpes simplex virus type 1 (HSV-1) thymidine kinase gene (TK⁺). This observation indicates that these compounds are not substrates for HSV type-1 TK, and are therefore unlikely to be useful in gene therapy based on the HSV gene therapy paradigm.

     

Synthesis and antimycobacterial activity of 4-[5-(substituted phenyl)-4, 5-dihydro-3-isoxazolyl]-2-methylphenols

Compounds based on the isoxazoline moiety were screened for their antimycobacterial activity in vitro against Mycobacterium tuberculosis H37R (MTB), and INH (isoniazid) resistant Mycobacterium tuberculosis (INHR-MTB) using the agar dilution method and bactec 460. Among the synthesized compounds, 4-[5-(4-bromophenyl)-4,5-dihydro-3-isoxazolyl]-2-methylphenol (4l) was found to be the most active agent against MTB and INHR-MTB with minimum inhibitory concentration of 0.62 μM. When compared to INH, compound (4l) was 1.12 fold and 3.0 fold more active against MTB and INHR-MTB, respectively.