H. K. Kumara

Synthesis and SAR Studies of Bisthiourea Derivatives of Dipeptides Lys/lys-Asp, Lys/lys-Trp Conjugated Benzo[d]isoxazole as Promising Antioxidants

A novel series of bisthiourea derivatives of four dipeptides consisting of Lys-Asp, lys-Asp, Lys-Trp and lys-Trp conjugated to 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole were synthesized and characterized by physical method and spectroscopic data. The molecules 1–24 were evaluated for their in vitro antioxidant activity and compared with commercial antioxidants ascorbic acid (AA) and gallic acid (GA), employing 1,1-diphenyl-2-picryl-hydrazyl (DPPH), N,N-dimethyl-p-phenylenediamine dihydrochloride (DMPD) and 2,2-azinobis-(3-ethylbenzothiazoline-6-sufonic acid) (ABTS) assays. The results revealed that IC50 of 8, 11, 20 and 23 with electron donating OCH3 group were lower than the IC50 of commercial standards AA and GA in all the three performed antioxidant assays indicating the good activities of these compounds. The analogues with Trp (13–24) showed better activity than the corresponding analogues with Asp (1–12). Further, the dipeptide derivatives with d-configuration (lys) were found to be more potent than the dipeptide derivatives with l-configuration (Lys).

Bisthiourea derivatives of dipeptide conjugated benzo[d]isoxazole as a new class of therapeutics: synthesis and molecular docking studies

BACKGROUND Studies on anti-inflammatory and antimicrobial agents remains a challenging and important area in medicinal chemistry research due to more toxic and rapid development of resistance against first effective drugs. In search of novel anti-inflammatory and antimicrobials agents, bisthiourea derivatives of dipeptide conjugated to 6-fluoro-3- (piperidin-4-yl)benzo[d]isoxazole were synthesized. METHODS The peptides were synthesized by solution phase method and conjugated to 6- fluoro-3-(piperidin-4-yl)benzo[d]isoxazole using 1-ethyl-3-(3-dimethyl aminopropyl)carbodiimide (EDCI)/hydroxybenzotriazole (HOBt) as a coupling agent and N-methylmorpholine (NMM) as a base. The protecting group, 2-chlorobenzyloxycarbonyl (2-ClZ) and tertbutyloxycarbonyl (Boc) were deblocked and further reacted with substituted phenyl isothiocyanates to obtain bisthiourea derivatives. RESULTS The molecules 1-24 were examined for their in vitro anti-inflammatory activity by employing human erythrocyte suspension test and it was found that the IC50 values of 9, 12, 21 and 24 were lower than the IC50 of standard references indomethacin and ibuprofen. Further, all the molecules were also evaluated for their in vitro antibacterial and antifungal activities against various pathogens of human origin by agar well diffusion method. In addition, binding interaction of active molecules (7-12 and 19-24) was performed on active site of cyclooxygenase-2 (COX-2) and Staphylococcus aureus (SA) TyrRS showing good binding profile. CONCLUSION Molecular docking result, along with the biological assay data, revealed that the compounds containing electron withdrawing group (F) on phenyl ring of thiourea moiety were potential anti-inflammatory and antimicrobial agents.

A correlation study of biological activity and molecular docking of Asp and Glu linked bis-hydrazones of quinazolinones

The present investigation involves the synthesis and spectroscopic and biological activity studies of the bis-hydrazones of quinazolinones derived from aspartic acid and glutamic acid. The antioxidant activities of the compounds were evaluated using DPPH, DMPD and ABTS radical scavenging assays whose results revealed that the IC50 of compounds 6, 7, 11, 12, 20, 21, 25 and 26 was lower than those of the standard references. The anti-inflammatory activity was evaluated with a haemolysis assay using a human blood erythrocytes suspension and the results demonstrated that compounds 8, 9, 13, 14, 22, 23, 27 and 28 were excellent anti-inflammatory agents. In addition, the antibacterial and antifungal activities against various clinical pathogens of human origin revealed that compounds 7, 9, 12, 14, 21, 23, 26 and 28 possessed potent antimicrobial properties. Furthermore, to understand the correlation between biological activity and drug–receptor interaction, molecular docking was performed on the active sites of tyrosine kinase (PDB ID: 2HCK), cyclooxygenase-2 (PDB ID: 1CX2) and glucosamine-6-phosphate (GlcN-6-P) synthase (PDB ID: 2VF5) which showed good binding profiles with the targets that can potentially hold the title compounds. The correlation study revealed that compounds containing EDGs (–OH, –OCH3) were excellent antioxidants, compounds with EWGs (–Cl, –NO2) exhibited good anti-inflammatory activity and compounds bearing –OH and –NO2 groups were very good antimicrobials.

Dipeptides as linker for multicomponent presentation—a facile, robust, and high-bioactivity yielding strategy

The need for multiple drugs arises when the response to pharmacological inflection is complicated and the disease conditions get worsened. The treatment requires a common platform to which multiple drugs are linked and this methodology is proven to be useful in drug delivery, biomaterial research, biomedicine, and vaccine development. In view of this, the present work is centered on dipeptides (KW/ KD/ KE/ kW/ kD/ kE), which are used as linkers and can potentially hold different functional group containing molecules (here, amino and carboxyl). First, we have demonstrated the incorporation of three components to the linker successfully followed by tetra component linking to those dipeptides, which contain trifunctional groups. To provide a proof of concept, these multisubstituted constructs were subjected to microbial growth suppression assay as well as anti-inflammatory assay. The biological results revealed that the multimers play a key role in enhancing the activity. Hence, the present system may be regarded as simple and straight forward which can be employed to develop various therapeutic agents as well as in different methodologies.

Urea and Thiourea Derivatives of Dipeptides Conjugated Piperazine Analogue as A New Class of AGE’s Inhibitors: Synthesis and Molecular Docking Studies

A novel class of urea and thiourea derivatives of dipeptides conjugated 2, 3-dichlorophenyl piperazine were synthesized and evaluated for their AGEs inhibition capacity. Antiglycation assay was performed by assessing fluorescence spectrum (exitation 370 nm), and change in fluorescence intensity (to emission 440 nm), based on AGEs were monitored by using spectrofluorimeter. Our results indicate that fluoro containing dipeptide-PZN derivatives have shown excellent curative potential. Interestingly, compounds 6, 7, 14, 15, 22, 23, 30 and 31 have shown excellent potency with IC50 values 13.5 ± 0.77, 8.0 ± 0.25, 14.5 ± 0.92, 7.8 ±0.44, 9.1 ± 0.41, 3.1 ± 0.45, 9.2 ± 0.80 and 2.5 ± 0.55, compared to the standard, rutin 41.9 μM. From our studies, we may draw certain conclusions like Lys containing dipeptides may serve as good antiglycating agents. On the other hand, its felt worthy to consider substitutions particularly at para position for the increase in potency. The IC50 values of the compounds were compared with the glide scores from the molecular studies. It was observed that the main interaction force of compounds with the active site was hydrophobic. The IC50 values and glide scores have exhibited better correlation. Thus, this synthetic novel urea and thioureas of dipeptide containing compounds may lead potent antiglycating agents.