Seema Bag

Pharmacophore mapping of a series of pyrrolopyrimidines, indolopyrimidines and their congeners as multidrug-resistance-associated protein (MRP1) modulators

AbstractPharmacophore mapping studies were undertaken for a series of molecules belonging to pyrrolopyrimidines, indolopyrimidines and their congeners as multidrug resistance-associated protein (MRP1) modulators. A five-point pharmacophore with two hydrogen bond acceptors (A), one lipophilic/hydrophobic group (H), one positive ionic feature (P) and one aromatic ring (R) as pharmacophoric features was developed. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a correlation coefficient of r2 = 0.799 for training set molecules. The model generated showed excellent predictive power, with a correlation coefficient Q2 = 0.679 for an external test set of 20 molecules. The pharmacophore was further validated using four structurally diverse compounds with MRP1 modulatory activity. These compounds mapped well onto four of the five features of the pharmacophore. The pharmacophore proposed here was then utilised for the successful retrieval of active molecules with diverse chemotypes from database search. The geometry and features of pharmacophore are expected to be useful for the design of selective MRP1 inhibitors. FigureAlignment of multidrug resistance-associated protein (MRP1) inhibitors with the developed pharmacophore.

Design, synthesis, biological evaluation and computational investigation of novel inhibitors of dihydrofolate reductase of opportunistic pathogens

The present work deals with design, synthesis and biological evaluation of novel, diverse compounds as potential inhibitors of dihydrofolate reductase (DHFR) from opportunistic microorganisms; Pneumocystis carinii (pc), Toxoplasma gondii (tg) and Mycobacterium avium (ma). A set of 14 structurally diverse compounds were designed with varying key pharmacophoric features of DHFR inhibitors, bulky distal substitutions and different bridges joining the distal part and 2,4-diaminopyrimidine nucleus. The designed compounds were synthesized and evaluated in enzyme assay against pc, tg and ma DHFR. The rat liver (rl) DHFR was used as mammalian standard. As the next logical step of the project, flexible molecular docking studies were carried out to predict the binding modes of these compounds in pcDHFR active site and the obtained docked poses were post processed using MM-GBSA protocol for prediction of relative binding affinity. The predicted binding modes were able to rationalize the experimental results in most cases. Of particular interest, both the docking scores and MM-GBSA predicted Delta G(bind) were able to distinguish between the active and low active compounds. Furthermore, good correlation coefficient of 0.797 was obtained between the IC(50) values and MM-GBSA predicted Delta G(bind). Taken together, the current work provides not only a novel scaffold for further optimization of DHFR inhibitors but also an understanding of the specific interactions of inhibitors with DHFR and structural modifications that improve selectivity.

In vitro biological evaluation of biguanides and dihydrotriazines against Brugia malayi and folate reversal studies.

Dihydrofolate reductase (DHFR) is a well-known target for antibacterial and anticancer therapy. DHFR inhibitors are useful for protozoan parasites, but are yet to be explored against metazoan species; hence the present work was designed to evaluate the efficacy of DHFR inhibitors against filariasis, one of the major neglected tropical diseases. Molecules from our in-house library of synthetic antifolate agents (biguanide and dihydrotriazine derivatives) were evaluated along with the antimalarial drug pyrimethamine and the antibacterial drug trimethoprim in an in vitro model against Brugia malayi microfilariae (Mf). Three biguanides and two dihydrotriazines were more potent than trimethoprim and pyrimethamine against B. malayi Mf. Trimethoprim, pyrimethamine and four of the five compounds active against Mf were also active against adult worms. To probe the mechanism of action of the compounds, reversal of activity of active compounds by folic acid and folinic acid was studied. In conclusion, DHFR inhibitors could be used as leads for new antifilarial drugs.

Synthesis and biological evaluation of biguanide and dihydrotriazine derivatives as potential inhibitors of dihydrofolate reductase of opportunistic microorganisms

Twenty-one biguanide and dihydrotriazine derivatives were synthesized and evaluated as inhibitors of dihydrofolate reductase (DHFR) from opportunistic microorganisms: Pneumocystis carinii (pc), Toxoplasma gondii (tg), Mycobacterium avium (ma), and rat liver (rl). The most potent compound in the series was B2-07 with 12 nM activity against tgDHFR. The most striking observation was that B2-07 showed similar potency to trimetrexate, ∼233-fold improved potency over trimethoprim and ∼7-fold increased selectivity as compared to trimetrexate against tgDHFR. Molecular docking studies in the developed homology model of tgDHFR rationalized the observed potency of B2-07. This molecule can act as a good lead for further design of molecules with better selectivity and improved potency.

Microwave assisted benzoin condensation using thiamine as catalyst

α-Hydroxyketones were prepared in appreciable yields at a very high speed, (by the benzoin condensation) under microwave irradiation using a catalytic amount of thiamine hydrochloride, from various aromatic as well as heteroaromatic aldehydes. They can be used as intermediates in NCE synthesis.

A review of molecular modelling studies of dihydrofolate reductase inhibitors against opportunistic microorganisms and comprehensive evaluation of new models.

Dihydrofolate reductase (DHFR) has been used as a target for antimicrobial drug discovery against a variety of pathogenic microorganisms, including opportunistic microorganisms; Pneumocystis carinii (pc), Toxoplasma gondii (tg) and Mycobacterium avium complex (ma). In this regard, several DHFR inhibitors are reported against pc and tg and ma. However, selectivity issue of these inhibitors over human DHFR often preclude their development and clinical use. In the first part of this work, various computational approaches including available crystallographic structures, binding affinity prediction, pharmacophore mapping, QSAR, homology modelling used for design of DHFR inhibitors against opportunistic microorganisms are reviewed, to understand specific interactions required for inhibition of microbial DHFR. Secondly, comprehensive molecular modelling techniques were used, to establish structure-chemical-feature-based pharmacophore models for pcDHFR, tgDHFR and mammalian DHFR. The results show that, the information encoded by ligand based approaches like pharmacophore mapping and 3D-QSAR methods are in well agreement with the information coded in the receptor structure. A combination of ligand and structure based approaches provides understanding of ligand-receptor interactions. The study indicated that the value of small alkyl moieties at position 5 of the bicyclic nitrogen containing nucleus along with a bulky group attached at the C-6 via suitable linker could optimize activity, with regard to both potency and selectivity.

Rational drug design, synthesis and biological evaluation of dihydrofolate reductase inhibitors as antituberculosis agents

BACKGROUND A series of 2,4-diamino-s-triazines was designed, with potential for activity against Mycobacterium tuberculosis (Mtb) dihydrofolate reductase enzyme, on the basis of virtual screening results and structure-based drug design. RESULTS The compounds were evaluated against Mtb (H37Rv) and their cytotoxicity was assessed using VERO cell lines. Of particular note, two compounds were found to have the most promising antituberculosis activity (6b minimum inhibitory concentration: 1.76 μM and 6i minimum inhibitory concentration: 1.57 μM) along with low cytotoxicity (CC50: >300 μM). The enzyme assay results of these two indicated significant inhibition of Mtb dihydrofolate reductase along with selectivity. Selected derivatives were tested against dormant tubercle bacilli in vivo and ex vivo indicating potential inhibition. CONCLUSION This study provides promising antituberculosis dihydrofolate reductase inhibitors that can act as potential leads for further development.