Harun M. Patel

Synthesis and in vitro antitumor activity of substituted quinazoline and quinoxaline derivatives: Search for anticancer agent

The synthesis of some 2-furano-4(3H)-quinazolinones, diamides (open ring quinazolines), quinoxalines and their biological evaluation as antitumor agents using National Cancer Institute (NCI) disease oriented antitumor screen protocol are investigated. Among the synthesize compounds, seventeen compounds were granted NSC code and screened at National Cancer Institute (NCI), USA for anticancer activity at a single high dose (10(-5) M) in full NCI 60 cell panel. Among the selected compounds, 3-(2-chloro benzylideneamine)-2-(furan-2-yl) quinazoline-4(3h)-one 21 was found to be the most active candidate of the series at five dose level screening against Ovarian OVCAR-4 and Non-small cell lung cancer NCI-H522 with GI50 1.82 & 2.14 μM respectively. Rational approach and QSAR techniques enabled the understanding of the pharmacophoric requirement for quinazoline, diamides and quinoxaline derivatives.

Synthesis and anticancer evaluation of novel 2-cyclopropylimidazo[2,1-b][1,3,4]-thiadiazole derivatives.

A series of 2,5,6-trisubstituted imidazo[2,1-b][1,3,4]-thiadiazole derivatives 4(a-k) have been prepared by reaction of 2-amino-5-cyclopropyl-1,3,4-thiadiazole and an appropriate phenacyl bromide. Further 5-bromo 5(a-k) and 5-thiocyanato 6(a-k) derivatives were synthesized in order to study the effect of these substituents on antitumor activity. Structures of these compounds were established by IR, (1)H NMR, (13)C NMR and Mass spectroscopy. Seven compounds were granted NSC code at National Cancer Institute (NCI), USA for anticancer activity at a single high dose (10(-5) M) in full NCI 60 cell panel. Among the compounds tested, 5-bromo-6-(4-chlorophenyl)-2-cyclopropylimidazo[2,1-b][1,3,4]thiadiazole 5b (NSC D-96022/1) was found to be the most active candidate of the series at five dose level screening with degree of selectivity toward Leukemic cancer cell line.

Benzothiazoles: Search for anticancer agents

Novel derivatives of 2-amino benzothiazoles 4(a-j) have been synthesized and tested for their antitumor activity using National Cancer Institute (NCI) disease oriented antitumor screen protocol against nine panel of cancer cell lines. Among the synthesized compounds, two compounds were granted NSC code and screened at National Cancer Institute (NCI)-USA for anticancer activity at a single high dose (10(-5) M) and five dose in full NCI 60 cell panel. Among the selected compounds, 7-chloro-N-(2,6-dichlorophenyl)benzo[d]thiazol-2-amine (4i) with GI(50) values of 7.18 × 10(-8) M against Non-Small Cell HOP-92 Lung Cancer cell line proved to be the most active members in this study. Virtual screening was carried out through docking the designed compounds into the ATP binding site of epidermal growth factor receptor (EGFR) to predict if these compounds have analogous binding mode to the EGFR inhibitors.

2,6-Disubstituted imidazo[2,1-b][1,3,4]thiadiazoles: search for anticancer agents.

In this study, some novel 2,6-disubstituted imidazo[2,1-b][1,3,4]thiadiazoles 4 (a-i), 7 (a-p) and 11 (a-i) were synthesized from 5-substituted-1,3,4-thiadiazol-2-amine. The newly synthesized compounds 4a, 4b, 4c, 4e, 4g, 7j, 7l, 11b and 11c were evaluated in the National Cancer Institute for single dose in vitro primary cytotoxicity assay. Among the tested nine compounds, compound 4b (107166/760239) and 4c (107168/760240) were passed the criteria for activity in this assay and scheduled automatically for evaluation against the full panel of 60 human tumor cell lines at a minimum of five concentrations at 10-fold dilutions. 3-(2-(4-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl)aniline (4c) exhibited significant in vitro anticancer activity against Non Small Cell Lung Cancer HOP-92 cell line (GI(50): 0.114 μM) and Renal Cancer CAKI-1 cell line (GI(50): 0.743 μM).

Quinazolino–benzothiazoles: Fused pharmacophores as anticonvulsant agents

A series of 6-bromo-2-ethyl-3-(substitutedbenzo[d]thiazol-2-yl)quinazolin-4(3H)-one 3 (a-j) were synthesized using appropriate synthetic route and evaluated experimentally by the Maximal Electro Shock (MES) and the PTZ-induced seizure methods. Among the tested compounds, 3-(benzo[d]thiazol-2-yl)-6-bromo-2-ethylquinazolin-4(3H)-one (3a) has shown significant activity against tonic seizure by the MES model and 6-bromo-2-ethyl-3-(6-methoxybenzo[d]thiazol-2-yl)quinazolin-4(3H)-one (3h) against clonic seizure by PTZ-induced seizure model. Not one of the selected compounds demonstrated any sign of neurotoxicity and hepatotoxicity.

Recent updates on third generation EGFR inhibitors and emergence of fourth generation EGFR inhibitors to combat C797S resistance

EGFR T790M mutation leads to resistance to most of clinically available EGFR TKIs. Third-generation EGFR TKIs against the T790M mutation have been in active clinical development, which includes osimertinib, rociletinib, HM61713, ASP8273, EGF816, and PF-06747775. On the other hand recently EGFR C797S mutation was reported to be a leading mechanism of resistance to the third-generation inhibitors. The C797S mutation appears to be an ideal target for overcoming the acquired resistance to the third generation inhibitors. This review summarizes the third generation inhibitors, synthesis, their mechanism of resistance and latest development on the discovery of a fourth-generation EGFR TKIs and U to Y allosteric strategies to combat the C797S EGFR resistance problem.

Design and synthesis of novel carbazolo–thiazoles as potential anti-mycobacterial agents using a molecular hybridization approach

Various substituted carbazolo–thiazoles (compounds 6a–6o) were synthesized in good yields using a molecular hybridization approach. The synthesized compounds were evaluated for their in vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain at the National Institute of Allergy and Infectious Diseases (Bethesda, MD, USA). Among the tested series, compound 6c (minimum inhibitory concentration 21 μM) showed the most promising anti-mycobacterial activity. Brief structure–activity relationship studies showed that the electron-donating groups (OCH3 and OH), particularly on the phenyl ring of the thiazole motif, had a positive correlation with the anti-mycobacterial activity. In addition, they displayed low cytotoxicity against a mammalian Vero cell line using the MTT assay, thereby having a high therapeutic index. This study shows the importance of molecular hybridization and the scope for the development of carbazole–thiazole compounds as potential anti-mycobacterial agents.

Sulphonamido-quinoxalines: search for anticancer agent.

A series of new sulphonamido-quinoxaline derivatives 3(a-p) have been prepared which are structurally similar to the High Throughput Screening (HTS) hit identified by Porter and collaborator. The newly synthesized compounds 3b, 3c, 3f, 3i, 3j, 3l, 3n and 3o were further evaluated in the National Cancer Institute for in vitro cytotoxicity assay among them compound 3l showed highest activity against Leukemia RPMI-8226 cell lines (GI50: 1.11 μM) as compared to other tested compounds. It is to be noted that compound 3l shows significant activity (GI50: 1.11 μM) compared to the High Throughput Screening (HTS) hit identified by Porter and collaborator (IC50 = 1.3 μM). Further docking study confirms the c-Met kinase inhibitory mechanism of the synthesized compounds.

Brain–blood ratio: implications in brain drug delivery

Introduction: The brain–blood ratio is an important model correlating the brain-targeting ability of neurotherapeutics with the CNS pharmacokinetics, which need to be presented before the scientific community for exploration of its scientific worth. The purpose of this article is to bring this key concept and its precise discussion to the attention of the researchers. Areas covered: Three major points are discussed herein: First, the significance of brain–blood ratio with respect to investigational neurotherapeutics, and carrier systems and correlation of its research findings with the brain targeting efficiency. Second, the various factors influencing the brain–blood ratio. Third, the various strategies for enhancing the brain–blood ratio. In addition, the benchmark criteria for CNS-likeness of drug molecules and the correlation of brain–blood ratio with brain targeting ability of neurotherapeutics have been tabulated. Expert opinion: The brain–blood ratio (also referred to as the brain–plasma ratio) represents one of the tools available today for estimation of CNS pharmacokinetics. It is preferred over other complicated techniques (in situ brain perfusion and microdialysis) due to its ease of use and practicality. We are optimistic that the brain–blood ratio offers an excellent way of evaluating brain-targeting efficiency of neurotherapeutics effectively. In our opinion, it is a very fundamental aspect of brain bioavailability and needs to be presented in a precise way.

Quantitative structure-activity relationship (QSAR) studies as strategic approach in drug discovery

Drug design is a process which is driven by technological breakthroughs implying advanced experimental and computational methods. Nowadays, the techniques or the drug design methods are of paramount importance for prediction of biological profile, identification of hits, generation of leads, and moreover to accelerate the optimization of leads into drug candidates. Quantitative structure–activity relationship (QSAR) has served as a valuable predictive tool in the design of pharmaceuticals and agrochemicals. From decades to recent research, QSAR methods have been applied in the development of relationship between properties of chemical substances and their biological activities to obtain a reliable statistical model for prediction of the activities of new chemical entities. Classical QSAR studies include ligands with their binding sites, inhibition constants, rate constants, and other biological end points, in addition molecular to properties such as lipophilicity, polarizability, electronic, and steric properties or with certain structural features. 3D-QSAR has emerged as a natural extension to the classical Hansch and Free–Wilson approaches, which exploit the three-dimensional properties of the ligands to predict their biological activities using robust chemometric techniques such as PLS, G/PLS, and ANN. This paper provides an overview of 1-6 dimension-based developed QSAR methods and their approaches. In particular, we present various dimensional QSAR approaches, such as comparative molecular field analysis (CoMFA), comparative molecular similarity analysis, Topomer CoMFA, self-organizing molecular field analysis, comparative molecule/pseudo receptor interaction analysis, comparative molecular active site analysis, and FLUFF-BALL, 4D-QSAR, and G-QSAR approaches.