Synthesis and antituberculosis activity evaluation of cyclohexane-1,2-diamine derivatives CHEMISTRY & BIOLOGY INTERFACE (original) (raw)
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Synthesis and antituberculosis activity evaluation of cyclohexane-1,2-diamine derivatives
2014
Mycobacterium tuberculosis is responsible for a large number of deaths worldwide. This bacterium is a matter of great concern as it has developed resistance against most of the anti-TB drugs available today. A series of new cyclohexane-1,2-diamine derivatives was synthesized and evaluated for their anti-tubercular activity against Mycobacterium tuberculosis H37Rv in vitro. These compounds were found to be moderate to weakly active. Two compounds showed signifi - cant activity with minimum inhibitory concentrations of 11.8 and 13.1 µM (Optical Density).
A library of unsymmetrical cyclohexane-1,2-diamine derivatives were synthesized and evaluated for their activity against Mycobacterium tuberculosis H37Rv in vitro. Out of the 46 compounds synthesized, eight compounds (11h, 13a, 13e, 13f, 14a, 14c, 14d, and 15d) were found to be active at or below 6.25 uM concentration, with negligible toxicity to human red blood cells at a concentration much higher than the MIC99. Compound 13a was the best active compound showing inhibition at 3.125–6.25 uM, and was found to be non-hemolytic up to 500 ug/mL concentration.
2013
A library of symmetrical trans-cyclohexane-1,4-diamine derivatives have been synthesized and evaluated for their activity against the M. tb H 37 Rv strain. Most of the synthesized compounds show moderate to weak activity against M. tb H 37 Rv strain. Out of twenty-seven compounds tested, four compounds having substitution at p-position on the aromatic ring exhibit activity with MIC 99 value ranging from 12.5-25 µM. Compound 9u having i-propyl group substitution at p-position is found to be the most potent among all the tested compounds with MIC 99 value of 12.5 µM against M. tb H 37 Rv strain. All these compounds have also been tested against Methicilin resistant Staphylococcus aureus (MRSA), and four of the compounds 9c, 9i, 9p and 9s possess good antibacterial activity with IC 50 ranging from 128 mg/L-256 mg/L.
ChemInform, 2014
A library of symmetrical trans-cyclohexane-1,4-diamine derivatives have been synthesized and evaluated for their activity against the M. tb H 37 Rv strain. Most of the synthesized compounds show moderate to weak activity against M. tb H 37 Rv strain. Out of twenty-seven compounds tested, four compounds having substitution at p-position on the aromatic ring exhibit activity with MIC 99 value ranging from 12.5-25 µM. Compound 9u having i-propyl group substitution at p-position is found to be the most potent among all the tested compounds with MIC 99 value of 12.5 µM against M. tb H 37 Rv strain. All these compounds have also been tested against Methicilin resistant Staphylococcus aureus (MRSA), and four of the compounds 9c, 9i, 9p and 9s possess good antibacterial activity with IC 50 ranging from 128 mg/L-256 mg/L.
International journal of antimicrobial agents, 2018
The presented study reports in vitro antituberculosis potential of 2-(((2-hydroxyphenyl) amino)methylene)-5,5-dimethylcyclohexane-1,3-dione (PAMCHD) against Mycobacterium tuberculosis H37Rv. PAMCHD proved to be tuberculostatic as well as tuberculocidal agent by agar and broth dilution methods with MIC and MBC values equivalent to some standard antituberculosis drugs (ATDs). The dynamics of M. tuberculosis killing revealed its time as well as concentration dependent antituberculosis activity and it sterilized M. tuberculosis culture at or above 10.0 µg/mL concentration. PAMCHD acts either synergistically or additively with ATDs. INH and PAMCHD post-antibiotic effects increased with concentration from 16.18 ± 13.30 and 31.64 ± 13.30 to 127.9 ± 27.60 and 138.71 ± 16.42 hrs respectively from 1x MIC to 8x MIC; no significant difference was observed between INH and PAMCHD PAEs. M. tuberculosis mutation frequency against PAMCHD is lower than those of INH. Mutant prevention concentration (M...
MedChemComm, 2017
The present study utilised whole cell based phenotypic screening of thousands of diverse small molecules against H37Rv () and identified the cyclohexane-1,3-dione-based structures and as hits. The selected hit molecules were used for further synthesis and a library of 37 compounds under four families was synthesized for lead generation. Evaluation of the library against lead to the identification of three lead antituberculosis agents (, and ). The most potential compound, 2-(((2-hydroxyphenyl)amino)methylene)-5,5-dimethylcyclohexane-1,3-dione () showed an MIC of 2.5 μg mL, which falls in the range of MICs values found for the known antituberculosis drugs ethambutol, streptomycin and levofloxacin. Additionally, this compound proved to be non-toxic (<20% inhibition at 50 μM concentration) against four human cell lines. Like first line antituberculosis drugs (isoniazid, rifampicin and pyrazinamide) this compound lacks activity against general Gram positive and Gram negative bacteria...
A series of forty two adamantyl based cyclohexane diamine derivatives were synthesized and the antibacterial activities of these compounds were assessed against 29 strains of methicillin resistant Staphylococcus aureus (MRSA) and a virulent strain of Mycobacterium tuberculosis. The compounds showed potent to moderate activity against MRSA while moderate to weak activity against the virulent strain of M. tuberculosis. The compound 8e showed the most potent activity against MRSA having minimum inhibitory concentration (MIC) values in the range of 8–64 mg mL 1 against 26 MRSA strains out of the 29 strains examined. It exhibited improved inhibitory activity compared to oxacillin.Compound 8i with an MIC value of 13.7 mM against M. tuberculosis, was bactericidal with rapid kill kinetics demonstrating a 4 log reduction in viability of M. tuberculosis within 7 days.
Bioorganic & Medicinal Chemistry, 2013
The alarming increase in bacterial resistance over the last decade along with a dramatic decrease in new treatments for infections has led to problems in the healthcare industry. Tuberculosis (TB) is caused mainly by Mycobacterium tuberculosis which is responsible for 1.4 million deaths per year. A worldwide threat with HIV co-infected with multi and extensively drug-resistant strains of TB has emerged. In this regard, herein, novel acrylic acid ethyl ester derivatives were synthesized in simple, efficient routes and evaluated as potential agents against several Mycobacterium species. These were synthesized via a stereospecific process for structure activity relationship (SAR) studies. Minimum inhibitory concentration (MIC) assays indicated that esters 12, 13, and 20 exhibited greater in vitro activity against Mycobacterium smegmatis than rifampin, one of the current, first-line anti-mycobacterial chemotherapeutic agents. Based on these studies the acrylic ester 20 has been developed as a potential lead compound which was found to have an MIC value of 0.4 μg/mL against Mycobacterium tuberculosis. The SAR and biological activity of this series is presented; a Michael-acceptor mechanism appears to be important for potent activity of this series of analogs.
Compounds with Potential Activity against Mycobacterium tuberculosis
Antimicrobial Agents and Chemotherapy
The high acquisition rate of drug resistance by Mycobacterium tuberculosis necessitates the ongoing search for new drugs to be incorporated in the tuberculosis (TB) regimen. Compounds used for the treatment of other diseases have the potential to be repurposed for the treatment of TB. In this study, a high-throughput screening of compounds against thiol-deficient Mycobacterium smegmatis strains and subsequent validation with thiol-deficient M. tuberculosis strains revealed that ΔegtA and ΔmshA mutants had increased susceptibility to azaguanine (Aza) and sulfaguanidine (Su); ΔegtB and ΔegtE mutants had increased susceptibility to bacitracin (Ba); and ΔegtA, ΔmshA, and ΔegtB mutants had increased susceptibility to fusaric acid (Fu). Further analyses revealed that some of these compounds were able to modulate the levels of thiols and oxidative stress in M. tuberculosis. This study reports the activities of Aza, Su, Fu, and Ba against M. tuberculosis and provides a rationale for further...