ABSTRACT
The increasing resistance of bacteria against clinically approved antibiotics is resulting in an alarming decrease in therapeutic options for today's clinicians. We have targeted the essential interaction between bacterial RNA polymerase and σ(70)/σ(A) for the development of lead molecules exhibiting a novel mechanism of antibacterial activity. Several classes of structurally related bis-indole inhibitors of bacterial transcription initiation complex formation were synthesized and their antimicrobial activities were evaluated. Condensation of indole-7- and indole-2-carbohydrazides with 7- and 2-trichloroacetylindoles or indole-7- and indole-2-glyoxyloyl chlorides resulted in the successful synthesis of 7,7'-, 2,2'-, 2,7'- and 3,2'-linked bis-indole derivatives with -CO-NH-NH-CO- and -CO-CO-NH-NH-CO- linkers. Indole-7-glyoxyloyl chlorides were reacted with hydrazine hydrate in different ratios to afford respective -CO-CO-NH-NH-CO-CO- bis-indole or hydrazide derivatives. The resulting compounds were found to be active against the ß'-CH-σ(70)/σ interaction in ELISA assays and inhibited the growth of both Gram-positive and Gram-negative bacteria. Structure-activity relationship (SAR) studies were performed in order to identify the structural features of the synthesized inhibitors required for biological activity.
Subject(s)
Bacillus subtilis/genetics , Escherichia coli/genetics , Indoles/chemical synthesis , Indoles/pharmacology , Transcription Initiation, Genetic/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacillus subtilis/drug effects , Bacillus subtilis/growth & development , DNA-Directed RNA Polymerases/metabolism , Escherichia coli/drug effects , Escherichia coli/growth & development , Indoles/chemistryABSTRACT
5-Methoxyflavenes and 6-methoxyflavenes were found to undergo stereoselective acid-catalyzed rearrangement to generate a range of novel chromeno[2,3-b]chromene derivatives. When subjected to an in vitro antiplasmodial growth inhibition assay using Plasmodium falciparum (3D7 line) the chromene analogues were shown to display IC(50) values ranging from 6.8 to 39.8 µM.
Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Benzopyrans/chemical synthesis , Benzopyrans/pharmacology , Plasmodium falciparum/drug effects , Antimalarials/chemistry , Benzopyrans/chemistry , Cell Line , Humans , Inhibitory Concentration 50 , Isoflavones/chemical synthesis , Isoflavones/chemistry , Isoflavones/pharmacology , Molecular StructureABSTRACT
7-Methoxyflavenes and 5,7,8-trimethoxyflavenes were found to undergo stereoselective acid-catalyzed rearrangement to generate the benzopyrano[4,3-b]benzopyran ring system present in the natural product, dependensin. Dependensin and its analogs were subjected to antimalarial growth inhibition assays against Plasmodium falciparum and found to have IC(50) values ranging between 1.9 and 3.9 µM.
Subject(s)
Antimalarials/chemical synthesis , Benzopyrans/chemistry , Acids/chemistry , Antimalarials/chemistry , Antimalarials/pharmacology , Benzopyrans/chemical synthesis , Benzopyrans/pharmacology , Catalysis , Crystallography, X-Ray , Dimerization , Molecular Conformation , Plasmodium falciparum/drug effects , StereoisomerismABSTRACT
Thirty-four newer 1-cyclopropyl-1,4-dihydro-6-fluoro-7-(substituted secondary amino)-8-methoxy-5-(sub)-4-oxoquinoline-3-carboxylic acids were synthesized from 1,2,3,4-tetrafluoro benzene and evaluated for in vitro and in vivo antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant M. tuberculosis (MDR-TB) and Mycobacterium smegmatis (MC(2)) and also tested for the ability to inhibit the supercoiling activity of DNA gyrase. Among the synthesized compounds, 7-(1-(4-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinolin-2(1H)-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylic acid (13n) was found to be the most active compound in vitro with MIC of 0.16 and 0.33 microM against MTB and MDR-TB, respectively. In the in vivo animal model 13n decreased the bacterial load in lung and spleen tissues with 2.54 and 2.92-log10 protections, respectively, at the dose of 50mg/kg body weight. Compound 13n also inhibited the supercoiling activity of mycobacterial DNA gyrase with IC(50) of 30.0 microg/ml.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Cyclopropanes/chemistry , Fluorine Compounds/chemical synthesis , Fluorine Compounds/pharmacology , Hydroxyquinolines/chemical synthesis , Hydroxyquinolines/pharmacology , Amination , Animals , Anti-Bacterial Agents/chemistry , Cell Survival/drug effects , Chlorocebus aethiops , DNA Gyrase/metabolism , Fluorine Compounds/chemistry , Hydroxyquinolines/chemistry , Molecular Structure , Mycobacterium/drug effects , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/chemistry , Photosensitizing Agents/toxicity , Structure-Activity Relationship , Topoisomerase II Inhibitors , Vero CellsABSTRACT
Various diclofenac acid hydrazones and amides were synthesized and evaluated for in vitro and in vivo antimycobacterial activities against Mycobacterium tuberculosis. Preliminary results indicated that most of the compounds demonstrated better in vitro antimycobacterial activity (MIC: 0.0383-7.53 microM) than diclofenac (MIC: 21.10 microM) and ciprofloxacin (MIC: 9.41 microM). Among the synthesized compounds, 1-cyclopropyl-6-fluoro-8-methoxy-7-[[N4-(2-(2-(2,6-dichlorophenylamino)phenyl)acetyl)-3-methyl]-N1-piperazinyl]-4-oxo-1,4-dihydro-3-quinoline carboxylic acid (5d) was found to be the most active compound in vitro with MIC of 0.0383 microM and was more potent than first line antitubercular drug isoniazid (MIC: 0.1822 microM). In the in vivo animal model 5d decreased the bacterial load in lung and spleen tissues with 2.42- and 3.66-log10 protections, respectively, at 25 mg/kg body weight.
