Comprehensive computational study in the identification of novel potential cholesterol lowering agents targeting proprotein convertase subtilisin/kexin type 9.

The enzymatic target proprotein convertase subtilisin/kexin type 9 (PCSK9) is critically involved in the regulation of the lipoprotein metabolism leading to the degradation of low-density lipoprotein receptors (LDLRs) upon binding. Drugs that lower LDL cholesterol (LDL-C) through the inhibition of PCSK9 are useful in the management of hypercholesterolemia which greatly reduces the associated risk of atherosclerotic cardiovascular disease (CVD). In 2015, anti-PCSK9 monoclonal antibodies (mAbs), alirocumab and evolocumab were approved but owing to their high costs their prior authorization practices were impeded, reducing their long-term adherence. This has drawn considerable attention for the development of small-molecule PCSK9 inhibitors. In this research work, novel and diverse molecules with affinity towards PCSK9 thereby having ability to lower cholesterol. A hierarchical multistep docking was implemented to identify small molecules from chemical libraries with a score cutoff -8.00 kcal/mol, thereby weeding all the non-potential molecules. A set of seven representative molecules Z1139749023, Z1142698190, Z2242867634, Z2242893449, Z2242894417, Z2242909019, and Z2242914794 have been identified from a comprehensive computational study which included assessment of pharmacokinetics and toxicity profiles and binding interactions along with in-depth analysis of structural dynamics and integrity using prolong molecular dynamics (MD) simulation (in-duplicate). Furthermore the binding affinity of these PCSK9 inhibitory candidates molecules was ascertained over 1000 trajectory frames using MM-GBSA calculations. The molecules reported herein are propitious candidates for further development through necessary experimental considerations.Communicated by Ramaswamy H. Sarma.

Novel peptidomimetic peptide deformylase (PDF) inhibitors of Mycobacterium tuberculosis.

Emergence of MDR-TB and XDR-TB led to the failure of available anti-tubercular drugs. In order to explore, identify and develop new anti-tubercular drugs, novel peptidomimetic series of Mtb-peptide deformylase (PDF) inhibitors was designed and synthesized. In vitro antimycobacterial potential of compounds was established by screening of compounds against Mycobacterium tuberculosis H37Rv strain using MABA. Among them, ester series of compounds 4a, 4b, 4c, 4d, and 4e were found most active, with compound 4c being highly active and exhibiting minimum inhibitory concentration of 6.25 µg/ml against M. tb H37Rv strain. Additionally, the compounds were docked to determine the probable binding interactions and understand the mechanism of action of most active molecules on Mtb-peptide deformylase (PDF), which is involved in the mycobacterium protein synthesis.

Novel fatty acid-thiadiazole derivatives as potential antimycobacterial agents.

The discovery of antibiotics around the middle twentieth century led to a decrease in the interest in antimycobacterial fatty acids. In order to re-establish the importance of naturally abundant fatty acid, a series of fatty acid-thiadiazole derivatives were designed and synthesized based on molecular hybridization approach. In vitro antimycobacterial potential was established by a screening of synthesized compounds against Mycobacterium tuberculosis H37Rv strain. Among them, compounds 5a, 5d, 5h, and 5j were the most active, with compound 5j exhibiting minimum inhibitory concentration of 2.34 µg/ml against M.tb H37Rv. Additionally, the compounds were docked to determine the probable binding interactions and understand the mechanism of action of most active molecules on enoyl-acyl carrier protein reductases (InhA), which is involved in the mycobacterium fatty acid biosynthetic pathway.

Transferrin conjugates of antitubercular drug isoniazid: Synthesis and in vitro efficacy.

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) has become the world's leading killer disease due to a single infectious agent which survives in the host macrophage for the indefinite period. Hence, it is necessary to enhance the efficacy of the clinically existing antitubercular agents or to discover new anti antitubercular agents. Here, we report the synthesis, characterization and antimycobacterial evaluation of protein-drug conjugates. A carrier protein, Transferrin (Tf) was covalently conjugated to isoniazid (INH) utilizing hydrazone and amide linkers. The purity of the reactions was confirmed by SDS-PAGE while conjugation was confirmed by UV-visible spectrophotometry, MALDI-TOF analysis, and FTIR spectrophotometry. The in vitro antitubercular assay result showed that the inhibitory activity of the parent drug was conserved in both the conjugates. The conjugates were effective against intracellular Mtb H37Rv and were devoid of cytotoxic effect at therapeutic concentration.

Chitosan based copolymer-drug conjugate and its protein targeted polyelectrolyte complex nanoparticles to enhance the efficiency and specificity of low potency anticancer agent.

The effective delivery of low potency anticancer drug is a major challenge. The present study introduces the novel chitosan-polylactic acid (CS-PLA)-drug conjugate and its transferrin receptor targeted polyelectrolyte complex nanoparticles (PEC Nps), encapsulating free drug to increase its potency and specificity. The model drug curcumin (CR) was used and incorporated in this system in both conjugated and encapsulated form. The synthesis of CS-PLA-CR copolymer was confirmed by 1H NMR, FTIR, UV-visible spectrum, DSC thermogram and zeta potential. Further, the nanoparticles engulfing free CR, with average 340 nm particle sizes, were prepared through simple ionic gelation technique utilizing positive charges on copolymer by polyanion sodium alginate (CS-PLA-CR/SA PEC Nps). The prepared Nps showed the high CR content of over 92% with extended period of CR release (60% and 85% at pH 7.4 and 5 respectively even after 8 days). The results were compared with the unmodified CS (without PLA) as a control to understand the effect of PLA side chain. Transferrin (Tf) conjugation on PEC Nps displayed superior cytotoxicity and cellular uptake compared to non-targeted Nps on MCF-7 cell line. Thus, CR loaded Tf-CS-PLA-CR/SA PEC Nps may provide an efficient and targeted delivery for cancer treatment.

Synthesis and biological evaluation of novel N' (4-aryloxybenzylidene)- 1H-benzimidazole-2 carbohydrazide derivatives as anti-tubercular agents.

A series of structurally novel, (E)-N'-(4-aryloxybenzylidene)-1H-benzimidazole-2-carbohydrazide derivatives were synthesized by molecular hybridization technique. All these compounds were evaluated against Mycobacterium tuberculosis H37Rv strains using Resazurin Microtiter assay (REMA) method. These compounds showed good antituberculosis activity with minimum inhibitory concentration (MIC) value of the range of 1.5-25 µg/mL.

Design, synthesis and antitubercular evaluation of novel series of N-[4-(piperazin-1-yl)phenyl]cinnamamide derivatives.

The analogs of N-[4-(piperazin-1-yl)phenyl]cinnamamide were designed and synthesized by molecular hybridization approach in which part C of the designed molecule was linked through amide and carbamate functionality that improves the physicochemical properties and govern the pharmacokinetic and pharmacodynamic behavior. The systematic modification was done around the Part C to explore the structure activity relationship of antitubercular cinnamamide. All 52 compounds were evaluated for its antitubercular activity against Mycobacterium tuberculosis (M. tb) using Resazurin microtitre plate assay (REMA). Compound 11 g with trifluoromethyl substitution exhibited good antitubercular activity of 3.125 µg/ml. The synthesized N-[4-(piperazin-1-yl)phenyl]cinnamamide derivatives showed promising activity against M. tb.

Novel 2-(2-benzylidenehydrazinyl)benzo[d]thiazole as potential antitubercular agents.

Molecular hybridization approach was used to synthesize substituted 2-(2-(4-aryl oxy benzylidene) hydrazinyl)benzo thiazole derivatives with 2-hydrazinobenzothiazole and 4-(alicycli/aryl/biaryl/heteroaryl oxy)benzaldehyde as new anti-TB agents. The synthesized compounds, when tested against H37Rv strains of Mtb using Resazurin Microtitre Assay (REMA) method, showed promising activity (MIC 1.35-36.50 µg/mL). 6-chloro-2-(2-(4- (pyridin-4-yloxy) benzylidene) hydrazinyl) benzo[d]thiazole (10v) gave MIC of 1.35 µg/mL. Thus making it, a potential lead could be developed for further antitubercular studies.

Novel N'-benzylidene benzofuran-3-carbohydrazide derivatives as antitubercular and antifungal agents.

Tuberculosis constitutes today a serious threat to human health worldwide, aggravated by the increasing number of identified multi-drug resistant strains of Mycobacterium tuberculosis (Mtb), its causative agent, as well as by the lack of development of novel mycobactericidal compounds for the last few decades. A novel series of benzofuran-3-carbohydrazide and its analogs was synthesized and characterized spectroscopically. All the compounds were characterized and screened for in vitro anti-tuberculosis (anti-TB) activity against Mycobacterium tuberculosis H37Rv strains by using resazurin assay utilizing microtiter-plate method (REMA). These compounds also showed good antifungal activity against Candida albicans. Thus, the high level of activity shown by the compounds (8a, 8k) suggests that these compounds could serve as leads for development of novel synthetic compounds with enhanced anti-TB and antifungal activity.

Novel 2-(2-(4-aryloxybenzylidene) hydrazinyl)benzothiazole derivatives as anti-tubercular agents.

A series of structurally novel, substituted 2-(2-(4-aryloxybenzylidene) hydrazinyl)benzothiazole derivatives incorporating 2-hydrazinyl benzothiazole and 4-(aryloxy)benzaldehyde were designed and synthesized using molecular hybridization approach. All the synthesized compounds exhibited promising activity (MIC 1.5-29.00µg/ml) against Mycobacteriumtuberculosis H37Rv strains of using REMA. Five of the evaluated compounds exhibit MIC <3.0µg/ml. Compound (E)-6-chloro-2-(2-(4-(2,4-dichlorophenoxy)benzylidene)hydrazinyl) benzothiazole showed MIC of 1.5µg/ml. Thus, this compound could act as a potential lead for further development of new anti-tubercular drugs.

Pharmacophore development and docking studies of the hiv-1 integrase inhibitors derived from N-methylpyrimidones, Dihydroxypyrimidines, and bicyclic pyrimidinones.

To elucidate the crucial structural features for the HIV-1 integrase inhibitors, a three-dimensional pharmacophore model was developed based on N-methyl pyrimidones, dihydroxypyrimidines, and bicyclic pyrimidinones derivatives using Phase. N-methyl pyrimidone derivative raltegravir, the first US-FDA approved drug by Merck, belongs to this series. The best-fitted common pharmacophore hypothesis was characterized by two acceptor, two hydrophobic, and two ring features having a correlation coefficient of 0.895, cross-validated Q(2) value of 0.631, and survival score of 8.862, suggesting that a highly predictive pharmacophore model was developed. The cross-validation studies using 23 test set molecules and fifteen structurally diverse HIV-integrase inhibitors give extra confidence about the correctness of the pharmacophore model. The cross-validation studies proved that our developed model can successfully differentiate between active and inactive HIV-integrase inhibitors. The docking studies were also carried out wherein the molecules were docked against the active site of HIV integrase to analyze the binding mode and the necessary structural requirement for their respective enzymatic inhibition. The results obtained from our studies provide a valuable tool for designing of new lead molecules with potent activity.

Synthesis and evaluation of novel chloropyrrole molecules designed by molecular hybridization of common pharmacophores as potential antimicrobial agents.

In an attempt to identify new potential lead as antimicrobial agent, 31 novel chloropyrrole derivatives of aroyl hydrazones and chalcones incorporating common pharmacophore of pyoluteorin derivatives were synthesized. Antimicrobial activity of the synthesized compounds was evaluated using broth dilution technique. Based on biological evaluation data it was observed that activity increases as the number of chlorines on pyrrole core increases. Few 1H-pyrrole-2-carbohydrazide derivatives shows activity equivalent to the standard drug ciprofloxacin. Thus, these compounds can act as potential lead for further antibacterial studies.