Medicinal Chemistry - Volume 9, Issue 2, 2013

The discovery and development of a new drug are time-consuming, difficult and expensive. This complex process has evolved from classical methods into an integration of modern technologies and innovative strategies addressed to the design of new chemical entities to treat a variety of diseases. The development of new drug candidates is often limited by initial compounds lacking reasonable chemical and biological properties for further lead optimization. Huge libraries of compounds are frequently selected for biological screening using a variety of techniques and standard models to assess potency, affinity and selectivity. In this context, it is very important to study the pharmacokinetic profile of the compounds under investigation. Recent advances have been made in the collection of data and the development of models to assess and predict pharmacokinetic properties (ADME - absorption, distribution, metabolism and excretion) of bioactive compounds in the early stages of drug discovery projects. This paper provides a brief perspective on the evolution of in silico ADME tools, addressing challenges, limitations, and opportunities in medicinal chemistry.

A series of twelve benzopyran linked pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) have been synthesized. They exhibit significant DNA-binding activity and excellent cytotoxic activity against various human cancer cell lines.

The potential of quercetin (QUE), being a member of the whole family of structurally different flavonoids, to serve as an anti-tumor agent has been recognized, but not fully understood. The interactions between DNA and a series of the flavonoids have so far been mainly investigated using a variety of experimental techniques. Herein, the specificity of QUE for DNA is explored using sophisticated density functional theory (DFT) methods employed to generate the optimized structure of QUE in complex with adenine (A), guanine (G), thymine (T) and cytosine (C), respectively. As far as a preference of QUE is concerned, structural and energetic as well as NMR chemical shift arguments clearly indicate a highest for G and a lowest for C. This observation is further substantiated by analyzing the binding modes of QUE docked in a quadruplex receptor structure of DNA and in a duplex receptor structure of DNA. Among all possible single point mutations of the DNA quadruplex and duplex residues, several critical ones causing a conspicuous stabilizing effect on the original complexes of QUE with the DNA receptors are identified. Consequently, several fundamental standpoints shedding new light on the molecular mechanisms underlying the interactions between QUE and DNA are discussed.

A quantitative structure-activity relationship (QSAR) study has been made on two different series of anticancer tyrosine kinase inhibitors, namely a series of 4-alkynyl and 4-alkenyl-quinazolines and a series of N-4,6-pyrimidine-Nalkyl- N'-phenyl ureas. For the first series, QSAR results indicate that the activity is controlled by the hydrophobicity of the molecules and molecular connectivity index of the substituent, whereas for the second series of compounds the activity is found to be controlled by the molecular connectivity index of the substituent and some indicator variables.

Kinases have been known as important molecular targets for various diseases and p38 kinase is found to be vital target among all mitogen activated protein kinases for inflammatory diseases. P38 kinase inhibitors bearing urea scaffold have shown potent kinase inhibitory activity and also selectivity over other kinases. We present here the synthesis, p38 kinase inhibitory and anti-inflammatory activities of compounds containing N', N”-diarylurea scaffold. Compound 7f demonstrated IC50 value of 1.09 μM in p38 kinase assay and 79.41% inhibition of rat paw edema at the 2nd hour of carrageenan challenge. The molecular docking studies of synthesized compounds indicated some of the important hydrogen bonding interactions and also revealed the minor change in the binding pose when compared to BIRB796.

QSAR study was performed on a series of aryl carboxylic acid amide derivatives (62 analogs) to establish structural features required for human dihydroorotate dehydrogenase (hDHODH) inhibition. Statistical significant QSAR models were developed for the prediction of hDHODH inhibitory activity by applying MLR analysis (r2 = 0.851 and q2 = 0.795), PCR analysis (r2 = 0.713 and q2 = 0.667) and PLS analysis (r2 = 0.848 and q2 = 0.802). QSAR study emphasized the importance of topological, estate number, hydrophobic and alignment independent descriptors for the prediction of hDHODH inhibitory activity. SaasCcount descriptor suggested the presence of carbon atoms in five member aryl ring system. Positive impact of alignment independent descriptors reveals the presence of carbonyl oxygen and chloro group in this series of compounds. DistTopo signifies basic connectivity of atoms in the molecules. High degree of predictability of the proposed QSAR models offers a great potential for the design and development of potent hDHODH inhibitors.

A series of novel 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one aliphatic/ aromatic/ heterocyclic amine derivatives were synthesized in good yield. The synthesized compounds were characterized by 1H-NMR, FTIR and elemental analysis. All the synthesized compounds were screened for their in vitro antibacterial activity by agar well diffusion and micro dilution method against standard strains of Gram-Positive (Bacillus Subtilis MTCC 121 and Staphylococcus epidermidis 435), and Gram-negative (Xanthomonas Campestris 7903 and Pseudomonas aeruginosa MTCC 7908) bacteria. Compounds with substituted heterocyclic piperazine moiety showed good activity. In particular, compound 6i showed two fold better activity compared to the standard drug Strepyomycin sulphate.

A series of naphthalen-1-yl-acetic acid benzylidene/(1-phenyl-ethylidene)-hydrazides (1-36) was synthesized and tested, in vitro, for antiviral, antibacterial and antifungal activities. The antibacterial and antifungal screening results indicated that compounds having o-bromo, methoxy and hydroxy substitutents were the most active ones. The results of antiviral evaluation showed that none of the synthesized derivatives inhibited the viral infection at subtoxic concentrations. QSAR investigations revealed that the multi-target QSAR model was more effective in describing the antimicrobial activity than the one-target QSAR models. Further, it revealed the importance of the partition coefficient (log P) followed by energies of the highest occupied molecular orbital (HOMO) and topological parameters, molecular connectivity indices (1χ, 3χ and 3χv) in describing the antimicrobial activity of substituted hydrazides.

A simple and efficient method has been developed for the synthesis of series of N-Mannich bases of (E)-3- (phenylimino/4-chlorophenylimino)-2,3-dihydro-1-[(N-substituted piperazinyl) methyl]quinoxaline-2-(1H)-one 3a-f and 4a-f. The requisite 2a and 2b were obtained by reactionbetween quinoxaline-2,3-dione 1 and aniline / p-chloroaniline. These compounds underwent NMannich reaction with various substituted piperazines to yield (title compounds 3a-f and 4a-f respectively. Structures of synthesized compounds were confirmed by spectral studies (IR, 1H NMR, 13C NMR and Mass) and elemental analysis. All the synthesized compounds were screened for in vitro leptospirocidal activty against Leptospira interrogans. The potent compounds 4a, 4b and 4c which showed maximum activity during in vitro studies were subjected to in vivo studies. The inhibitory activity of enzymes carboxypeptidase and transpeptidase, in leptospirosis by the synthesized compounds were determined. 3D-QSAR studies model developed showed the need for more hydrophobic and less steric groups as substituent groups to enhance the in vitro activity.

A series of novel 2-(1H-indol-3-yl)-N-(3, 4-diphenylthiazol-2(3H)-ylidene) ethanamine derivatives (5a-o) were synthesized by cyclization of corresponding 1-(2-(1H-indol-3-yl) ethyl)-3-phenylthiourea 3 with 2-bromoacetophenone. All synthesized compounds were evaluated for in vitro antibacterial activity using Gram-positive bacteria and Gramnegative bacteria. In vitro antifungal activity also determined against the five fungal species. Structures of the synthesized compounds were established by elemental analysis and spectral data.

To study the target proteins of oleanolic acid, a series of novel photoaffinity probes were designed and synthesized. Their affinity for the target proteins was evaluated in an enzyme inhibition assay against glycogen phosphorylase, a known target protein of oleanolic acid. Among these compounds, probe 2 exhibited the most potent activity with an IC50 value of 5.98 μM, which was about 2.5-fold more potent than its parent compound oleanolic acid. The results showed that the synthesized photoaffinity probes retained the binding affinity for their target proteins, and might be used as powerful tools to fish out the target proteins of oleanolic acid.

A series of new halophenols were synthesized, and their structures were established on the basis of 1H, 13C NMR and mass spectral data. All of the prepared compounds were screened for their in vitro protein tyrosine kinase (PTK) and vascular smooth muscle cell (VSMC) proliferation inhibitory activity. Twelve halophenols showed significant PTK inhibitory activity, most of them exhibited stronger activities than that of genistein, a positive reference compound. Several halophenols also displayed moderate VSMC proliferation inhibitory activity, compound 8c showed higher activity than that of tetrandrine, a positive reference compound. The preliminary structure-activity relationships of these compounds were investigated and discussed. The results provided a foundation for the action mechanism study and further structure optimization of the halophenols.